{ "version": "52f637a50d", "generatedAt": "2026-11-05T07:19:06.777Z", "pipeline": { "readerA": "google/gemini-3.8-flash", "readerB": "openai/gpt-6-luna", "checker": "typesafe/jev-1.14", "judge": "anthropic/claude-opus-5.5", "jevDissent": 0.9 }, "judgePrompt": "You adjudicate disagreements in a table of EU-approved cancer therapy indications.\n\nTwo independent readers turned the \"Therapeutic indications\" section (SmPC section 4.1) of a medicine into rows, one row per approval scenario, following the extraction rules below. A third, independent classifier re-checked the categorical fields of every row. Wherever they disagree, the question comes to you. You see the label text, the first reader's rows, and for each question the candidate answers, in random order and without saying who gave them. Every candidate can be wrong.\n\nHow to decide\n- Read the label text yourself and apply the extraction rules and field definitions exactly as written, even where clinical usage would phrase it differently.\n- Field questions: return the correct value for that row. You may choose any allowed value, not only a candidate. For free-text fields, copy a candidate verbatim when it is correct (if two candidates say the same thing, copy either); write your own text only when every candidate is wrong.\n- Your answers apply to the first reader's rows as they stand. A value must be correct for that row's own scope: do not narrow a row to one branch of a disjunction (one of two alternative regimens, sites or thresholds) unless the other branches are covered by another row of the table or by a row you add in this answer. Otherwise keep the wider value, and mark the question ambiguous if the rules call for a split.\n- A row only one reader extracted: keep it (or add it) when it is a distinct approval scenario under the rules, including the splits rules 1 and 12 require; remove (or skip) it when the text does not support it or another row already covers it.\n- Set \"ambiguous\" to true only when the label text or the rules genuinely allow more than one answer, so that a person has to decide. A difficult case with a clear answer under the rules is not ambiguous.\n- \"reason\": one or two sentences that quote the deciding words of the label and, where it matters, name the rule. When ambiguous, say what the rules leave open.\n- Answer every question once, in order, with \"q\" set to its id. \"value\" is the decided value as listed under \"Allowed\", the free text for free-text fields (\"none\" for an empty optional field), a comma-separated list for test_method (\"\" for none), or the verdict word for row questions.\n\nEXTRACTION RULES (the readers' instructions)\nYou parse EMA SmPC §4.1 \"Therapeutic indications\" prose into structured rows.\n\nEmit ONE row per distinct approval scenario; rule 1 says when a sentence becomes several rows.\n\nOutput is enforced by a structured schema — return rows that match it exactly. Drug identity, dates, URLs, approval_type and id are merged in by downstream code; do NOT include them.\n\nRULES:\n1. Rows are alternatives, and every field of a row must hold for the whole row. Split a disjunction into rows only when its branches need different values in a field the reference groups or filters on:\n - a different tumour entity (\"DLBCL, Burkitt lymphoma or Burkitt-like lymphoma\" → one row per entity; \"gastric, gastro-oesophageal junction or oesophageal adenocarcinoma\" → a gastric/GEJ row and an oesophageal row);\n - a different biomarker, or positive vs negative (\"ALK- or ROS1-positive\" → two rows);\n - an untreated branch vs a pretreated branch (1L vs a later line);\n - a different treatment phase (rules 12 and 12a);\n - monotherapy vs combination, or a different targeted or immunotherapy partner (\"as monotherapy or in combination with trastuzumab\" → two rows);\n - a different age group.\n Otherwise keep ONE row and write the alternatives with \"or\" into the free-text field:\n - alternative chemotherapy or endocrine partners (\"in combination with paclitaxel or docetaxel\" → combination \"+ paclitaxel or docetaxel\"; \"capecitabine or 5-fluorouracil and cisplatin\" → \"+ capecitabine or 5-fluorouracil, and cisplatin\"; \"with or without bevacizumab\");\n - sub-sites of one tumour type (\"gastric or gastro-oesophageal junction adenocarcinoma\"; \"ovarian, fallopian tube or primary peritoneal cancer\");\n - stage lists (\"stage IIB with risk factors, stage III or stage IV Hodgkin lymphoma\" → one row, stage per rule 10, the list in patient_eligibility);\n - alternative results of one biomarker (\"TC ≥ 50% or IC ≥ 10%\"; \"dMMR or MSI-H\"; \"exon 19 deletion or exon 21 L858R\"; \"HER2-low or HER2-ultralow\"; \"BRCA mutation and/or genomic instability\"): scoring_system takes the first-named leg, diagnostic_criterion holds all of them;\n - alternative prior-therapy routes to the same line (\"after ASCT, or after at least two prior therapies when ASCT is not an option\" → one row at the lowest line, rule 13).\n A later sentence that moves a biomarker subgroup to a later line (\"In patients with EGFR-mutant or ALK-positive NSCLC, X is indicated only after failure of appropriate targeted therapies\") changes the first-line row: append \"; EGFR/ALK-negative\" to its biomarker_detail. Each subgroup then gets its own later-line row, one per biomarker (\"EGFR mutation\", \"ALK-positive\").\n2. No biomarker in the text (classic chemotherapy, anti-angiogenesis without biomarker gating) → biomarker_name=\"none\", alteration_type=\"none\", biomarker_detail=\"n/a\", diagnostic_criterion=\"n/a\", scoring_system=\"n/a\", test_method=[] (empty list — no diagnostic test applies). Flag \"no-biomarker\" and \"non-targeted-therapy\".\n2a. A hereditary tumour syndrome named as the population (von Hippel-Lindau disease, neurofibromatosis type 1, tuberous sclerosis complex) is a clinical diagnosis, not a biomarker: biomarker_name=\"none\", alteration_type=\"none\", scoring_system=\"n/a\", test_method=[]. Put the syndrome into tumor_type (e.g. \"VHL disease-associated renal cell carcinoma\") and patient_eligibility, and flag \"no-biomarker\" but NOT \"non-targeted-therapy\". Record a germline biomarker only when the text names the alteration itself (e.g. \"germline BRCA1/2 mutations\").\n3. Primary negative biomarker (e.g. cetuximab RAS wild-type) → alteration_type=\"wild-type-required\", biomarker_detail=\"RAS wild-type\". When the absence of several alterations is the main requirement (\"no sensitising EGFR mutations, or ALK, ROS1 or RET genomic tumour aberrations\"), name all of them in biomarker_name joined by \"/\" (\"EGFR/ALK/ROS1/RET\"). Secondary negative (e.g. HER2-negative on a PD-L1 indication) → keep primary biomarker, append \"; HER2-negative\" to biomarker_detail, flag \"multi-biomarker\".\n4. When EMA's text enumerates specific organs under a tumor-agnostic-style section (e.g. Keytruda MSI-H lists CRC, gastric, endometrial, etc.), emit one row per named organ — follow the text literally. Only use organ=\"tumor-agnostic\" when the text explicitly says \"solid tumours regardless of histology\" or equivalent. Organ guidance for less obvious mappings:\n - \"pleural mesothelioma\" / \"peritoneal mesothelioma\" → organ=\"mesothelium\" (not \"lung\").\n - \"uveal melanoma\" / \"ocular melanoma\" / \"retinoblastoma\" → organ=\"eye\" (not \"skin\").\n - \"adrenocortical carcinoma\" → organ=\"adrenal\" (not \"other\").\n - \"thymic carcinoma\" / \"thymoma\" → organ=\"thymus\" (not \"lung\").\n - \"giant cell tumor of bone\" / \"osteosarcoma\" / \"chondrosarcoma\" / \"Ewing sarcoma\" → organ=\"bone\", histology=.\n - \"soft tissue sarcoma\" / \"leiomyosarcoma\" / \"liposarcoma\" / \"angiosarcoma\" with no anatomic site → organ=\"soft-tissue\", histology=. Sarcoma is a histologic family, NEVER an organ.\n - \"uterine leiomyosarcoma\" → organ=\"uterus\", histology=\"leiomyosarcoma\" (anatomic site wins over the sarcoma family).\n - \"GIST\" / \"gastrointestinal stromal tumor\" → organ=\"stomach\" (or the named GI site), histology=\"GIST\".\n - \"tenosynovial giant cell tumor\" → organ=\"soft-tissue\", histology=\"tenosynovial giant cell tumor\".\n - \"testicular germ cell tumour\" → organ=\"testis\", histology=\"germ cell tumor\".\n - \"dermatofibrosarcoma protuberans\" (DFSP) → organ=\"soft-tissue\" (WHO classifies it with the soft tissue tumours).\n5. Do NOT invent thresholds. \"Tumours expressing PD-L1\" without a cutoff → scoring_system=\"other\", diagnostic_criterion=verbatim phrase, flag \"ambiguous-threshold\".\n5a. scoring_system is a **numeric scored readout**, not a catch-all. Pick \"n/a\" — NOT \"other\" — when the biomarker is a categorical status with no score:\n - Mutation/fusion presence (\"BRCA1/2 mutation\", \"ALK rearrangement\", \"NTRK fusion\", \"FLT3-ITD positive\") → scoring_system=\"n/a\".\n - MMR/MSI status by IHC or PCR (dMMR, pMMR, MSI-H, MSS) → scoring_system=\"n/a\".\n - HRD categorical (\"HRD positive\", \"HRD deficient\") without a numeric HRD score in the text → scoring_system=\"n/a\".\n - Wild-type-required (RAS wild-type, EGFR wild-type) → scoring_system=\"n/a\".\n - Secondary biomarker mentions in biomarker_detail (e.g. \"; HER2-negative\") do NOT promote scoring_system away from the primary biomarker's value.\n Reserve \"other\" for **assay-specific composite scores** that are quantitative but lack a canonical short name (e.g. zolbetuximab CLDN18.2 \"moderate-to-strong membranous staining in ≥ 75% of tumour cells\"). Put the verbatim composite in diagnostic_criterion.\n5b. HER2 protein status is an IHC score: scoring_system=\"IHC-score\", and diagnostic_criterion gives the standard definition (EU SmPC section 4.2), even when the text names only the category:\n - HER2-positive / \"HER2 overexpression or HER2 gene amplification\" → \"IHC 3+ or IHC 2+/ISH-positive\" (keep stricter wording the text gives, e.g. \"IHC 3+\").\n - HER2-low → \"IHC 1+ or IHC 2+/ISH-negative\".\n - HER2-ultralow → \"IHC 0 with membrane staining (faint, incomplete, ≤10% of tumour cells)\".\n \"HER2-low or HER2-ultralow\" stays one row with both definitions. HER2 (ERBB2) mutation → alteration_type=\"mutation\", scoring_system=\"n/a\". A secondary \"HER2-negative\" does not change scoring_system.\n6. \"PD L1\" / \"PD-L1\" are the same — use \"PD-L1\". PD-L1 scoring_system mapping by SmPC phrasing:\n - \"tumour cell PD-L1 expression ≥ X%\" / \"PD-L1 expression in tumour cells ≥ X%\" / \"TPS ≥ X\" / \"tumour proportion score ≥ X%\" → scoring_system=\"TPS\" (Tumor Proportion Score = % PD-L1+ tumor cells, pembrolizumab/nivolumab).\n - \"combined positive score ≥ X\" / \"CPS ≥ X\" → scoring_system=\"CPS\".\n - \"PD-L1 positive immune cells ≥ X%\" / \"tumour-infiltrating immune cells covering ≥ X%\" / \"IC ≥ X\" → scoring_system=\"IC\" (Immune Cell score, atezolizumab SP142).\n - \"TC ≥ X%\" / \"PD-L1 stained tumour cells ≥ X%\" as the SP142-style tumour-cell leg paired with an IC leg → scoring_system=\"TC\" (atezolizumab tumour-cell score, distinct from TPS).\n - \"TAP score ≥ X%\" / \"tumour area positivity ≥ X%\" / \"PD-L1 expression with a TAP score ≥ X%\" → scoring_system=\"TAP\" (tislelizumab SP263).\n - A PD-L1 percentage that names no cells or score (\"PD-L1 expression ≥ 1%\", \"tumours expressing PD-L1 ≥ 1%\", \"PD-L1 positive cells ≥ X%\") → scoring_system=\"TPS\" (tumour-cell expression, as in the pivotal trials). Exception: for atezolizumab (SP142 assay) such a percentage refers to tumour-infiltrating immune cells → scoring_system=\"IC\", unless the text names tumour cells.\n - PD-L1 below a threshold (\"tumour cell PD-L1 expression < 1%\") is still a PD-L1 expression result → alteration_type=\"overexpression\", with the threshold in diagnostic_criterion.\n7. Gene symbols uppercase (BRAF, EGFR, ERBB2). Use \"PD-L1\" (protein) not CD274. An HLA type is a germline genotype, never a mutation: \"HLA-A*02:01-positive\" → biomarker_name=\"HLA-A*02:01\", alteration_type=\"overexpression\", biomarker_detail=\"HLA-A*02:01-positive\", scoring_system=\"n/a\", test_method=[\"molecular\"]. Hormone receptors are proteins measured by IHC: \"hormone receptor-positive\" → biomarker_name=\"HR\", \"oestrogen receptor-positive\" → \"ER\", progesterone receptor → \"PR\"; use \"ESR1\" only for ESR1 mutations.\n8. If uncertain on an enum, pick the closest and flag. Never leave blanks.\n9. source_sentence must be a verbatim substring of indication_text.\n10. `disease_stage` is REQUIRED. Enum: early | locally-advanced | advanced | metastatic | any. Pick the closest match per ESMO conventions — \"advanced\" is the umbrella for locally advanced unresectable and/or metastatic disease, not a synonym for metastatic:\n - \"Resectable X\" / \"early stage X\" / \"early X\" / \"localised X\" / \"stage I-II X\" → early. Treat \"resectable\" as the marker of early-stage even when downstream pathology may be stage II or IIIA.\n - \"Locally advanced X\" (alone, NO \"or metastatic\"), also \"locally advanced, unresectable X\" → locally-advanced.\n - \"Advanced X\"; \"advanced or metastatic X\"; \"advanced/metastatic X\"; \"locally advanced or metastatic X\" → advanced (one row). Do NOT split these into two rows just on stage wording.\n - \"Unresectable X\", \"unresectable or metastatic X\", \"inoperable X\", \"not amenable to curative surgery or radiotherapy\" → advanced.\n - \"Recurrent or metastatic\", \"recurrent and/or metastatic\", \"persistent, recurrent or metastatic\", \"locally recurrent unresectable or metastatic\" → advanced (recurrent disease need not be metastatic). \"Recurrent\" or \"relapsed\" alone in a solid tumour → advanced.\n - \"Metastatic X\" / \"stage IV X\" (no \"advanced\" umbrella phrasing) → metastatic.\n - Small cell lung cancer: extensive-stage (ES-SCLC) → advanced (ESMO: stage IV, or stage III not eligible for curative treatment); limited-stage (LS-SCLC) → locally-advanced.\n - \"Non-metastatic\" without other stage words (e.g. non-metastatic castration-resistant prostate cancer) → locally-advanced; keep \"non-metastatic\" in tumor_type.\n - Lymphomas: Ann Arbor stage I-II → early; stage III-IV, a stage list reaching III-IV, or \"advanced stage\" → advanced (never metastatic).\n - Leukaemias, myeloma and other haematological malignancies, CNS tumours, and benign or locally aggressive tumours without TNM staging (plexiform neurofibroma, tenosynovial giant cell tumour, desmoid tumour, giant cell tumour of bone, SEGA) → any, unless the text uses one of the stage words above.\n - Neoadjuvant and adjuvant rows: set a stage only when the text names exactly one category (\"early\", \"resectable\" → early; \"resected stage III\" → locally-advanced; resected metastatic disease only → metastatic). When it names none (\"following complete resection\", \"after nephrectomy\", \"after radical resection\") or several (\"stage IB-IIIA\", \"stage IIB, IIC or III\") → any, and copy the stage wording into patient_eligibility.\n - An alternative to advanced disease that can be localised (\"locally advanced, metastatic or where surgical resection is likely to result in severe morbidity\") → any, and copy the whole wording into patient_eligibility.\n - \"Localised\" before a list governs every tumour in it (\"who require therapy for associated, localised renal cell carcinoma, CNS haemangioblastomas, or pancreatic neuroendocrine tumours\" → early for each row).\n - \"Inoperable\" or \"symptomatic\" describes a benign tumour (plexiform neurofibroma), not its stage → any.\n - If the text gives no stage, use \"any\" — do NOT guess.\n\n11. `treatment_phase` is OPTIONAL — set it ONLY when the SmPC explicitly names one of the five phases. Default is null. Do NOT use it as a catch-all for \"non-perioperative\" therapy.\n - SmPC says \"adjuvant treatment\" → treatment_phase=\"adjuvant\".\n - SmPC says \"neoadjuvant treatment\" → treatment_phase=\"neoadjuvant\".\n - SmPC says \"induction treatment\" → treatment_phase=\"induction\" (most often hematology, e.g. bortezomib in transplant-eligible MM).\n - SmPC says \"consolidation\" → treatment_phase=\"consolidation\" (e.g. brentuximab post-ASCT in Hodgkin lymphoma).\n - Treatment of locally advanced or limited-stage disease \"whose disease has not progressed following (platinum-based) chemoradiation\" is consolidation after definitive chemoradiation, even without the word: treatment_phase=\"consolidation\", line_of_therapy=\"any\".\n - SmPC says \"maintenance\" → treatment_phase=\"maintenance\" (e.g. rituximab in follicular lymphoma).\n - SmPC says \"treatment of metastatic X\" with no phase word → treatment_phase=null.\n - A regimen that continues as maintenance in the same sentence is split by phase (rule 12a).\n\n12. Perioperative regimens that span both phases (e.g. \"neoadjuvant + adjuvant\", \"as neoadjuvant treatment, and then continued as adjuvant treatment\") MUST be emitted as TWO rows, not one. Each row has its own `treatment_phase`, `combination`, and `prior_therapy`:\n - Row A (neoadjuvant): combination = the neoadjuvant regimen as written; prior_therapy = null.\n - Row B (adjuvant): combination = the adjuvant regimen as written; prior_therapy must reference Row A's regimen + surgical resection (e.g. \"neoadjuvant pembrolizumab + platinum-based chemotherapy and surgical resection\"). Without this link Row B reads as a stand-alone adjuvant indication, which is a different (separately-approved) entity.\n Both rows share the same `disease_stage` and `tumor_type`.\n\n12a. A regimen that continues as maintenance in the same sentence (\"in combination with carboplatin and paclitaxel, followed by maintenance with X\"; \"in combination with chemotherapy, followed by X maintenance\") is emitted as one row per phase in which the medicine is given, like rule 12:\n - Row A (first phase): combination = the first-phase regimen; treatment_phase = null, or \"induction\" if the text says induction; line from the text.\n - Row B (maintenance): treatment_phase=\"maintenance\"; combination = the maintenance regimen; prior_therapy = \" without progression\"; same line as Row A.\n - When maintenance depends on a biomarker (e.g. dMMR → monotherapy maintenance, pMMR → + olaparib), the biomarker goes on the maintenance rows; Row A carries it only if the first phase itself is restricted.\n - If the medicine is not given in the first phase (\"after first-line induction with atezolizumab, carboplatin and etoposide\"), emit only the maintenance row, with the induction in prior_therapy.\n\n13. `line_of_therapy` counts the minimum number of prior lines of systemic therapy that the wording guarantees: 0 → 1L, at least 1 → 2L, at least 2 → 3L+. A 2L row means \"after one or more prior lines\".\n - \"first-line\", \"previously untreated\", \"treatment-naive\", \"no prior systemic therapy (or chemotherapy) for metastatic disease\" → 1L.\n - \"second-line\", \"after one prior line\", \"after failure of prior platinum-based therapy\", \"relapsed\", \"refractory\", \"relapsed or refractory\", \"previously treated\", \"pretreated\", \"after prior therapy\", \"progressed on or after\", \"platinum-resistant\", \"platinum-sensitive relapsed\" → 2L.\n - An upper bound (\"no more than two prior chemotherapy regimens\", \"one or two prior regimens\") → 2L; write the cap into prior_therapy.\n - \"after at least two prior therapies\", \"after ≥2 prior lines\", \"third-line or later\", \"heavily pretreated\", \"after multiple prior therapies\" → 3L+.\n - Autologous stem cell transplant (ASCT): in lymphomas, salvage chemotherapy plus ASCT is the second line, so \"relapsed or refractory after (failed) ASCT\" → 3L+, and post-ASCT consolidation without relapse (\"at increased risk of relapse or progression following ASCT\") → 2L. In multiple myeloma, induction, ASCT, consolidation and maintenance together are the first line (IMWG) → 1L.\n - Branches with different counts in one sentence → one row at the lowest count (rule 1); split only when one branch is untreated (1L) and another pretreated.\n - Naivety to one drug class (\"EGFR TKI-naive\", \"BRAF inhibitor-naive\", \"not previously treated with endocrine therapy\") does not set a line → any, unless other words fix it; write e.g. \"No prior EGFR TKI\" or \"No prior endocrine therapy\" into prior_therapy.\n - A disease state is not a prior line. Refractoriness to radioactive iodine (thyroid cancer) and castration resistance (\"castration-resistant\", \"after failure of androgen deprivation therapy\") describe the disease; count only systemic therapy given for it. Metastatic castration-resistant prostate cancer before chemotherapy → 1L; after docetaxel → 2L. RAI-refractory thyroid cancer with no prior systemic therapy → 1L.\n - A prior therapy the label waives guarantees nothing: \"previously treated with an anthracycline and a taxane … unless patients were not suitable for these treatments\", \"previously treated with, or are not considered candidates for, available therapies\" → any. Keep the wording in prior_therapy.\n - Count the lines given for advanced (unresectable or metastatic) disease. Neoadjuvant or adjuvant therapy counts only when the label ties it to early relapse (\"relapsed during or within 6 months of completing adjuvant therapy\"). \"Two or more prior systemic therapies, at least one of them for advanced disease\" → 2L. A prior regimen \"in any setting\" may have been neoadjuvant or adjuvant → any. Prior regimens whose setting the label leaves open count as lines (\"at least 2 prior anti-HER2 treatment regimens\" → 3L+).\n - Radiotherapy is not systemic therapy: \"at least one prior radiation and/or chemotherapy treatment\" → any.\n - A switch within first-line therapy before progression (\"upon detection of an ESR1 mutation and without disease progression during first-line endocrine therapy in combination with a CDK4/6 inhibitor\") → 1L, prior_therapy \"During first-line endocrine therapy + CDK4/6 inhibitor, before progression\".\n - Neoadjuvant and adjuvant rows → any. Induction, consolidation and maintenance rows take the line of the therapy they belong to when the text says so (\"newly diagnosed\", \"following first-line chemotherapy\" → 1L; \"relapsed\", \"platinum-sensitive relapsed\" → 2L); otherwise any.\n - If no line information at all → \"any\".\n\n14. Patient-status eligibility criteria — \"cisplatin-ineligible\", \"transplant-eligible\", \"BCG-unresponsive\", \"high risk of recurrence\", \"postmenopausal\", \"ECOG 0-1\" — go in `patient_eligibility`. They are NOT prior therapy (the patient hasn't received them), NOT biomarkers (not molecular), NOT stage. The most common slip is putting \"cisplatin-ineligible\" into `prior_therapy` — that is wrong; the patient was deemed *unable* to receive cisplatin, they didn't take it. Multiple criteria joined with \"; \". Null if none. The age group goes into `age_group` (enum); explicit age bounds go here as well. Also in `patient_eligibility`:\n - a population limited by sex (\"women with HR-positive …\" → \"Women\"; \"women and men\");\n - explicit age bounds (\"up to and including 25 years of age\", \"26 years of age and above\", \"aged 6 months to less than 18 years\", \"aged 1 year and older\");\n - how a subgroup receives it, from the same paragraph (\"In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist\") → append to every row of that indication;\n - every restriction on recurrent disease (\"not amenable to curative surgery or radiation therapy\");\n - a disease-state threshold such as \"MRD ≥ 0.1%\" or \"in first or second complete remission\", which is no biomarker cut-off: keep it out of diagnostic_criterion.\n A condition that qualifies one alternative stays with that alternative in one clause (\"following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option\" → all of it in prior_therapy), and alternatives within one condition stay one clause joined by \"or\" (\"progressed on or are intolerant to imatinib and sunitinib\" → prior_therapy \"Progressed on or intolerant to imatinib and sunitinib\"). Do not split them between prior_therapy and patient_eligibility.\n What the label says about its trial is no condition: \"The patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor\" → notes, not prior_therapy. A sentence that qualifies the benefit without changing who may be treated (\"an increase in overall survival is established only in patients with low tumour PD-L1 expression\"; \"a possible lower benefit in patients without a RET mutation\") → copy it into notes.\n\n15. `age_group` is REQUIRED. Map SmPC wording:\n - \"adult patients\" / \"adults\" / \"patients ≥18 years\" → age_group=\"adult\".\n - \"pediatric patients\" / \"children aged 1-17\" with no adult inclusion → age_group=\"pediatric\".\n - \"adults and adolescents aged 12 and older\" / \"patients aged ≥6 months\" / any indication that mixes adult and pediatric populations → age_group=\"mixed\".\n - \"women\", \"men\", \"postmenopausal women\", \"pre- or perimenopausal women\" → age_group=\"adult\" (adult populations by definition).\n - A section-level statement such as \"X is indicated in adults for the following indications\" applies to every indication under it → age_group=\"adult\".\n - SmPC says \"patients\" with no age qualifier and no such statement → age_group=\"any\".\n\n15a. Keep the qualifiers of a regimen verbatim in combination, including what is left out (\"alternating with R-DHAP (or R-DHAOx) without IMBRUVICA\").\n\n16. `test_method` is a workflow-level descriptor — what kind of pathology lab test the indication implies. Pick from:\n - \"IHC\" — protein expression by immunohistochemistry (PD-L1, HER2 IHC, MMR proteins, ER/PR).\n - \"ISH\" — in situ hybridization, umbrella for FISH/CISH/SISH (HER2 amplification, ALK/ROS1 fusions when ordered as FISH).\n - \"molecular\" — any DNA/RNA assay regardless of platform: PCR, Sanger sequencing, NGS, ddPCR (mutation detection like EGFR/BRAF/KRAS, fusion detection by RNA-seq, MSI by PCR).\n - \"cytogenetics\" — conventional karyotype / cytogenetic analysis (heme malignancies).\n - \"flow-cytometry\" — phenotypic marker detection in heme (e.g. CD30, CD20, CD22).\n Multiple values are valid when the criterion is algorithmic (HER2: [\"IHC\", \"ISH\"]). Empty list `[]` when biomarker_name=\"none\" — no test applies.\n\n17. MMR / MSI alteration_type disambiguation. The text can present MMR/MSI status in two framings, and both carry clinical meaning but the enum forces a single choice:\n - Protein-loss framing (\"deficient mismatch repair (dMMR)\", \"loss of MLH1/MSH2/MSH6/PMS2\", \"MMR protein loss by IHC\") → biomarker_alteration_type=\"loss\".\n - MSI framing (\"microsatellite instability-high (MSI-H)\", \"MSI by PCR/NGS\" alone, no mention of MMR protein loss) → biomarker_alteration_type=\"MSI\".\n - When the SmPC uses BOTH framings together (\"dMMR or MSI-H\", \"mismatch repair deficient or microsatellite instability high\", \"MMR deficient / MSI high\") → prefer biomarker_alteration_type=\"loss\". Rationale: the primary molecular defect is MMR protein deficiency; MSI-H is the downstream consequence. Pathology labs diagnose this most commonly by IHC for MMR protein loss, so \"loss\" better captures the diagnostic workflow implied by the indication.\n\nFIELD DEFINITIONS\norgan: one of lung | mesothelium | thymus | breast | colorectal | stomach | esophagus | pancreas | liver | biliary | ovary | uterus | cervix | prostate | kidney | bladder | testis | skin | eye | CNS | thyroid | adrenal | head-and-neck | bone | soft-tissue | hematologic | tumor-agnostic | other\n lung: lung cancer incl. NSCLC, SCLC\n mesothelium: pleural or peritoneal mesothelioma\n thymus: thymoma, thymic carcinoma\n breast: breast cancer\n colorectal: colon, rectal, colorectal cancer\n stomach: gastric or gastro-oesophageal junction adenocarcinoma, GIST of stomach/GI tract\n esophagus: oesophageal cancer (squamous or adenocarcinoma of the oesophagus)\n pancreas: pancreatic cancer, pancreatic neuroendocrine tumours\n liver: hepatocellular carcinoma\n biliary: biliary tract cancer, cholangiocarcinoma, gallbladder cancer\n ovary: ovarian, fallopian tube, primary peritoneal cancer\n uterus: endometrial cancer, uterine sarcoma\n cervix: cervical cancer\n prostate: prostate cancer\n kidney: renal cell carcinoma\n bladder: urothelial carcinoma, bladder cancer\n testis: testicular germ cell tumour\n skin: cutaneous melanoma, basal cell carcinoma, cutaneous squamous cell carcinoma, Merkel cell\n eye: uveal/ocular melanoma, retinoblastoma\n CNS: glioma, glioblastoma, brain tumours\n thyroid: thyroid cancer\n adrenal: adrenocortical carcinoma, pheochromocytoma\n head-and-neck: head and neck squamous cell carcinoma, nasopharyngeal carcinoma\n bone: bone tumours: osteosarcoma, giant cell tumour of bone\n soft-tissue: soft tissue sarcoma without a named organ, tenosynovial giant cell tumour, dermatofibrosarcoma protuberans\n hematologic: leukaemia, lymphoma, myeloma, myelodysplastic and myeloproliferative neoplasms\n tumor-agnostic: ONLY when the text says solid tumours regardless of histology/tumour type\n other: none of the listed sites\n\ndisease_stage: one of early | locally-advanced | advanced | metastatic | any\n Extent of disease at the point of treatment, per ESMO conventions. 'early' = localized/resectable (stage I-II); 'locally-advanced' = regional spread, often unresectable, still curative-intent (stage III-ish); 'advanced' = ESMO umbrella covering locally-advanced-unresectable AND/OR metastatic — use when the SmPC says 'advanced', 'advanced or metastatic', 'advanced/metastatic', or 'locally advanced or metastatic'; 'metastatic' = distant spread (stage IV) explicitly, WITHOUT the 'advanced' umbrella wording; 'any' = text does not specify.\n\ntreatment_phase: one of none | neoadjuvant | adjuvant | induction | consolidation | maintenance\n OPTIONAL positional marker. Set ONLY when the SmPC explicitly uses one of: 'neoadjuvant' (before primary curative local therapy / surgery), 'adjuvant' (after primary curative local therapy), 'induction' (initial intensive systemic therapy, often hematology), 'consolidation' (time-limited systemic therapy after response to induction, e.g. post-ASCT), 'maintenance' (continuous systemic therapy after response). Otherwise leave null. Do NOT use as a catch-all for advanced-disease therapy.\n\nline_of_therapy: one of 1L | 2L | 3L+ | any\n 1L: first-line, previously untreated, treatment-naive, no prior systemic therapy for metastatic disease; multiple myeloma induction, ASCT and maintenance; castration-resistant prostate cancer before chemotherapy, or radioactive-iodine-refractory thyroid cancer, with no prior systemic therapy for it (castration resistance and RAI refractoriness are disease states, not lines); a switch during first-line therapy before progression\n 2L: at least one prior line for advanced disease guaranteed: second-line, after one prior therapy, relapsed, refractory, previously treated, after prior platinum, platinum-sensitive or -resistant relapse, at most two prior regimens, two or more prior therapies with at least one for advanced disease; lymphoma consolidation after ASCT\n 3L+: at least two prior lines: after two or more prior therapies, third-line or later, heavily pretreated; lymphoma relapsed after ASCT\n any: no line information, naivety to one drug class only (e.g. EGFR TKI-naive), a prior therapy the label waives ('unless not suitable', 'or not candidates for'), a prior regimen 'in any setting', prior radiotherapy only, or a neoadjuvant/adjuvant row\n\nbiomarker_alteration_type: one of mutation | fusion | amplification | overexpression | loss | MSI | TMB | signature | wild-type-required | none\n mutation: gene mutation (e.g. EGFR exon 19 deletion, BRAF V600E, KRAS G12C, BRCA mutation, FLT3 mutation)\n fusion: gene fusion / rearrangement (ALK, ROS1, NTRK, RET)\n amplification: gene amplification\n overexpression: protein expression or overexpression, also below a threshold (PD-L1 expression ≥ or < X%, HER2 positive/low/ultralow, CD20 positive, CLDN18.2)\n loss: protein loss, incl. deficient mismatch repair (dMMR), also when written 'dMMR or MSI-H'\n MSI: microsatellite instability (MSI-H) framing only, without MMR deficiency wording\n TMB: tumour mutational burden\n signature: genomic signature, e.g. HRD positive / genomic instability\n wild-type-required: biomarker must be ABSENT / wild-type (e.g. RAS wild-type)\n none: no biomarker gates this row, including hereditary syndromes diagnosed clinically (VHL disease, NF1)\n\nscoring_system: one of TPS | CPS | IC | TC | TAP | H-score | Allred | IRS | percent-positive | IHC-score | other | n/a\n TPS: PD-L1 tumour proportion score / tumour cell PD-L1 expression ≥ X%, or a PD-L1 percentage that names no cells (pembrolizumab, nivolumab, cemiplimab)\n CPS: PD-L1 combined positive score\n IC: PD-L1 positive tumour-infiltrating immune cells (atezolizumab SP142)\n TC: PD-L1 stained tumour cells as the SP142 tumour-cell leg paired with an IC leg\n TAP: tumour area positivity (tislelizumab SP263)\n H-score: H-score\n Allred: Allred score\n IRS: immunoreactive score\n percent-positive: 'positive cells ≥ X%' for a marker other than PD-L1, without a named score\n IHC-score: IHC intensity score, including HER2-positive (IHC 3+ or 2+/ISH+), HER2-low and HER2-ultralow\n other: quantitative assay-specific composite score without a canonical name (e.g. ≥75% tumour cells with moderate-to-strong membranous staining), or PD-L1 expression without any cutoff\n n/a: no numeric score: categorical status or no biomarker\n\nage_group: one of adult | pediatric | mixed | any\n Age restriction of the indication. 'adult' = adults only (typically ≥18); 'pediatric' = pediatric only (e.g. childhood-cancer indications); 'mixed' = adults + adolescents/children (e.g. 'adults and adolescents aged 12 and older'); 'any' = text does not specify.\n adult: adults only, including 'women', 'men', 'postmenopausal', or a section-level 'indicated in adults'\n pediatric: children/paediatric only\n mixed: adults and adolescents/children, or a minimum age below 18 (e.g. ≥12 years, ≥6 months)\n any: 'patients' with no age qualifier\n\ntest_method: one of IHC | ISH | molecular | cytogenetics | flow-cytometry (a list; [] when no biomarker)\n\ntumor_type: free text\n Tumor entity, e.g. 'NSCLC', 'cutaneous melanoma', 'gastric adenocarcinoma', 'classical Hodgkin lymphoma'.\n\nbiomarker_name: free text\n Name of the biomarker — may be a gene (BRAF, EGFR, ERBB2, ALK, ROS1, RET, MET, KRAS, BRCA1, BRCA2), a protein (PD-L1), a pathway (MMR), or a gene family (RAS, NTRK1/NTRK2/NTRK3, FGFR2/FGFR3). Uppercase. Use 'PD-L1' (protein) not CD274. Use 'none' if no biomarker is required.\n\nbiomarker_detail: free text\n Qualitative descriptor — e.g. 'V600E/K', 'overexpression', 'RAS wild-type', 'MSI-H or dMMR'. Use 'n/a' if no biomarker.\n\ndiagnostic_criterion: free text\n Quantitative or algorithmic threshold — e.g. 'TPS ≥50%', 'CPS ≥10', 'IHC 3+ or IHC 2+ with ISH+', 'presence of fusion by validated assay'. Use 'n/a' if no biomarker.\n\ncombination: free text\n 'monotherapy', '+ pembrolizumab', '+ platinum-based chemotherapy', etc.\n\nprior_therapy: free text\n What the patient actually received in the past — e.g. 'after platinum-based chemotherapy', 'after surgical resection'. Do NOT use this for eligibility criteria like 'cisplatin-ineligible' (that's not a prior therapy, that's a status). Eligibility goes in `patient_eligibility`. Null if no prior therapy is specified.\n", "targetPrompt": "You read the \"Mechanism of action\" part of section 5.1 of an EU summary of product characteristics (SmPC) and state what the medicine targets. Use only what the text says.\n\nReturn:\n- targets: the molecular targets the text names, with standard gene or protein symbols (PD-1, PD-L1, CTLA-4, LAG-3, HER2, EGFR, MET, ALK, ROS1, RET, BRAF, MEK1/2, KRAS G12C, VEGFR2, PDGFRA, KIT, FGFR2, FLT3, IDH1, BTK, BCL-2, PARP, CDK4/6, mTOR, PI3Kα, AKT, CD19, CD20, CD22, CD30, CD33, CD38, CD79b, BCMA, GPRC5D, DLL3, CLDN18.2, TROP2, Nectin-4, FRα, CD3...). For a bispecific antibody list both arms. For an antibody-drug conjugate list the antibody target (the payload goes into label and mechanism). For a hormonal medicine name the receptor or enzyme (estrogen receptor, androgen receptor, aromatase, GnRH receptor). Order by importance; at most six, and for broad multikinase inhibitors only the main targets the text names first.\n- modality: one of small molecule | monoclonal antibody | antibody-drug conjugate | bispecific antibody | cell therapy | protein or peptide | radioligand | oncolytic virus | other.\n- label: how a clinician would name the medicine's class, at most seven words, e.g. \"PD-1 inhibitor (antibody)\", \"CD79b-directed antibody-drug conjugate\", \"KRAS G12C inhibitor\", \"BCMA × CD3 bispecific antibody\", \"Multikinase inhibitor (VEGFR, MET, RET)\", \"CD19-directed CAR T-cell therapy\", \"Selective estrogen receptor degrader\".\n- mechanism: one sentence of at most 220 characters in plain clinical language, faithful to the text (what it binds, what that does).\n- quote: one sentence copied verbatim from the text that names the target.", "targetJudgePrompt": "Two independent readers described what an EU-authorised cancer medicine targets, from the \"Mechanism of action\" text of SmPC section 5.1. Their readings disagree. Read the text yourself and return the correct reading, in the same format and under the same instructions they had. You may take either reading, combine them, or write your own; stay with what the text says. Set \"ambiguous\" to true only when the text itself leaves the answer open, and give a one-sentence reason quoting the text.\n\nThe readers' instructions:\nYou read the \"Mechanism of action\" part of section 5.1 of an EU summary of product characteristics (SmPC) and state what the medicine targets. Use only what the text says.\n\nReturn:\n- targets: the molecular targets the text names, with standard gene or protein symbols (PD-1, PD-L1, CTLA-4, LAG-3, HER2, EGFR, MET, ALK, ROS1, RET, BRAF, MEK1/2, KRAS G12C, VEGFR2, PDGFRA, KIT, FGFR2, FLT3, IDH1, BTK, BCL-2, PARP, CDK4/6, mTOR, PI3Kα, AKT, CD19, CD20, CD22, CD30, CD33, CD38, CD79b, BCMA, GPRC5D, DLL3, CLDN18.2, TROP2, Nectin-4, FRα, CD3...). For a bispecific antibody list both arms. For an antibody-drug conjugate list the antibody target (the payload goes into label and mechanism). For a hormonal medicine name the receptor or enzyme (estrogen receptor, androgen receptor, aromatase, GnRH receptor). Order by importance; at most six, and for broad multikinase inhibitors only the main targets the text names first.\n- modality: one of small molecule | monoclonal antibody | antibody-drug conjugate | bispecific antibody | cell therapy | protein or peptide | radioligand | oncolytic virus | other.\n- label: how a clinician would name the medicine's class, at most seven words, e.g. \"PD-1 inhibitor (antibody)\", \"CD79b-directed antibody-drug conjugate\", \"KRAS G12C inhibitor\", \"BCMA × CD3 bispecific antibody\", \"Multikinase inhibitor (VEGFR, MET, RET)\", \"CD19-directed CAR T-cell therapy\", \"Selective estrogen receptor degrader\".\n- mechanism: one sentence of at most 220 characters in plain clinical language, faithful to the text (what it binds, what that does).\n- quote: one sentence copied verbatim from the text that names the target.", "targets": { "abemaciclib__verzenios": { "url": "https://www.ema.europa.eu/en/documents/product-information/verzenios-epar-product-information_en.pdf", "text": "Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and\nCDK6), and most active against Cyclin D1/CDK4 in enzymatic assays. Abemaciclib prevents\nretinoblastoma protein (Rb) phosphorylation, blocking cell cycle progression from the G1 to the\nS-phase of cell division, leading to suppression of tumour growth. In oestrogen receptor-positive\nbreast cancer cell lines, sustained target inhibition with abemaciclib prevented rebound of Rb\nphosphorylation resulting in cell senescence and apoptosis. In vitro, Rb-negative and Rb-depleted\ncancer cell lines are generally less sensitive to abemaciclib. In breast cancer xenograft models,\nabemaciclib dosed daily without interruption at clinically relevant concentrations alone or in\ncombination with anti-oestrogens resulted in reduction of tumour size.\n\n13", "a": { "targets": [ "CDK4", "CDK6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Inhibits CDK4 and CDK6, blocking retinoblastoma protein phosphorylation and arresting cell cycle progression from the G1 to the S phase to suppress tumour growth.", "quote": "Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), and most active against Cyclin D1/CDK4 in enzymatic assays." }, "b": { "targets": [ "CDK4", "CDK6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Abemaciclib inhibits CDK4 and CDK6, preventing Rb phosphorylation and blocking cell-cycle progression from G1 to S phase, which suppresses tumour growth.", "quote": "Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), and most active against Cyclin D1/CDK4 in enzymatic assays." }, "decision": null }, "abiraterone-acetate__abiraterone-krka": { "url": "https://www.ema.europa.eu/en/documents/product-information/abiraterone-krka-epar-product-information_en.pdf", "text": "Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor.\nSpecifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This\nenzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic\ntumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone\nprecursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the\nC17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals\n(see section 4.4).\nAndrogen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.\nAndrogen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease\nandrogen production in the testes but do not affect androgen production by the adrenals or in the\ntumour. Treatment with abiraterone acetate decreases serum testosterone to undetectable levels (using\ncommercial assays) when given with LHRH analogues (or orchiectomy).", "a": { "targets": [ "CYP17" ], "modality": "small molecule", "label": "CYP17 inhibitor", "mechanism": "Selectively inhibits the CYP17 enzyme, blocking androgen biosynthesis in testicular, adrenal, and prostatic tumour tissues.", "quote": "Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17)." }, "b": { "targets": [ "CYP17A1" ], "modality": "small molecule", "label": "CYP17 inhibitor (androgen biosynthesis inhibitor)", "mechanism": "Abiraterone selectively inhibits CYP17, reducing androgen biosynthesis in testicular, adrenal and prostatic tumour tissues.", "quote": "Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17)." }, "decision": { "reason": "Both readings agree on the target: the text plainly says \"abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17)\". They differ only in the symbol and label wording, so the answer is not ambiguous; CYP17A1 is the standard gene symbol for this enzyme, and a short class label fits the instructions.", "targets": [ "CYP17A1" ], "modality": "small molecule", "label": "CYP17 inhibitor (androgen biosynthesis inhibitor)", "mechanism": "Abiraterone selectively inhibits CYP17 (17α-hydroxylase/C17,20-lyase), blocking androgen biosynthesis in testicular, adrenal and prostatic tumour tissue and lowering serum testosterone.", "quote": "Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17).", "ambiguous": false } }, "abiraterone__zytiga": { "url": "https://www.ema.europa.eu/en/documents/product-information/zytiga-epar-product-information_en.pdf", "text": "Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor.\nSpecifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This\nenzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic\ntumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone\nprecursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the\nC17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals\n(see section 4.4).\nAndrogen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.\nAndrogen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease\nandrogen production in the testes but do not affect androgen production by the adrenals or in the\ntumour. Treatment with ZYTIGA decreases serum testosterone to undetectable levels (using\ncommercial assays) when given with LHRH analogues (or orchiectomy).", "a": { "targets": [ "CYP17" ], "modality": "small molecule", "label": "CYP17 inhibitor", "mechanism": "Selectively inhibits the CYP17 enzyme to block androgen biosynthesis in testicular, adrenal, and prostatic tumour tissues, decreasing testosterone to undetectable levels.", "quote": "Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17)." }, "b": { "targets": [ "CYP17 (CYP17A1)" ], "modality": "small molecule", "label": "CYP17 inhibitor", "mechanism": "Abiraterone selectively inhibits CYP17, reducing androgen biosynthesis in testicular, adrenal and prostatic tumour tissues.", "quote": "Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17)." }, "decision": { "reason": "Both readings agree on target, modality and label; the text names a single enzyme, \"the enzyme 17α-hydroxylase/C17,20-lyase (CYP17)\", so the only difference is how the symbol is written. The mechanism also notes that testosterone becomes undetectable only when abiraterone is combined with LHRH analogues or orchiectomy.", "targets": [ "CYP17" ], "modality": "small molecule", "label": "CYP17 inhibitor (androgen biosynthesis inhibitor)", "mechanism": "Abiraterone selectively inhibits CYP17 (17α-hydroxylase/C17,20-lyase), blocking androgen synthesis in testes, adrenals and prostate tumour; with LHRH analogues it drops testosterone to undetectable levels.", "quote": "Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17).", "ambiguous": false } }, "acalabrutinib__calquence": { "url": "https://www.ema.europa.eu/en/documents/product-information/calquence-epar-product-information_en.pdf", "text": "Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK). BTK is a signalling molecule of the\nB-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in B-cell\nsurvival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis.\nAcalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the\nBTK active site, leading to irreversible inactivation of BTK with minimal off-target interactions.", "a": { "targets": [ "BTK" ], "modality": "small molecule", "label": "Selective BTK inhibitor", "mechanism": "Acalabrutinib covalently binds to the active site of Bruton tyrosine kinase (BTK), irreversibly inactivating it to block B-cell survival, proliferation, and trafficking.", "quote": "Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK)." }, "b": { "targets": [ "BTK" ], "modality": "small molecule", "label": "BTK inhibitor", "mechanism": "Acalabrutinib and its active metabolite covalently bind the BTK active site, irreversibly inactivating BTK with minimal off-target interactions.", "quote": "Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK)." }, "decision": null }, "adagrasib__krazati": { "url": "https://www.ema.europa.eu/en/documents/product-information/krazati-epar-product-information_en.pdf", "text": "Adagrasib is a selective, irreversible inhibitor of KRAS (Kirsten rat sarcoma viral oncogene homolog)\nG12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein\nin its inactive, GDP-bound conformation, which prevents KRAS-dependent downstream signalling.\nAdagrasib inhibits tumour cell growth and viability in cells harbouring KRAS G12C mutations and\nresults in regression in KRAS G12C-positive nonclinical tumour models with minimal off-target\nactivity.", "a": { "targets": [ "KRAS G12C" ], "modality": "small molecule", "label": "KRAS G12C inhibitor", "mechanism": "Covalently binds mutant cysteine in KRAS G12C, locking it in an inactive GDP-bound conformation to inhibit downstream signalling and tumour growth.", "quote": "Adagrasib is a selective, irreversible inhibitor of KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive, GDP-bound conformation, which prevents KRAS-dependent downstream signalling." }, "b": { "targets": [ "KRAS G12C" ], "modality": "small molecule", "label": "KRAS G12C inhibitor", "mechanism": "Covalently binds mutant KRAS G12C and locks it in its inactive, GDP-bound conformation, preventing KRAS-dependent downstream signalling.", "quote": "Adagrasib is a selective, irreversible inhibitor of KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive, GDP-bound conformation, which prevents KRAS-dependent downstream signalling." }, "decision": null }, "afatinib__giotrif": { "url": "https://www.ema.europa.eu/en/documents/product-information/giotrif-epar-product-information_en.pdf", "text": "Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and\nirreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members\nEGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.", "a": { "targets": [ "EGFR", "HER2", "ErbB3", "ErbB4" ], "modality": "small molecule", "label": "Irreversible ErbB family inhibitor", "mechanism": "Afatinib covalently binds to and irreversibly blocks signalling from homo- and heterodimers formed by ErbB family members EGFR, HER2, ErbB3, and ErbB4.", "quote": "Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4." }, "b": { "targets": [ "EGFR", "HER2", "ERBB3", "ERBB4" ], "modality": "small molecule", "label": "Irreversible ErbB family inhibitor", "mechanism": "Afatinib covalently binds and irreversibly blocks signalling from homo- and heterodimers formed by EGFR, HER2, ERBB3 and ERBB4.", "quote": "Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4." }, "decision": null }, "aflibercept__zaltrap": { "url": "https://www.ema.europa.eu/en/documents/product-information/zaltrap-epar-product-information_en.pdf", "text": "Vascular endothelial growth factor A and B (VEGF-A, VEGF-B), and placental growth factor (PlGF)\nare members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic,\nand vascular permeability factors for endothelial cells. VEGF-A acts via two receptor tyrosine kinases,\nVEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF and VEGF-B bind only to\nVEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors\nby VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF is\nalso linked to pathological neovascularisation and recruitment of inflammatory cells into tumours.\nAflibercept, also known as VEGF TRAP in the scientific literature, is a recombinant fusion protein\nconsisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and\n2 fused to the Fc portion of the human IgG1. Aflibercept is produced by recombinant DNA technology\nin a Chinese hamster ovary (CHO) K-1 mammalian expression system. Aflibercept is a dimeric\nglycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation,\nconstituting an additional 15 % of the total molecular mass, resulting in a total molecular weight of\n115 kDa.\nAflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native\nreceptors, as well as the related ligands PlGF and VEGF-B. By acting as a ligand trap, aflibercept\nprevents binding of endogenous ligands to their cognate receptors and thereby blocks receptor\nmediated signaling.\n\n17\nAflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby\ninhibiting the growth of new vessels that supply tumours with oxygen and nutrients.\nAflibercept binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for\nVEGF-A165 and 0.36 pM for VEGF-A121), to human PlGF (KD of 39 pM for PlGF-2), and to human\nVEGF-B (KD of 1.92 pM) to form a stable, inert complex which has no detectable biological activity.", "a": { "targets": [ "VEGF-A", "PlGF", "VEGF-B" ], "modality": "protein or peptide", "label": "VEGF and PlGF trap fusion protein", "mechanism": "Acts as a soluble decoy receptor binding VEGF-A, VEGF-B, and PlGF, preventing activation of cognate VEGF receptors to inhibit endothelial cell proliferation and tumour angiogenesis.", "quote": "Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native receptors, as well as the related ligands PlGF and VEGF-B." }, "b": { "targets": [ "VEGF-A", "VEGF-B", "PlGF" ], "modality": "protein or peptide", "label": "VEGF ligand trap (fusion protein)", "mechanism": "Aflibercept acts as a soluble decoy receptor that binds VEGF-A, VEGF-B and PlGF, preventing them from binding their receptors and blocking receptor-mediated signaling.", "quote": "Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native receptors, as well as the related ligands PlGF and VEGF-B." }, "decision": null }, "alectinib__alecensa": { "url": "https://www.ema.europa.eu/en/documents/product-information/alecensa-epar-product-information_en.pdf", "text": "Alectinib is a highly selective and potent ALK and rearranged during transfection (RET) tyrosine\nkinase inhibitor. In pre-clinical studies, inhibition of ALK tyrosine kinase activity led to blockage of\ndownstream signalling pathways including signal transducer and activator of transcription 3 (STAT 3)\nand phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and induction of tumour cell death\n(apoptosis).\nAlectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme,\nincluding mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4)\nhas shown similar in vitro potency and activity.\nBased on preclinical data, alectinib is not a substrate of P-gp or BCRP, which are both efflux\ntransporters in the blood brain barrier, and is therefore able to distribute into and be retained within the\ncentral nervous system.", "a": { "targets": [ "ALK", "RET" ], "modality": "small molecule", "label": "ALK and RET kinase inhibitor", "mechanism": "Alectinib selectively inhibits ALK and RET tyrosine kinases, blocking downstream STAT3 and PI3K/AKT signalling pathways and inducing tumour cell death.", "quote": "Alectinib is a highly selective and potent ALK and rearranged during transfection (RET) tyrosine kinase inhibitor." }, "b": { "targets": [ "ALK", "RET" ], "modality": "small molecule", "label": "ALK and RET tyrosine kinase inhibitor", "mechanism": "Alectinib inhibits ALK and RET tyrosine kinase activity, blocking downstream signalling pathways and inducing tumour cell death.", "quote": "Alectinib is a highly selective and potent ALK and rearranged during transfection (RET) tyrosine kinase inhibitor." }, "decision": null }, "alpelisib__piqray": { "url": "https://www.ema.europa.eu/en/documents/product-information/piqray-epar-product-information_en.pdf", "text": "Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor. Gain-of-function\nmutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα\nand AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivo\nmodels.\nIn breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets\nincluding AKT, and showed activity in cell lines harbouring a PIK3CA mutation.\nIn vivo, alpelisib inhibited the PI3K/AKT signalling pathway and reduced tumour growth in xenograft\nmodels, including models of breast cancer.\nPI3K inhibition by alpelisib treatment has been shown to induce an increase in oestrogen receptor\n(ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated\nincreased anti-tumour activity compared to either treatment alone in xenograft models derived from\nER-positive, PIK3CA mutated breast cancer cell lines.\nThe PI3K/AKT signalling pathway is responsible for glucose homeostasis, and hyperglycaemia is an\nexpected on-target adverse reaction of PI3K inhibition.", "a": { "targets": [ "PI3Kα" ], "modality": "small molecule", "label": "PI3Kα inhibitor", "mechanism": "Alpelisib selectively inhibits PI3Kα, blocking downstream PI3K/AKT signalling and reducing tumour growth in cancers harbouring PIK3CA mutations.", "quote": "Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor." }, "b": { "targets": [ "PI3Kα" ], "modality": "small molecule", "label": "PI3Kα inhibitor", "mechanism": "Alpelisib inhibits PI3Kα, reducing PI3K/AKT signalling and downstream target phosphorylation.", "quote": "Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor." }, "decision": null }, "amivantamab__rybrevant": { "url": "https://www.ema.europa.eu/en/documents/product-information/rybrevant-epar-product-information_en.pdf", "text": "Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune\ncell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions,\nExon 21 L858R substitution, and Exon 20 insertion mutations. Amivantamab binds to the extracellular\ndomains of EGFR and MET.\nAmivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and\nenhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The\npresence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells for\ndestruction by immune effector cells, such as natural killer cells and macrophages, through\nantibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.", "a": { "targets": [ "EGFR", "MET" ], "modality": "bispecific antibody", "label": "EGFR × MET bispecific antibody", "mechanism": "Binds extracellular domains of EGFR and MET, blocking ligand binding, promoting receptor degradation, and directing immune effector cell destruction via ADCC and trogocytosis.", "quote": "Amivantamab binds to the extracellular domains of EGFR and MET." }, "b": { "targets": [ "EGFR", "MET" ], "modality": "bispecific antibody", "label": "EGFR × MET bispecific antibody", "mechanism": "Binds the extracellular domains of EGFR and MET, blocking ligand binding and enhancing receptor degradation to prevent tumour growth and progression.", "quote": "Amivantamab binds to the extracellular domains of EGFR and MET." }, "decision": null }, "apalutamide__erleada": { "url": "https://www.ema.europa.eu/en/documents/product-information/erleada-epar-product-information_en.pdf", "text": "Apalutamide is an orally administered, selective Androgen Receptor (AR) inhibitor that binds directly\nto the ligand-binding domain of the AR. Apalutamide prevents AR nuclear translocation, inhibits\nDNA binding, impedes AR-mediated transcription, and lacks androgen receptor agonist activity.\nApalutamide treatment decreases tumour cell proliferation and increases apoptosis leading to potent\nantitumour activity. A major metabolite, N-desmethyl apalutamide, exhibited one-third the in vitro\nactivity of apalutamide.\nProstate Specific Antigen (PSA) reduction\nApalutamide 240 mg daily in combination with ADT in patients with mHSPC (in TITAN study)\nreduced PSA to undetectable levels (<0.2 ng/mL) at any time in 68% of patients compared to 32% of\npatients taking ADT alone. Median time to undetectable PSA for patients receiving apalutamide in\ncombination with ADT was 1.9 months. Apalutamide in combination with ADT led to a ≥ 50% PSA\nreduction from baseline at any time in 90% of patients compared to 55% of patients taking ADT alone.\nApalutamide 240 mg daily in combination with ADT in patients with nmCRPC (in SPARTAN study)\nreduced PSA to undetectable levels (<0.2 ng/mL) at any time in 38% of patients compared to no\npatients (0%) taking ADT alone. Median time to undetectable PSA for patients receiving apalutamide\nin combination with ADT was 2.8 months. Apalutamide in combination with ADT led to a ≥ 50%\nPSA reduction from baseline at any time in 90% of patients compared to 2.2% of patients taking ADT\nalone.", "a": { "targets": [ "androgen receptor" ], "modality": "small molecule", "label": "Androgen receptor inhibitor", "mechanism": "Apalutamide binds the androgen receptor ligand-binding domain, blocking nuclear translocation, DNA binding, and mediated transcription to reduce tumor proliferation and induce apoptosis.", "quote": "Apalutamide is an orally administered, selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR." }, "b": { "targets": [ "AR" ], "modality": "small molecule", "label": "Selective androgen receptor inhibitor", "mechanism": "Apalutamide binds the androgen receptor’s ligand-binding domain, preventing nuclear translocation and DNA binding and inhibiting AR-mediated transcription.", "quote": "Apalutamide is an orally administered, selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR." }, "decision": { "reason": "Both readings agree on the target and differ only in wording; the text clearly names one target, calling apalutamide a \"selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR\", and the instructions ask for the receptor by name.", "targets": [ "androgen receptor" ], "modality": "small molecule", "label": "Selective androgen receptor inhibitor", "mechanism": "Binds the androgen receptor ligand-binding domain, preventing AR nuclear translocation, DNA binding and AR-mediated transcription, with no agonist activity; reduces tumour proliferation and increases apoptosis.", "quote": "Apalutamide is an orally administered, selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR.", "ambiguous": false } }, "arsenic-trioxide__trisenox": { "url": "https://www.ema.europa.eu/en/documents/product-information/trisenox-epar-product-information_en.pdf", "text": "The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes\nmorphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in\nNB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage or\ndegradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha\n(PML/RAR alpha).", "a": { "targets": [ "PML-RARA" ], "modality": "small molecule", "label": "PML-RARA degrader", "mechanism": "Arsenic trioxide causes apoptosis with DNA fragmentation and induces damage or degradation of the PML/RAR alpha fusion protein.", "quote": "Arsenic trioxide also causes damage or degradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha (PML/RAR alpha)." }, "b": { "targets": [ "PML/RARA" ], "modality": "small molecule", "label": "PML/RARA-degrading agent", "mechanism": "Its mechanism is not completely understood; arsenic trioxide induces apoptosis-associated changes and damages or degrades the PML/RARA fusion protein.", "quote": "Arsenic trioxide also causes damage or degradation of the fusion protein promyelocytic leukaemia/retinoic acid receptor-alpha (PML/RAR alpha)." }, "decision": null }, "asciminib__scemblix": { "url": "https://www.ema.europa.eu/en/documents/product-information/scemblix-epar-product-information_en.pdf", "text": "Asciminib is a potent inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1\nkinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.", "a": { "targets": [ "BCR::ABL1", "ABL1" ], "modality": "small molecule", "label": "Allosteric BCR::ABL1 kinase inhibitor", "mechanism": "Asciminib inhibits the kinase activity of BCR::ABL1 and ABL by specifically binding to the ABL myristoyl pocket.", "quote": "Asciminib is a potent inhibitor of ABL/BCR::ABL1 tyrosine kinase." }, "b": { "targets": [ "BCR::ABL1" ], "modality": "small molecule", "label": "BCR::ABL1 inhibitor", "mechanism": "Asciminib targets the ABL myristoyl pocket of the BCR::ABL1 fusion protein, inhibiting its ABL1 kinase activity.", "quote": "Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket." }, "decision": { "reason": "The text says asciminib is \"a potent inhibitor of ABL/BCR::ABL1 tyrosine kinase\" and acts \"by specifically targeting the ABL myristoyl pocket\", so it names both BCR::ABL1 and ABL1 as targets and the binding site is clear; the text is not ambiguous.", "targets": [ "BCR::ABL1", "ABL1" ], "modality": "small molecule", "label": "Allosteric BCR::ABL1 inhibitor (myristoyl pocket)", "mechanism": "Binds the ABL myristoyl pocket of the BCR::ABL1 fusion protein, inhibiting its ABL1 tyrosine kinase activity.", "quote": "Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.", "ambiguous": false } }, "atezolizumab__tecentriq": { "url": "https://www.ema.europa.eu/en/documents/product-information/tecentriq-epar-product-information_en.pdf", "text": "Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating\nimmune cells, and can contribute to the inhibition of the antitumour immune response in the tumour\nmicroenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen\npresenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.\nAtezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that\ndirectly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing\nPD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour\nimmune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the\nPD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.", "a": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Atezolizumab binds directly to PD-L1, blocking its interaction with PD-1 and B7.1 receptors to relieve immune suppression and reactivate the antitumor immune response.", "quote": "Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity." }, "b": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Binds PD-L1, blocking its interaction with PD-1 and B7.1 to release inhibition of the antitumour immune response while sparing PD-L2/PD-1 signalling.", "quote": "Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity." }, "decision": null }, "avapritinib__ayvakyt": { "url": "https://www.ema.europa.eu/en/documents/product-information/ayvakyt-epar-product-information_en.pdf", "text": "Avapritinib is a Type 1 kinase inhibitor that has demonstrated biochemical in vitro activity on the\nPDGFRA D842V and KIT D816V mutants associated with resistance to imatinib, sunitinib and\nregorafenib with half maximal inhibitory concentrations (IC50) of 0.24 nM and 0.27 nM, respectively,\nand greater potency against clinically relevant KIT exon 11, KIT exon 11/17 and KIT exon 17 mutants\nthan against the KIT wild-type enzyme.\nIn cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V\nwith IC50 of 4 nM and 30 nM, respectively. In cellular assays, avapritinib inhibited the proliferation in\nKIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukaemia cell\nline. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma\nwith KIT exon 17 mutation.", "a": { "targets": [ "PDGFRA", "KIT" ], "modality": "small molecule", "label": "PDGFRA and KIT kinase inhibitor", "mechanism": "Avapritinib is a type 1 kinase inhibitor that targets mutant PDGFRA and KIT, inhibiting receptor autophosphorylation and the proliferation of tumor cells harboring these mutations.", "quote": "Avapritinib is a Type 1 kinase inhibitor that has demonstrated biochemical in vitro activity on the PDGFRA D842V and KIT D816V mutants associated with resistance to imatinib, sunitinib and regorafenib with half maximal inhibitory concentrations (IC50) of 0.24 nM and 0.27 nM, respectively, and greater potency against clinically relevant KIT exon 11, KIT exon 11/17 and KIT exon 17 mutants than against the KIT wild-type enzyme." }, "b": { "targets": [ "PDGFRA", "KIT" ], "modality": "small molecule", "label": "Type 1 kinase inhibitor (PDGFRA, KIT)", "mechanism": "Inhibits kinase activity and autophosphorylation of mutant PDGFRA and KIT, suppressing proliferation of KIT-mutant cells.", "quote": "In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V with IC50 of 4 nM and 30 nM, respectively." }, "decision": null }, "avelumab__bavencio": { "url": "https://www.ema.europa.eu/en/documents/product-information/bavencio-epar-product-information_en.pdf", "text": "Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed\ndeath ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the\nprogrammed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 on\ncytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses. Avelumab has also\nshown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependent\ncell-mediated cytotoxicity (ADCC).\n\n19", "a": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "A human IgG1 monoclonal antibody that binds PD-L1, blocking interaction with PD-1 and B7.1 to restore anti-tumour T-cell responses and induce tumour cell lysis via ADCC.", "quote": "Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1)." }, "b": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Binds PD-L1 and blocks its interaction with PD-1 and B7.1, restoring anti-tumour T-cell responses; it also induces NK cell-mediated tumour lysis via ADCC.", "quote": "Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1)." }, "decision": null }, "axicabtagene-ciloleucel__yescarta": { "url": "https://www.ema.europa.eu/en/documents/product-information/yescarta-epar-product-information_en.pdf", "text": "Yescarta, an engineered autologous T-cell immunotherapy product, binds to CD19 expressing cancer\ncells and normal B-cells. Following anti-CD19 CAR T-cell engagement with CD19 expressing target\ncells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signalling cascades that\nlead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory\ncytokines and chemokines. This sequence of events leads to apoptosis and necrosis of CD19-\nexpressing target cells.", "a": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "Engineered autologous T cells bind CD19-expressing target cells, triggering activation, proliferation, and cytokine release, resulting in apoptosis and necrosis of target cells.", "quote": "Yescarta, an engineered autologous T-cell immunotherapy product, binds to CD19 expressing cancer cells and normal B-cells." }, "b": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "The engineered T cells bind CD19 on cancer cells and normal B cells, activating T cells and leading to target-cell apoptosis and necrosis.", "quote": "Yescarta, an engineered autologous T-cell immunotherapy product, binds to CD19 expressing cancer cells and normal B-cells." }, "decision": null }, "axitinib__inlyta": { "url": "https://www.ema.europa.eu/en/documents/product-information/inlyta-epar-product-information_en.pdf", "text": "Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor\nreceptors (VEGFR)-1, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologic\nangiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to\npotently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the\nphosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo and\nproduced tumour growth delay, regression, and inhibition of metastases in many experimental models\nof cancer.\n\n14\nEffect on QTc interval\nIn a randomised, 2-way crossover study, 35 healthy subjects were administered a single oral dose of\naxitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study\nindicated that axitinib plasma exposures up to two-fold greater than therapeutic levels expected\nfollowing a 5 mg dose, did not produce clinically-significant QT interval prolongation.", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3" ], "modality": "small molecule", "label": "VEGFR tyrosine kinase inhibitor", "mechanism": "Axitinib selectively inhibits VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinases, blocking VEGF-mediated endothelial cell proliferation and survival to inhibit pathologic angiogenesis and tumor growth.", "quote": "Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3." }, "b": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR1/2/3)", "mechanism": "Axitinib inhibits VEGFR1, VEGFR2 and VEGFR3, reducing VEGF-mediated endothelial cell proliferation and survival.", "quote": "Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3." }, "decision": null }, "belantamab-mafodotin__blenrep": { "url": "https://www.ema.europa.eu/en/documents/product-information/blenrep-epar-product-information_en.pdf", "text": "Belantamab mafodotin is a humanised IgG1 kappa monoclonal antibody conjugated with a cytotoxic\nagent, mcMMAF. Belantamab mafodotin binds to cell surface BCMA and is rapidly internalised.\nOnce inside the tumour cell, the cytotoxic agent (cys-mcMMAF) is released disrupting the\nmicrotubule network, leading to cell cycle arrest and apoptosis. The antibody also enhances\nrecruitment and activation of immune effector cells, killing tumour cells by antibody-dependent\ncellular cytotoxicity and phagocytosis. Apoptosis induced by belantamab mafodotin is accompanied\n\n16\nby markers of immunogenic cell death, which may contribute to an adaptive immune response to\ntumour cells.", "a": { "targets": [ "BCMA" ], "modality": "antibody-drug conjugate", "label": "BCMA-directed antibody-drug conjugate", "mechanism": "Binds to cell surface BCMA and internalises to release mcMMAF, disrupting microtubules to cause apoptosis, while also recruiting immune effector cells to kill tumour cells.", "quote": "Belantamab mafodotin binds to cell surface BCMA and is rapidly internalised." }, "b": { "targets": [ "BCMA" ], "modality": "antibody-drug conjugate", "label": "BCMA-directed antibody-drug conjugate", "mechanism": "Binds cell-surface BCMA and is internalised; its mcMMAF payload disrupts microtubules, while the antibody also promotes immune-mediated tumour-cell killing.", "quote": "Belantamab mafodotin binds to cell surface BCMA and is rapidly internalised." }, "decision": null }, "belzutifan__welireg": { "url": "https://www.ema.europa.eu/en/documents/product-information/welireg-epar-product-information_en.pdf", "text": "Belzutifan is an inhibitor of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α). Under\nnormal oxygen levels, HIF-2α is targeted for degradation by VHL protein. Impairment of VHL protein\nfunction results in accumulation of HIF-2α. Consequently, HIF-2α translocates into the nucleus and\nregulates expression of genes associated with cellular proliferation, angiogenesis, and tumour growth.\nBelzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function,\nbelzutifan blocks the HIF-2α-HIF-1β interaction, leading to reduced transcription and expression of\nHIF-2α target genes.", "a": { "targets": [ "HIF-2α" ], "modality": "small molecule", "label": "HIF-2α inhibitor", "mechanism": "Belzutifan binds to HIF-2α, blocking the HIF-2α-HIF-1β interaction and reducing the transcription and expression of HIF-2α target genes.", "quote": "Belzutifan is an inhibitor of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α)." }, "b": { "targets": [ "HIF2A" ], "modality": "small molecule", "label": "HIF-2α inhibitor", "mechanism": "Belzutifan binds HIF-2α and blocks its interaction with HIF-1β, reducing transcription and expression of HIF-2α target genes.", "quote": "Belzutifan is an inhibitor of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α)." }, "decision": { "reason": "The two readings differ only in symbol style, and the text clearly names the protein target as \"hypoxia-inducible factor 2 alpha (HIF-2α)\". The protein symbol HIF-2α matches the instructions' style better than the gene symbol HIF2A.", "targets": [ "HIF-2α" ], "modality": "small molecule", "label": "HIF-2α inhibitor", "mechanism": "Belzutifan binds HIF-2α and blocks its interaction with HIF-1β, reducing transcription and expression of HIF-2α target genes linked to proliferation, angiogenesis and tumour growth.", "quote": "Belzutifan is an inhibitor of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α).", "ambiguous": false } }, "bevacizumab__avastin": { "url": "https://www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf", "text": "Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis\nand angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and\nKDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF\nregresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the\nformation of new tumour vasculature, thereby inhibiting tumour growth.", "a": { "targets": [ "VEGF" ], "modality": "monoclonal antibody", "label": "Anti-VEGF monoclonal antibody", "mechanism": "Bevacizumab binds to VEGF, preventing its interaction with VEGFR-1 and VEGFR-2 to regress tumour vasculature and inhibit angiogenesis.", "quote": "Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells." }, "b": { "targets": [ "VEGF" ], "modality": "monoclonal antibody", "label": "VEGF inhibitor (antibody)", "mechanism": "Binds VEGF and prevents it from binding VEGFR-1 and VEGFR-2, inhibiting tumour angiogenesis and growth.", "quote": "Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells." }, "decision": null }, "bexarotene__targretin": { "url": "https://www.ema.europa.eu/en/documents/product-information/targretin-epar-product-information_en.pdf", "text": "Bexarotene is a synthetic compound that exerts its biological action through selective binding and\nactivation of the three RXRs: , , and . Once activated, these receptors function as transcription\nfactors that regulate processes such as cellular differentiation and proliferation, apoptosis, and insulin\nsensitisation. The ability of the RXRs to form heterodimers with various receptor partners that are\nimportant in cellular function and in physiology indicates that the biological activities of bexarotene\nare more diverse than those of compounds that activate the RARs.\nIn vitro, bexarotene inhibits the growth of tumour cell lines of haematopoietic and squamous cell\norigin. In vivo, bexarotene causes tumour regression in some animal models and prevents tumour\ninduction in others. However, the exact mechanism of action of bexarotene in the treatment of\ncutaneous T-cell lymphoma (CTCL) is unknown.\nClinical results\nBexarotene capsules were evaluated in clinical trials of 193 patients with CTCL of whom 93 had\nadvanced stage disease refractory to prior systemic therapy. Among the 61 patients treated at an initial\ndose of 300 mg/m2/day, the overall response rate, according to a global assessment by the physician,\nwas 51% (31/61) with a clinical complete response rate of 3%. Responses were also determined by a\ncomposite score of five clinical signs (surface area, erythema, plaque elevation, scaling and\nhypo/hyperpigmentation) which also considered all extracutaneous CTCL manifestations. The overall\nresponse rate according to this composite assessment was 31% (19/61) with a clinical complete\nresponse rate of 7% (4/61).", "a": { "targets": [ "RXRα", "RXRβ", "RXRγ" ], "modality": "small molecule", "label": "RXR agonist", "mechanism": "Bexarotene selectively binds and activates retinoid X receptors (RXR-α, -β, and -γ), which function as transcription factors regulating cellular differentiation, proliferation, and apoptosis.", "quote": "Bexarotene is a synthetic compound that exerts its biological action through selective binding and activation of the three RXRs: , , and ." }, "b": { "targets": [ "RXRA", "RXRB", "RXRG" ], "modality": "small molecule", "label": "Retinoid X receptor agonist", "mechanism": "Bexarotene selectively binds and activates RXRα, RXRβ and RXRγ, which then regulate processes including cellular differentiation, proliferation and apoptosis.", "quote": "Bexarotene is a synthetic compound that exerts its biological action through selective binding and activation of the three RXRs: , , and ." }, "decision": { "reason": "Both readings agree in substance; the text names \"the three RXRs\", with the Greek letters lost in extraction, so the subtypes are inferred as α, β and γ. Listing them as RXRα, RXRβ and RXRγ in protein form matches the requested style.", "targets": [ "RXRα", "RXRβ", "RXRγ" ], "modality": "small molecule", "label": "Retinoid X receptor (RXR) agonist (rexinoid)", "mechanism": "Bexarotene selectively binds and activates the three retinoid X receptors, which act as transcription factors regulating cell differentiation, proliferation and apoptosis. Its exact action in CTCL is unknown.", "quote": "Bexarotene is a synthetic compound that exerts its biological action through selective binding and activation of the three RXRs: , , and .", "ambiguous": false } }, "binimetinib__mektovi": { "url": "https://www.ema.europa.eu/en/documents/product-information/mektovi-epar-product-information_en.pdf", "text": "Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated\nextracellular signal regulated kinase 1 (MEK1) and MEK2. In cell free system, binimetinib inhibits\nMEK1 and MEK2 with the half maximal inhibitory concentration (IC50)’s in the 12-46 nM. MEK\nproteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which\npromotes cellular proliferation. In melanoma and other cancers, this pathway is often activated by\nmutated forms of BRAF which activates MEK. Binimetinib inhibits activation of MEK by BRAF and\ninhibits MEK kinase activity. Binimetinib inhibits growth of BRAF V600 mutant melanoma cell lines\nand demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.\nCombination with encorafenib\nBinimetinib and encorafenib (a BRAF inhibitor, see section 5.1 of encorafenib SmPC) both inhibit the\nMAPK pathway resulting in higher anti-tumour activity, compared to treatment with either drug\nalone.\n\n17", "a": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK inhibitor", "mechanism": "Binimetinib is an ATP-uncompetitive, reversible inhibitor of MEK1 and MEK2 kinase activity, blocking downstream ERK signaling to suppress cancer cell proliferation.", "quote": "Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2." }, "b": { "targets": [ "MEK1", "MEK2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Binimetinib reversibly inhibits MEK1 and MEK2 kinase activity, inhibiting MEK activation by BRAF and the MAPK pathway.", "quote": "Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2." }, "decision": { "reason": "Both readers agree on the target; they differ only in how it is written. The text plainly names MEK1 and MEK2 (\"inhibitor of the kinase activity of ... (MEK1) and MEK2\"), so the answer is not ambiguous, and the reading uses the MEK1/2 form from the instructions' list.", "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Binimetinib is an ATP-uncompetitive, reversible inhibitor of MEK1 and MEK2 kinase activity that blocks MEK activation by BRAF, suppressing ERK/MAPK pathway signalling and proliferation.", "quote": "Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2.", "ambiguous": false } }, "blinatumomab__blincyto": { "url": "https://www.ema.europa.eu/en/documents/product-information/blincyto-epar-product-information_en.pdf", "text": "Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on\nthe surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates\nendogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign\nand malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on\nT-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal in\nnature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomab\nmediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing\nproteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated with\ntransient upregulation of cell adhesion molecules, production of cytolytic proteins, release of\ninflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.", "a": { "targets": [ "CD19", "CD3" ], "modality": "bispecific antibody", "label": "CD19 × CD3 bispecific antibody", "mechanism": "Binds CD19 on B cells and CD3 on T cells to form a cytolytic synapse, activating endogenous T cells to induce targeted lysis of CD19-positive cells.", "quote": "Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells." }, "b": { "targets": [ "CD19", "CD3" ], "modality": "bispecific antibody", "label": "CD19 × CD3 bispecific T-cell engager", "mechanism": "Binds CD19 on B-lineage cells and CD3 on T-cells, bringing them together to activate T-cells and kill CD19+ cells.", "quote": "Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells." }, "decision": null }, "bortezomib__velcade": { "url": "https://www.ema.europa.eu/en/documents/product-information/velcade-epar-product-information_en.pdf", "text": "Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like\nactivity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex\nthat degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in\nregulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of\nthe 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within\nthe cell, ultimately resulting in cancer cell death.\nBortezomib is highly selective for the proteasome. At 10 M concentrations, bortezomib does not\ninhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more\nselective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibition\nwere evaluated in vitro, and bortezomib was shown to dissociate from the proteasome with a t½ of\n20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible.\nBortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but\nnot limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor\nkappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis.\nNF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis,\nincluding cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma,\nbortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.\nExperiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that\ncancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells.\n\n22\nBortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including\nmultiple myeloma.\nData from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast\ndifferentiation and activity and inhibits osteoclast function. These effects have been observed in\npatients with multiple myeloma affected by an advanced osteolytic disease and treated with\nbortezomib.\nClinical efficacy in previously untreated multiple myeloma\nA prospective Phase III, international, randomised (1:1), open-label clinical study (MMY-3002\nVISTA) of 682 patients was conducted to determine whether VELCADE (1.3 mg/m2 injected\nintravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in\nimprovement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone\n(60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a\nmaximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or\nunacceptable toxicity. The median age of the patients in the study was 71 years, 50% were male, 88%\nwere Caucasian and the median Karnofsky performance status score for the patients was 80. Patients\nhad IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median haemoglobin of 105 g/l, and a\nmedian platelet count of 221.5 x 109/l. Similar proportions of patients had creatinine clearance\n≤ 30 ml/min (3% in each arm).\nAt the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and\npatients in the M+P arm were offered Vc+M+P treatment. Median follow-up was 16.3 months. The\nfinal survival update was performed with a median duration of follow-up of 60.1 months. A\nstatistically significant survival benefit in favour of the Vc+M+P treatment group was observed\n(HR=0.695; p=0.00043) despite subsequent therapies including VELCADE-based regimens. Median\nsurvival for the Vc+M+P treatment group was 56.4 months compared to 43.1 for the M+P treatment\ngroup. Efficacy results are presented in Table 11:\nTable 11: Efficacy results following the final survival update to VISTA study\nEfficacy endpoint Vc+M+P\nn=344\nM+P\nn=338\nTime to progression\nEvents n (%) 101 (29) 152 (45)\nMediana (95% CI) 20.7 mo\n(17.6, 24,7)\n15.0 mo\n(14.1, 17.9)\nHazard ratiob\n(95% CI)\n0.54\n(0.42, 0.70)\np-valuec 0.000002\nProgression-free survival\nEvents n (%) 135 (39) 190 (56)\nMediana (95% CI) 18.3 mo\n(16.6, 21.7)\n14.0 mo\n(11.1, 15.0)\nHazard ratiob\n(95% CI)\n0.61\n(0.49, 0.76)\np-value c 0.00001\nOverall survival*\nEvents (deaths) n (%) 176 (51.2) 211 (62.4)\nMediana\n(95% CI)\n56.4 mo\n(52.8, 60.9)\n43.1 mo\n(35.3, 48.3)\nHazard ratiob\n(95% CI)\n0.695\n(0.567, 0.852)\np-valuec 0.00043\nResponse rate\npopulatione n=668\nn=337 n=331\nCRf n (%) 102 (30) 12 (4)\nPRf n (%) 136 (40) 103 (31)\n\n23\nnCR n (%) 5 (1) 0\nCR+PRf n (%) 238 (71) 115 (35)\np-valued < 10-10\nReduction in serum M-protein\npopulationg n=667\nn=336 n=331\n≥90% n (%) 151 (45) 34 (10)\nTime to first response in CR + PR\nMedian 1.4 mo 4.2 mo\nMediana response duration\nCRf 24.0 mo 12.8 mo\nCR+PRf 19.9 mo 13.1 mo\nTime to next therapy\nEvents n (%) 224 (65.1) 260 (76.9)\nMediana\n(95% CI)\n27.0 mo\n(24.7, 31.1)\n19.2 mo\n(17.0, 21.0)\nHazard ratiob\n(95% CI)\n0.557\n(0.462, 0.671)\np-valuec < 0.000001\na Kaplan-Meier estimate.\nb Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors:\n2-microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VMP\nc Nominal p-value based on the stratified log-rank test adjusted for stratification factors: 2-microglobulin, albumin, and\nregion\nd p-value for Response Rate (CR+PR) from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification\nfactors\ne Response population includes patients who had measurable disease at baseline\nf CR=Complete Response; PR=Partial Response. EBMT criteria\ng All randomised patients with secretory disease\n* Survival update based on a median duration of follow-up at 60.1 months\nmo: months\nCI=Confidence Interval\nPatients eligible for stem cell transplantation\nTwo randomised, open-label, multicentr", "a": { "targets": [ "26S proteasome" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Reversibly inhibits the chymotrypsin-like activity of the 26S proteasome, disrupting protein turnover and inducing cell cycle arrest and apoptosis.", "quote": "It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells." }, "b": { "targets": [ "26S proteasome" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome, preventing targeted protein degradation and leading to cell-cycle arrest and apoptosis.", "quote": "Bortezomib is a proteasome inhibitor." }, "decision": null }, "bosutinib__bosulif": { "url": "https://www.ema.europa.eu/en/documents/product-information/bosulif-epar-product-information_en.pdf", "text": "Bosutinib belongs to a pharmacological class of medicinal products known as kinase inhibitors.\nBosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modelling studies indicate that\nbosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinases\nincluding Src, Lyn and Hck. Bosutinib minimally inhibits platelet-derived growth factor (PDGF)\nreceptor and c-Kit.\nIn in vitro studies, bosutinib inhibits proliferation and survival of established CML cell lines,\nPh+ ALL cell lines, and patient-derived primary primitive CML cells. Bosutinib inhibited 16 of\n18 imatinib-resistant forms of BCR-ABL expressed in murine myeloid cell lines. Bosutinib treatment\nreduced the size of CML tumours growing in nude mice and inhibited growth of murine myeloid\ntumours expressing imatinib-resistant forms of BCR-ABL. Bosutinib also inhibits receptor tyrosine\nkinases c-Fms, EphA and B receptors, Trk family kinases, Axl family kinases, Tec family kinases,\nsome members of the ErbB family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of\nthe Ste20 family, and 2 calmodulin-dependent protein kinases.", "a": { "targets": [ "BCR-ABL", "SRC", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL and Src kinase inhibitor", "mechanism": "Bosutinib binds and inhibits the abnormal BCR-ABL kinase and Src family kinases, suppressing proliferation and survival of leukemic cells.", "quote": "Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML." }, "b": { "targets": [ "BCR-ABL", "SRC", "LYN", "HCK", "PDGFR", "KIT" ], "modality": "small molecule", "label": "BCR-ABL/Src family kinase inhibitor", "mechanism": "Bosutinib binds the BCR-ABL kinase domain and inhibits Src family kinases; it minimally inhibits PDGF receptor and c-Kit.", "quote": "Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML." }, "decision": { "reason": "The text names BCR-ABL first, then Src family kinases (\"Src, Lyn and Hck\"), and says it only \"minimally inhibits\" PDGF receptor and c-Kit, so those two are not main targets and Reading 1's target list is correct.", "targets": [ "BCR-ABL", "SRC", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL and Src family kinase inhibitor", "mechanism": "Bosutinib binds the kinase domain of the abnormal BCR-ABL kinase and also inhibits Src family kinases (Src, Lyn, Hck), suppressing proliferation and survival of CML and Ph+ ALL cells.", "quote": "Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML.", "ambiguous": false } }, "brentuximab-vedotin__adcetris": { "url": "https://www.ema.europa.eu/en/documents/product-information/adcetris-epar-product-information_en.pdf", "text": "Brentuximab vedotin is an ADC that delivers an antineoplastic agent that results in apoptotic cell\ndeath selectively in CD30-expressing tumour cells. Non-clinical data suggest that the biological\nactivity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the\ncell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomal\ncompartment. Within the cell, a single defined active species, MMAE, is released via proteolytic\ncleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell\ncycle arrest and results in apoptotic death of the CD30-expressing tumour cell.\nClassical HL, sALCL and subtypes of CTCL (including MF and pcALCL) express CD30 as an\nantigen on the surface of their malignant cells. This expression is independent of disease stage, line of\ntherapy or transplant status. These features make CD30 a target for therapeutic intervention. Because\nof the CD30-targeted mechanism of action brentuximab vedotin is able to overcome chemo-resistance\nas CD30 is consistently expressed in patients who are refractory to multi-agent chemotherapy,\nirrespective of prior transplant status. The CD30-targeted mechanism of action of brentuximab\nvedotin, the consistent expression of CD30 throughout the classical HL, sALCL and CD30+ CTCL\ndisease and therapeutic spectrums and clinical evidence in CD30-positive malignancies following\nmultiple lines of treatment provide a biologic rationale for its use in patients with relapsed and\nrefractory classical HL, sALCL with or without prior ASCT and CD30+ CTCL after at least 1 prior\nsystemic therapy.\nContributions to the mechanism of action by other antibody associated functions have not been\nexcluded.", "a": { "targets": [ "CD30" ], "modality": "antibody-drug conjugate", "label": "CD30-directed antibody-drug conjugate", "mechanism": "Binds CD30, internalises, and releases MMAE to disrupt the microtubule network via tubulin binding, leading to cell cycle arrest and apoptosis.", "quote": "Brentuximab vedotin is an ADC that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumour cells." }, "b": { "targets": [ "CD30" ], "modality": "antibody-drug conjugate", "label": "CD30-directed antibody-drug conjugate", "mechanism": "The ADC binds CD30 and is internalised; intracellular release of MMAE disrupts microtubules, causing cell-cycle arrest and apoptosis in CD30-expressing tumour cells.", "quote": "Binding of the ADC to CD30 on the cell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomal compartment." }, "decision": null }, "brexucabtagene-autoleucel__tecartus": { "url": "https://www.ema.europa.eu/en/documents/product-information/tecartus-epar-product-information_en.pdf", "text": "Tecartus, a CD19-directed genetically modified autologous T-cell immunotherapy, binds to CD19\nexpressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19\nexpressing target cells, the CD28 co-stimulatory domain and CD3-zeta signalling domain activate\ndownstream signalling cascades that lead to T-cell activation, proliferation, acquisition of effector\nfunctions and secretion of inflammatory cytokines and chemokines. This sequence of events leads to\nkilling of CD19-expressing cells.", "a": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "Binds to CD19-expressing cancer and normal B cells, activating intracellular signaling that induces T-cell proliferation, effector functions, and killing of target cells.", "quote": "Tecartus, a CD19-directed genetically modified autologous T-cell immunotherapy, binds to CD19 expressing cancer cells and normal B cells." }, "b": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "The CAR T cells bind CD19 on cancer and normal B cells, triggering T-cell activation and ultimately killing CD19-expressing cells.", "quote": "Tecartus, a CD19-directed genetically modified autologous T-cell immunotherapy, binds to CD19 expressing cancer cells and normal B cells." }, "decision": null }, "brigatinib__alunbrig": { "url": "https://www.ema.europa.eu/en/documents/product-information/alunbrig-epar-product-information_en.pdf", "text": "Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like\ngrowth factor 1 receptor (IGF-1R). Brigatinib inhibited autophosphorylation of ALK and\nALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo\nassays.\nBrigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK\nfusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC\nxenograft growth in mice. Brigatinib inhibited the in vitro and in vivo viability of cells expressing\nmutant forms of EML4-ALK associated with resistance to ALK inhibitors, including G1202R and\nL1196M.", "a": { "targets": [ "ALK", "ROS1", "IGF-1R" ], "modality": "small molecule", "label": "ALK and ROS1 tyrosine kinase inhibitor", "mechanism": "Tyrosine kinase inhibitor targeting ALK, ROS1, and IGF-1R that inhibits ALK autophosphorylation and downstream STAT3 signalling to suppress tumor cell growth.", "quote": "Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R)." }, "b": { "targets": [ "ALK", "ROS1", "IGF1R" ], "modality": "small molecule", "label": "Multikinase inhibitor (ALK, ROS1, IGF-1R)", "mechanism": "Brigatinib targets ALK, ROS1, and IGF-1R; it inhibits ALK autophosphorylation and ALK-mediated phosphorylation of STAT3.", "quote": "Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R)." }, "decision": null }, "cabozantinib__cabometyx": { "url": "https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf", "text": "Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in\ntumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastatic\nprogression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of\nkinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and\nVEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine\nkinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor\nreceptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.", "a": { "targets": [ "MET", "VEGFR", "AXL", "RET", "ROS1", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (MET, VEGFR, RET)", "mechanism": "Cabozantinib is a small-molecule multikinase inhibitor that targets MET, VEGF receptors, and other receptor tyrosine kinases to inhibit tumor growth, angiogenesis, and metastatic progression.", "quote": "Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors." }, "b": { "targets": [ "MET", "VEGFR", "AXL", "RET", "ROS1", "TYRO3" ], "modality": "small molecule", "label": "Multikinase inhibitor", "mechanism": "Inhibits MET, VEGF receptors, and other tyrosine kinases involved in tumour growth, angiogenesis, bone remodelling, drug resistance, and cancer progression.", "quote": "Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors." }, "decision": { "reason": "The text names MET and VEGF receptors first (\"identified as an inhibitor of MET ... and VEGF ... receptors\") and then lists others in the order \"AXL, RET, ROS1, TYRO3, MER, ... KIT\", so the main targets are clear; only the choice among the secondary kinases differs, and following the text's order favours AXL, RET, ROS1 and TYRO3.", "targets": [ "MET", "VEGFR", "AXL", "RET", "ROS1", "TYRO3" ], "modality": "small molecule", "label": "Multikinase inhibitor (MET, VEGFR, AXL, RET)", "mechanism": "Small-molecule inhibitor of multiple receptor tyrosine kinases, chiefly MET and VEGF receptors, plus AXL, RET, ROS1 and others, blocking tumour growth, angiogenesis and metastatic progression.", "quote": "Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors.", "ambiguous": false } }, "cabozantinib__cometriq": { "url": "https://www.ema.europa.eu/en/documents/product-information/cometriq-epar-product-information_en.pdf", "text": "Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in\ntumour growth and angiogenesis, pathologic bone remodelling, and metastatic progression of cancer.\nCabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an\ninhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor)\nreceptors. In addition, cabozantinib inhibits other tyrosine kinases including RET, the GAS6 receptor (AXL),\nthe stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3).", "a": { "targets": [ "MET", "VEGFR", "RET", "AXL", "KIT", "FLT3" ], "modality": "small molecule", "label": "Multikinase inhibitor (MET, VEGFR, RET)", "mechanism": "Small molecule that inhibits multiple receptor tyrosine kinases, primarily MET and VEGF receptors, as well as RET, AXL, KIT, and FLT3.", "quote": "Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors." }, "b": { "targets": [ "MET", "VEGFR", "RET", "AXL", "KIT", "FLT3" ], "modality": "small molecule", "label": "Multikinase inhibitor (MET, VEGFR, RET)", "mechanism": "Cabozantinib inhibits MET and VEGF receptors, as well as RET, AXL, KIT and FLT3, kinases implicated in tumour growth, angiogenesis and cancer progression.", "quote": "Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors." }, "decision": null }, "camizestrant__etcamah": { "url": "https://www.ema.europa.eu/en/documents/product-information/etcamah-epar-product-information_en.pdf", "text": "Camizestrant is an oral selective oestrogen receptor degrader (SERD) and oestrogen receptor (ER)\nantagonist.\nCamizestrant binds to the ligand binding domain of ERα, antagonising the activity of ERα encoded by\nboth wild-type ESR1 and mutated ESR1, and inducing proteasome-dependent degradation of ERα,\nwithout agonising ERα.", "a": { "targets": [ "estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Binds the ligand-binding domain of ERα, antagonising wild-type and mutated ERα activity and inducing its proteasome-dependent degradation without agonistic activity.", "quote": "Camizestrant binds to the ligand binding domain of ERα, antagonising the activity of ERα encoded by both wild-type ESR1 and mutated ESR1, and inducing proteasome-dependent degradation of ERα, without agonising ERα." }, "b": { "targets": [ "ESR1 (ERα)" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader (SERD)", "mechanism": "Camizestrant binds ERα, blocks its activity and induces its proteasome-dependent degradation without agonising it.", "quote": "Camizestrant binds to the ligand binding domain of ERα, antagonising the activity of ERα encoded by both wild-type ESR1 and mutated ESR1, and inducing proteasome-dependent degradation of ERα, without agonising ERα." }, "decision": { "reason": "Both readings agree on substance; the instructions say to name the receptor for hormonal medicines, and the text names ERα (\"binds to the ligand binding domain of ERα\"), so the target is given as ERα (estrogen receptor alpha) and the answer is not ambiguous.", "targets": [ "ERα (estrogen receptor alpha)" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader (SERD)", "mechanism": "Oral SERD that binds the ERα ligand-binding domain, antagonising wild-type and ESR1-mutant ERα and inducing its proteasome-dependent degradation without agonist activity.", "quote": "Camizestrant binds to the ligand binding domain of ERα, antagonising the activity of ERα encoded by both wild-type ESR1 and mutated ESR1, and inducing proteasome-dependent degradation of ERα, without agonising ERα.", "ambiguous": false } }, "capivasertib__truqap": { "url": "https://www.ema.europa.eu/en/documents/product-information/truqap-epar-product-information_en.pdf", "text": "Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine\nkinase AKT (AKT1, AKT2 and AKT3). AKT is a pivotal node in the phosphatidylinositol 3-kinase\n(PI3K) signalling cascade regulating multiple cellular processes including cellular survival,\nproliferation, cell cycle, metabolism, gene transcription and cell migration. AKT activation in tumours\nis a result of upstream activation from other signalling pathways, mutations of AKT1, loss of\nPhosphatase and Tensin Homolog (PTEN) function and mutations in the catalytic subunit of PI3K\n(PIK3CA).\nCapivasertib reduces growth of cell lines derived from solid tumours and haematological disease,\nincluding breast cancer cell lines with and without PIK3CA or AKT1 mutations, or PTEN alterations.\nTreatment with capivasertib and fulvestrant demonstrated anti-tumour response in a range of ER+\nhuman breast cancer PDX models representative of different breast cancer subsets. This included\nmodels with and without detectable mutations or alterations in PIK3CA, PTEN or AKT1.", "a": { "targets": [ "AKT1", "AKT2", "AKT3" ], "modality": "small molecule", "label": "Pan-AKT inhibitor", "mechanism": "Capivasertib selectively inhibits the kinase activity of all three AKT isoforms (AKT1, AKT2, AKT3), inhibiting downstream signalling involved in tumour cell survival and proliferation.", "quote": "Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3)." }, "b": { "targets": [ "AKT1", "AKT2", "AKT3" ], "modality": "small molecule", "label": "AKT inhibitor", "mechanism": "Capivasertib selectively inhibits the kinase activity of AKT1, AKT2 and AKT3.", "quote": "Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3)." }, "decision": null }, "capmatinib__tabrecta": { "url": "https://www.ema.europa.eu/en/documents/product-information/tabrecta-epar-product-information_en.pdf", "text": "Capmatinib is an inhibitor of the MET receptor tyrosine kinase. Capmatinib inhibits MET\nphosphorylation (both autophosphorylation and phosphorylation triggered by the ligand hepatocyte\ngrowth factor [HGF]), MET-mediated phosphorylation of downstream signalling proteins, as well as\nproliferation and survival of MET-dependent cancer cells.", "a": { "targets": [ "MET" ], "modality": "small molecule", "label": "MET tyrosine kinase inhibitor", "mechanism": "Capmatinib inhibits MET phosphorylation and downstream signalling, blocking the proliferation and survival of MET-dependent cancer cells.", "quote": "Capmatinib is an inhibitor of the MET receptor tyrosine kinase." }, "b": { "targets": [ "MET" ], "modality": "small molecule", "label": "MET inhibitor", "mechanism": "Capmatinib inhibits MET kinase activity and downstream signalling, reducing proliferation and survival of MET-dependent cancer cells.", "quote": "Capmatinib is an inhibitor of the MET receptor tyrosine kinase." }, "decision": null }, "carfilzomib__kyprolis": { "url": "https://www.ema.europa.eu/en/documents/product-information/kyprolis-epar-product-information_en.pdf", "text": "Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds\nto the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle\nwithin the 26S proteasome, and displays little to no activity against other protease classes. Carfilzomib\nhad antiproliferative and proapoptotic activities in preclinical models in haematologic tumours. In\nanimals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumour growth in\nmodels of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity and\nminimal reaction to non-proteasomal proteases.", "a": { "targets": [ "20S proteasome" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Selectively and irreversibly binds the active sites of the 20S proteasome, inhibiting proteasome activity and inducing proapoptotic and antiproliferative effects.", "quote": "Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, and displays little to no activity against other protease classes." }, "b": { "targets": [ "20S proteasome" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Carfilzomib selectively and irreversibly binds active sites in the 20S proteasome, inhibiting its proteolytic activity.", "quote": "Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, and displays little to no activity against other protease classes." }, "decision": null }, "catumaxomab__korjuny": { "url": "https://www.ema.europa.eu/en/documents/product-information/korjuny-epar-product-information_en.pdf", "text": "Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed\nagainst the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen.\nThe EpCAM antigen is expressed on most cancers especially carcinomas. CD3 is expressed on\nmature T-cells as a component of the T-cell receptor. A third functional binding site in the Fc-\nregion of catumaxomab enables interaction with accessory immune cells via Fc-gamma receptors.\nDue to catumaxomab’s binding properties, tumour cells, T-cells and accessory immune cells come\nin close proximity. Thereby, a concerted immunoreaction against tumour cells is induced which\nincludes different mechanisms of action such as T-cell activation, T-cell mediated killing via the\ngranzyme / perforin system, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-\ndependent cytotoxicity (CDC) and phagocytosis. This results in destruction of tumour cells in the\nperitoneal cavity, thereby eliminating a major cause of malignant ascites.", "a": { "targets": [ "EpCAM", "CD3" ], "modality": "bispecific antibody", "label": "EpCAM × CD3 bispecific trifunctional antibody", "mechanism": "It binds EpCAM on tumour cells, CD3 on T cells, and Fc-gamma receptors on accessory immune cells, bringing them together to induce T-cell activation, ADCC, CDC, and phagocytosis.", "quote": "Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen." }, "b": { "targets": [ "EpCAM", "CD3", "Fcγ receptors (FCGR)" ], "modality": "bispecific antibody", "label": "EpCAM × CD3 trifunctional antibody", "mechanism": "Binds EpCAM on tumour cells and CD3 on T cells, while its Fc region engages accessory immune cells, bringing them together to induce tumour-cell destruction.", "quote": "Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen." }, "decision": { "reason": "The text says the antibody is \"specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen\", which are its two antigen-binding arms, so only these two belong in targets; the Fc-gamma receptor engagement (\"interaction with accessory immune cells via Fc-gamma receptors\") is an effector function and goes into the mechanism, which Reading 2 gets right.", "targets": [ "EpCAM", "CD3" ], "modality": "bispecific antibody", "label": "EpCAM × CD3 bispecific trifunctional antibody", "mechanism": "Binds EpCAM on tumour cells and CD3 on T cells, and engages accessory immune cells via its Fc region, bringing them together to kill tumour cells (T-cell killing, ADCC, CDC, phagocytosis).", "quote": "Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen.", "ambiguous": false } }, "cemiplimab__libtayo": { "url": "https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_en.pdf", "text": "Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the\nprogrammed cell death-1 (PD-1) receptor and blocks its interaction with its ligands PD-L1 and\n\n18\nPD-L2. Engagement of PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen\npresenting cells and may be expressed by tumour cells and/or other cells in the tumour\nmicroenvironment, results in inhibition of T cell function such as proliferation, cytokine secretion, and\ncytotoxic activity. Cemiplimab potentiates T cell responses, including anti-tumour responses, through\nblockade of PD-1 binding to PD-L1 and PD-L2 ligands.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds to the PD-1 receptor and blocks interaction with PD-L1 and PD-L2, potentiating T-cell anti-tumour responses.", "quote": "Cemiplimab potentiates T cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds PD-1 and blocks its interaction with PD-L1 and PD-L2, potentiating T-cell responses, including anti-tumour responses.", "quote": "Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with its ligands PD-L1 and PD-L2." }, "decision": null }, "ceritinib__zykadia": { "url": "https://www.ema.europa.eu/en/documents/product-information/zykadia-epar-product-information_en.pdf", "text": "Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation\nof ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of\nALK-dependent cancer cells both in vitro and in vivo.\nALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK\nsignaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this\ngenerates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the\nN-terminal part of EML4. Ceritinib was demonstrated to be effective against EML4-ALK activity in a\nNSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of\ntumours in H2228-derived xenografts in mouse and rat.", "a": { "targets": [ "ALK" ], "modality": "small molecule", "label": "ALK inhibitor", "mechanism": "Ceritinib selectively inhibits autophosphorylation of ALK and downstream signalling, blocking proliferation of ALK-dependent cancer cells.", "quote": "Ceritinib is an orally highly selective and potent ALK inhibitor." }, "b": { "targets": [ "ALK" ], "modality": "small molecule", "label": "ALK inhibitor", "mechanism": "Ceritinib inhibits ALK autophosphorylation and downstream signalling, suppressing proliferation of ALK-dependent cancer cells.", "quote": "Ceritinib is an orally highly selective and potent ALK inhibitor." }, "decision": null }, "cetuximab__erbitux": { "url": "https://www.ema.europa.eu/en/documents/product-information/erbitux-epar-product-information_en.pdf", "text": "Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermal\ngrowth factor receptor (EGFR).\nEGFR signalling pathways are involved in the control of cell survival, cell cycle progression,\nangiogenesis, cell migration and cellular invasion/metastasis.\n\n14\nCetuximab binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of\nendogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition of\nthe function of the receptor. It further induces the internalisation of EGFR, which can lead to down-\nregulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-\nexpressing tumour cells (antibody dependent cell-mediated cytotoxicity, ADCC).\nCetuximab does not bind to other receptors belonging to the HER family.\nThe protein product of the proto-oncogene RAS (rat sarcoma) is a central down-stream signal-\ntransducer of EGFR. In tumours, activation of RAS by EGFR contributes to EGFR-mediated\nincreased proliferation, survival and the production of pro-angiogenic factors.\nRAS is one of the most frequently activated family of oncogenes in human cancers. Mutations of RAS\ngenes at certain hot-spots on exons 2, 3 and 4 result in constitutive activation of RAS proteins\nindependently of EGFR signalling.", "a": { "targets": [ "EGFR" ], "modality": "monoclonal antibody", "label": "EGFR-directed monoclonal antibody", "mechanism": "Binds EGFR to block ligand binding, induce receptor internalisation and down-regulation, and trigger antibody-dependent cell-mediated cytotoxicity (ADCC).", "quote": "Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermal growth factor receptor (EGFR)." }, "b": { "targets": [ "EGFR" ], "modality": "monoclonal antibody", "label": "EGFR inhibitor (chimeric monoclonal antibody)", "mechanism": "Cetuximab binds EGFR, blocks endogenous ligand binding, promotes receptor internalisation and can direct immune effector cells to EGFR-expressing tumour cells.", "quote": "Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermal growth factor receptor (EGFR)." }, "decision": null }, "ciltacabtagene-autoleucel__carvykti": { "url": "https://www.ema.europa.eu/en/documents/product-information/carvykti-epar-product-information_en.pdf", "text": "CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which\ninvolves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor\n(CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the\nsurface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells.\nThe CARVYKTI CAR protein features two BCMA-targeting single domain antibodies designed to\nconfer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ)\nsignaling cytoplasmic domain. Upon binding to BCMA expressing cells, the CAR promotes T cell\nactivation, expansion, and elimination of target cells.", "a": { "targets": [ "BCMA" ], "modality": "cell therapy", "label": "BCMA-directed CAR T-cell therapy", "mechanism": "Autologous T cells engineered with a CAR targeting BCMA bind BCMA-expressing cells to promote T-cell activation, expansion, and elimination of target cells.", "quote": "CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA." }, "b": { "targets": [ "BCMA" ], "modality": "cell therapy", "label": "BCMA-directed CAR T-cell therapy", "mechanism": "The engineered T cells bind BCMA on target cells, promoting T-cell activation, expansion and elimination of those cells.", "quote": "CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA." }, "decision": null }, "cobimetinib__cotellic": { "url": "https://www.ema.europa.eu/en/documents/product-information/cotellic-epar-product-information_en.pdf", "text": "Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated\nprotein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated\nkinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-\nregulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by\nthe MAPK pathway through inhibition of the MEK1/2 signalling node.\nIn the preclinical models, the combination of cobimetinib and vemurafenib showed that by\nsimultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, the\ncombination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in a\nstronger inhibition of intracellular signalling and decreased tumour cell proliferation", "a": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Cobimetinib is an allosteric inhibitor of MEK1 and MEK2 that blocks ERK phosphorylation, preventing MAPK pathway-driven cell proliferation.", "quote": "Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal- regulated kinase (ERK) 1 and ERK 2." }, "b": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Cobimetinib selectively and reversibly inhibits MEK1/2, reducing ERK1/2 phosphorylation and MAPK pathway-driven cell proliferation.", "quote": "Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and ERK 2." }, "decision": null }, "crizotinib__xalkori": { "url": "https://www.ema.europa.eu/en/documents/product-information/xalkori-epar-product-information_en.pdf", "text": "Crizotinib is a selective small-molecule inhibitor of the ALK receptor tyrosine kinase (RTK) and its\noncogenic variants (i.e. ALK fusion events and selected ALK mutations). Crizotinib is also an\ninhibitor of the Hepatocyte Growth Factor Receptor (HGFR, c-Met) RTK, ROS1 (c-ros) and\nRecepteur d’Origine Nantais (RON) RTK. Crizotinib demonstrated concentration-dependent\ninhibition of the kinase activity of ALK, ROS1, and c-Met in biochemical assays and inhibited\nphosphorylation and modulated kinase-dependent phenotypes in cell-based assays. Crizotinib\ndemonstrated potent and selective growth inhibitory activity and induced apoptosis in tumour cell\nlines exhibiting ALK fusion events (including echinoderm microtubule-associated protein-like 4\n[EML4]-ALK and nucleophosmin [NPM]-ALK), ROS1 fusion events, or exhibiting amplification of\nthe ALK or MET gene locus. Crizotinib demonstrated antitumour efficacy, including marked\ncytoreductive antitumour activity, in mice bearing tumour xenografts that expressed ALK fusion\nproteins. The antitumour efficacy of crizotinib was dose-dependent and correlated to\npharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and\nNPM-ALK) in tumours in vivo. Crizotinib also demonstrated marked antitumour activity in mouse\nxenograft studies, where tumours were generated using a panel of NIH-3T3 cell lines engineered to\nexpress key ROS1 fusions identified in human tumours. The antitumour efficacy of crizotinib was\ndose-dependent and demonstrated a correlation with inhibition of ROS1 phosphorylation in vivo. In\nvitro studies in 2 ALCL-derived cell lines (SU-DHL-1 and Karpas-299, both containing NPM-ALK)\nshowed that crizotinib was able to induce apoptosis, and in Karpas-299 cells, crizotinib inhibited\nproliferation and ALK-mediated signaling at clinically achievable doses. In vivo data obtained in a\nKarpas-299 model showed complete regression of the tumour at a dose of 100 mg/kg once daily.\nClinical studies\nPreviously untreated ALK-positive advanced NSCLC – randomised Phase 3 Study 1014\nThe efficacy and safety of crizotinib for the treatment of patients with ALK-positive metastatic\nNSCLC, who had not received previous systemic treatment for advanced disease, were demonstrated\nin a global, randomised, open-label Study 1014.\nThe full analysis population included 343 patients with ALK-positive advanced NSCLC as identified\nby Fluorescence In Situ Hybridisation (FISH) prior to randomisation: 172 patients were randomised to\ncrizotinib and 171 patients were randomised to chemotherapy (pemetrexed + carboplatin or cisplatin;\nup to 6 cycles of treatment). The demographic and disease characteristics of the overall study\npopulation were 62% female, median age of 53 years, baseline Eastern Cooperative Oncology Group\n(ECOG) performance status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past\nsmokers and 64% never smokers. The disease characteristics of the overall study population were\nmetastatic disease in 98% of patients, 92% of patients’ tumours were classified as adenocarcinoma\nhistology and 27% of patients had brain metastases.\nPatients could continue crizotinib treatment beyond the time of Response Evaluation Criteria in Solid\nTumours (RECIST)-defined disease progression at the discretion of the investigator if the patient was\nstill experiencing clinical benefit. Sixty-five of 89 (73%) patients treated with crizotinib and 11 of\n132 (8.3%) patients treated with chemotherapy continued treatment for at least 3 weeks after objective\ndisease progression. Patients randomised to chemotherapy could cross over to receive crizotinib upon\nRECIST-defined disease progression confirmed by independent radiology review (IRR).\nOne hundred forty-four (84%) patients in the chemotherapy arm received subsequent crizotinib\ntreatment.\nCrizotinib significantly prolonged progression-free survival (PFS), the primary objective of the study,\ncompared to chemotherapy as assessed by IRR. The PFS benefit of crizotinib was consistent across\nsubgroups of baseline patient characteristics such as age, gender, race, smoking class, time since\ndiagnosis, ECOG performance status and presence of brain metastases. There was a numerical\nimprovement in overall survival (OS) in the patients treated with crizotinib, although this\nimprovement was not statistically significant. Efficacy data from randomised Phase 3 Study 1014 are\n\n27\nsummarised in Table 11, and the Kaplan-Meier curves for PFS and OS are shown in Figure 1 and 2,\nrespectively.\nTable 11. Efficacy results from randomised Phase 3 Study 1014 (full analysis population) in\npatients with previously untreated ALK-positive advanced NSCLC*\nResponse parameter Crizotinib\nN=172\nChemotherapy\nN=171\nProgression-free survival (based on IRR)\nNumber with event, n (%) 100 (58%) 137 (80%)\nMedian PFS in months (95% CI) 10.9 (8.3, 13.9) 7.0a (6.8, 8.2)\nHR (95% CI)b 0.45 (0.35, 0.60)\np-valuec <0.0001\nOverall survivald\nNumber of deaths, n (%) 71 (41%) 81 (47%)\nMedian OS in months (95% CI) NR (45.8, NR) 47.5 (32.2, NR)\nHR (95% CI)b 0.76 (0.55, 1.05)\np-valuec 0.0489\n12-Month survival probability,d % (95% CI) 83.5 (77.0, 88.3) 78.4 (71.3, 83.9)\n18-Month survival probability,d % (95% CI) 71.5 (64.0, 77.7) 66.6 (58.8, 73.2)\n48-Month survival probability,d % (95% CI) 56.6 (48.3, 64.1) 49.1 (40.5, 57.1)\nObjective response rate (based on IRR)\nObjective response rate % (95% CI) 74% (67, 81) 45%e (37, 53)\np-valuef <0.0001\nDuration of response\nMonthsg (95% CI) 11.3 (8.1, 13.8) 5.3 (4.1, 5.8)\nAbbreviations: CI=confidence interval; HR=hazard ratio; IRR=independent radiology review; N/n=number\nof patients; NR=not reached; PFS=progression-free survival; ORR=objective response rate; OS=overall\nsurvival.\n* PFS, Objective Response Rate and Duration of Response are based on the data cutoff date of\n30 November 2013; OS is based on the last patient last visit date of 30 November 2016, and is based on\na median follow up of approximately 46 months.\na. Median", "a": { "targets": [ "ALK", "ROS1", "MET", "RON" ], "modality": "small molecule", "label": "ALK, ROS1, and MET inhibitor", "mechanism": "Inhibits ALK, ROS1, c-Met, and RON receptor tyrosine kinases, blocking oncogenic phosphorylation and downstream signaling to suppress tumour cell growth and induce apoptosis.", "quote": "Crizotinib is a selective small-molecule inhibitor of the ALK receptor tyrosine kinase (RTK) and its oncogenic variants (i.e. ALK fusion events and selected ALK mutations)." }, "b": { "targets": [ "ALK", "MET", "ROS1", "MST1R" ], "modality": "small molecule", "label": "Multikinase inhibitor (ALK, MET, ROS1)", "mechanism": "Inhibits ALK and its oncogenic variants, as well as MET, ROS1 and RON receptor tyrosine kinase activity.", "quote": "Crizotinib is also an inhibitor of the Hepatocyte Growth Factor Receptor (HGFR, c-Met) RTK, ROS1 (c-ros) and Recepteur d’Origine Nantais (RON) RTK." }, "decision": { "reason": "The two readings differ only in how they order and name the targets and in the label wording. The text puts ALK first (\"selective small-molecule inhibitor of the ALK receptor tyrosine kinase\"), then names c-Met, ROS1 and RON, and shows activity mainly against ALK and ROS1, so ALK, ROS1, MET, RON is the best order.", "targets": [ "ALK", "ROS1", "MET", "RON" ], "modality": "small molecule", "label": "ALK/ROS1/MET tyrosine kinase inhibitor", "mechanism": "Small-molecule inhibitor of the ALK tyrosine kinase and its oncogenic fusions/mutations, and of ROS1, c-Met and RON kinases, blocking their phosphorylation to inhibit tumour growth and induce apoptosis.", "quote": "Crizotinib is a selective small-molecule inhibitor of the ALK receptor tyrosine kinase (RTK) and its oncogenic variants (i.e. ALK fusion events and selected ALK mutations).", "ambiguous": false } }, "dabrafenib__finlee": { "url": "https://www.ema.europa.eu/en/documents/product-information/finlee-epar-product-information_en.pdf", "text": "Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive\nactivation of the RAS/RAF/MEK/ERK pathway. The most commonly observed BRAF mutation is\nV600E, which has been identified in 19% of paediatric LGG and approximately 5% of paediatric\nHGG.\nCombination with trametinib\nTrametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular\nsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are\ncomponents of the extracellular signal-related kinase (ERK) pathway. In human cancers, this pathway\nis often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of\nMEK by BRAF and inhibits MEK kinase activity.\nThus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the\ncombination provides concomitant inhibition of the pathway. The combination of dabrafenib with\ntrametinib has shown anti-tumour activity in BRAF V600 mutation-positive cancer cell lines in vitro\nand delays the emergence of resistance in vivo in BRAF V600 mutation-positive xenografts.", "a": { "targets": [ "BRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Dabrafenib is an inhibitor of RAF kinases that targets constitutively activated RAS/RAF/MEK/ERK signaling caused by oncogenic BRAF mutations.", "quote": "Dabrafenib is an inhibitor of RAF kinases." }, "b": { "targets": [ "RAF kinases" ], "modality": "small molecule", "label": "RAF kinase inhibitor", "mechanism": "Dabrafenib inhibits RAF kinases, which are part of the RAS/RAF/MEK/ERK pathway.", "quote": "Dabrafenib is an inhibitor of RAF kinases." }, "decision": { "reason": "The text says \"Dabrafenib is an inhibitor of RAF kinases\" and links this to \"Oncogenic mutations in BRAF\", so BRAF (the mutant V600 form) is the target in standard symbols; trametinib is a separate combination partner, not this medicine.", "targets": [ "BRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Dabrafenib inhibits RAF kinases, including mutant BRAF V600, blocking constitutive RAS/RAF/MEK/ERK signalling; it is used with the MEK inhibitor trametinib for dual pathway blockade.", "quote": "Dabrafenib is an inhibitor of RAF kinases.", "ambiguous": false } }, "dabrafenib__tafinlar": { "url": "https://www.ema.europa.eu/en/documents/product-information/tafinlar-epar-product-information_en.pdf", "text": "Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive\nactivation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high\nfrequency in specific cancers, including approximately 50% of melanoma. The most commonly\nobserved BRAF mutation is V600E which accounts for approximately 90% of the BRAF mutations\nthat are seen in melanoma.\nPreclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinases\nwith activating codon 600 mutations (Table 5).\nTable 5 Kinase inhibitory activity of dabrafenib against RAF kinases\nKinase Inhibitory concentration 50 (nM)\nBRAF V600E 0.65\nBRAF V600K 0.50\nBRAF V600D 1.8\nBRAF WT 3.2\nCRAF WT 5.0\nDabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated\nERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animal\nmodels.\nIn subjects with BRAF V600 mutation-positive melanoma, administration of dabrafenib resulted in\ninhibition of tumour phosphorylated ERK relative to baseline.\nCombination with trametinib\nTrametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular\nsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are\ncomponents of the extracellular signal-related kinase (ERK) pathway.\nThus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the\ncombination provides concomitant inhibition of the pathway. The combination of dabrafenib with\ntrametinib has shown anti-tumour activity in BRAF V600 mutation-positive melanoma cell lines in\nvitro and delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanoma\nxenografts.\n\n22\nDetermination of BRAF mutation status\nBefore taking dabrafenib or combination with trametinib, patients must have BRAF V600 mutation-\npositive tumour status confirmed by a validated test. In the Phase II and III clinical studies in\nmelanoma, screening for eligibility required central testing for BRAF V600 mutation using a BRAF\nmutation assay conducted on the most recent tumour sample available. Primary tumour or tumour\nfrom a metastatic site was tested with an investigational use only assay (IUO). The IUO is an allele-\nspecific polymerase chain reaction (PCR) assay performed on DNA extracted from formalin-fixed\nparaffin-embedded (FFPE) tumour tissue. The assay was specifically designed to differentiate between\nthe V600E and V600K mutations. Only subjects with BRAF V600E or V600K mutation-positive\ntumours were eligible for study participation.\nSubsequently, all patient samples were re-tested using the bioMerieux (bMx) THxID BRAF validated\nassay, which has CE marking. The bMx THxID BRAF assay is an allele-specific PCR performed on\nDNA extracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and\nV600K mutations with high sensitivity (down to 5% V600E and V600K sequence in a background of\nwild-type sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with\nretrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less\ncommon BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the\nspecimens from the non-clinical and clinical studies (n=876) that were mutation-positive by the\nTHxID BRAF assay and subsequently were sequenced using the reference method, the specificity of\nthe assay was 94%.", "a": { "targets": [ "BRAF", "CRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Dabrafenib inhibits BRAF kinases, particularly those with activating V600 mutations, suppressing downstream ERK phosphorylation and inhibiting tumour cell growth.", "quote": "Dabrafenib is an inhibitor of RAF kinases." }, "b": { "targets": [ "BRAF", "RAF1" ], "modality": "small molecule", "label": "BRAF inhibitor (RAF kinase inhibitor)", "mechanism": "Dabrafenib inhibits RAF kinases, including mutant BRAF, suppressing signalling through the RAS/RAF/MEK/ERK pathway.", "quote": "Dabrafenib is an inhibitor of RAF kinases." }, "decision": { "reason": "The text plainly states \"Dabrafenib is an inhibitor of RAF kinases\" and shows potent inhibition of BRAF V600 mutants, with CRAF also listed, so the readers differ only in the CRAF symbol (RAF1 vs CRAF) and label wording, not in the target itself.", "targets": [ "BRAF", "CRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Dabrafenib inhibits RAF kinases, particularly BRAF with activating V600 mutations, suppressing ERK phosphorylation in the RAS/RAF/MEK/ERK pathway and inhibiting tumour cell growth.", "quote": "Dabrafenib is an inhibitor of RAF kinases.", "ambiguous": false } }, "dacomitinib__vizimpro": { "url": "https://www.ema.europa.eu/en/documents/product-information/vizimpro-epar-product-information_en.pdf", "text": "Dacomitinib is a pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and\nHER4) inhibitor, with activity against mutated EGFR with deletions in exon 19 or the L858R\nsubstitution in exon 21. Dacomitinib binds selectively and irreversibly to its HER family targets\nthereby providing prolonged inhibition.", "a": { "targets": [ "EGFR", "HER2", "HER4" ], "modality": "small molecule", "label": "Pan-HER kinase inhibitor", "mechanism": "Dacomitinib selectively and irreversibly binds to HER family receptors (EGFR/HER1, HER2, and HER4) to provide prolonged inhibition, including against mutated EGFR.", "quote": "Dacomitinib is a pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and HER4) inhibitor, with activity against mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21." }, "b": { "targets": [ "EGFR", "HER2", "HER4" ], "modality": "small molecule", "label": "Pan-HER inhibitor", "mechanism": "Dacomitinib binds selectively and irreversibly to EGFR, HER2, and HER4, providing prolonged inhibition; it is active against EGFR exon 19 deletions and the L858R exon 21 substitution.", "quote": "Dacomitinib is a pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and HER4) inhibitor, with activity against mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21." }, "decision": null }, "daratumumab__darzalex": { "url": "https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf", "text": "Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein\nexpressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types\nand tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion,\nsignalling and enzymatic activity.\nDaratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.\nBased on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune\nmediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis\nthrough complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and\nantibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid\nderived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs)\nare decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known\nto express CD38 depending on the stage of development and the level of activation. Significant\nincreases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed\nwith daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor\nDNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating\nimmune modulatory effects that may contribute to clinical response.\nDaratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab\nmodulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the\nhydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications\non tumour growth, are not well-understood.", "a": { "targets": [ "CD38" ], "modality": "monoclonal antibody", "label": "Anti-CD38 monoclonal antibody", "mechanism": "Binds to CD38 on tumour cells, inducing cell lysis via complement-dependent cytotoxicity, ADCC, ADCP, and apoptosis, while depleting immunosuppressive cells.", "quote": "Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels." }, "b": { "targets": [ "CD38" ], "modality": "monoclonal antibody", "label": "CD38-directed monoclonal antibody", "mechanism": "Daratumumab binds CD38 and can promote immune-mediated tumour cell death through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and phagocytosis.", "quote": "Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels." }, "decision": null }, "darolutamide__nubeqa": { "url": "https://www.ema.europa.eu/en/documents/product-information/nubeqa-epar-product-information_en.pdf", "text": "Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole\nstructure that binds with high affinity directly to the receptor ligand binding domain.\nDarolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR mediated\ntranscription. A major metabolite, keto-darolutamide, exhibited similar in vitro activity to\ndarolutamide. Darolutamide treatment decreases prostate tumour cell proliferation leading to potent\nantitumour activity.", "a": { "targets": [ "androgen receptor" ], "modality": "small molecule", "label": "Androgen receptor inhibitor", "mechanism": "Competitively inhibits androgen binding to the androgen receptor, blocking AR nuclear translocation and AR-mediated transcription to decrease prostate tumour cell proliferation.", "quote": "Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole structure that binds with high affinity directly to the receptor ligand binding domain." }, "b": { "targets": [ "AR" ], "modality": "small molecule", "label": "Androgen receptor inhibitor", "mechanism": "Darolutamide binds the androgen receptor and competitively inhibits androgen binding, AR nuclear translocation and AR-mediated transcription.", "quote": "Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole structure that binds with high affinity directly to the receptor ligand binding domain." }, "decision": { "reason": "Both readings agree on substance and differ only in naming the target 'AR' versus 'androgen receptor'; the instructions say to name hormonal targets as the receptor, and the text plainly states 'Darolutamide is an androgen receptor (AR) inhibitor', so this is not ambiguous.", "targets": [ "androgen receptor" ], "modality": "small molecule", "label": "Androgen receptor inhibitor", "mechanism": "Binds the androgen receptor ligand-binding domain, competitively inhibiting androgen binding, AR nuclear translocation and AR-mediated transcription, decreasing prostate tumour cell proliferation.", "quote": "Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole structure that binds with high affinity directly to the receptor ligand binding domain.", "ambiguous": false } }, "dasatinib-anhydrous-__sprycel": { "url": "https://www.ema.europa.eu/en/documents/product-information/sprycel-epar-product-information_en.pdf", "text": "In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and\nresistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistance\nresulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate\nsignalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene\noverexpression. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations.\nIn vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of\nchronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines\ngrown at various sites, including the central nervous system.", "a": { "targets": [ "BCR-ABL", "SRC", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL and SRC kinase inhibitor", "mechanism": "Dasatinib inhibits BCR-ABL and SRC family kinases at subnanomolar concentrations, overcoming imatinib resistance and inhibiting leukaemic disease progression.", "quote": "Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations." }, "b": { "targets": [ "BCR-ABL", "SRC", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL/SRC family kinase inhibitor", "mechanism": "Dasatinib is active against leukaemic cells with BCR-ABL-related imatinib resistance and inhibits SRC family kinases, including LYN and HCK.", "quote": "These non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression." }, "decision": null }, "dasatinib__dasatinib-accord-healthcare": { "url": "https://www.ema.europa.eu/en/documents/product-information/dasatinib-accord-healthcare-epar-product-information_en.pdf", "text": "In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and\nresistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistance\nresulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate\nsignalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene\noverexpression. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations.\nIn vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of\nchronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines\ngrown at various sites, including the central nervous system.", "a": { "targets": [ "BCR-ABL", "SRC", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL and SRC kinase inhibitor", "mechanism": "Dasatinib inhibits BCR-ABL and SRC family kinases at subnanomolar concentrations, overcoming imatinib resistance mechanisms in leukaemic cells.", "quote": "Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations." }, "b": { "targets": [ "BCR-ABL", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL/SRC kinase inhibitor", "mechanism": "Dasatinib inhibits BCR-ABL and SRC-family kinases, including LYN and HCK, and can overcome some mechanisms of imatinib resistance.", "quote": "These non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression." }, "decision": { "reason": "The text names BCR-ABL and the SRC family kinases (LYN, HCK), and states that \"dasatinib inhibits SRC family kinases at subnanomolar concentrations\"; Reading 1 wrongly applied that subnanomolar potency to BCR-ABL too, so the answer itself is clear.", "targets": [ "BCR-ABL", "SRC family kinases", "LYN", "HCK" ], "modality": "small molecule", "label": "BCR-ABL/SRC kinase inhibitor", "mechanism": "Dasatinib inhibits SRC family kinases (incl. LYN, HCK) at subnanomolar levels and acts against BCR-ABL-driven leukaemic cells, overcoming several mechanisms of imatinib resistance.", "quote": "These non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression.", "ambiguous": false } }, "datopotamab-deruxtecan__datroway": { "url": "https://www.ema.europa.eu/en/documents/product-information/datroway-epar-product-information_en.pdf", "text": "Datopotamab deruxtecan is a TROP2-directed antibody-drug conjugate. The antibody is a humanised\nanti-TROP2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by a\ntetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The antibody\nbinds to TROP2 expressed on the surface of certain tumour cells. After binding, datopotamab\nderuxtecan undergoes internalisation into the tumour cells. Subsequently, the release of DXd results in\nDNA damage and apoptotic cell death via topoisomerase I inhibition. Datopotamab deruxtecan may\nalso exhibit indirect cytotoxicity as shown in vitro through mechanisms of antibody-dependent cellular\ncytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and bystander cytotoxicity of\nDXd against tumour cells.", "a": { "targets": [ "TROP2" ], "modality": "antibody-drug conjugate", "label": "TROP2-directed antibody-drug conjugate", "mechanism": "Binds to TROP2 on tumor cells and internalises, releasing a topoisomerase I inhibitor payload that induces DNA damage and apoptotic cell death.", "quote": "Datopotamab deruxtecan is a TROP2-directed antibody-drug conjugate." }, "b": { "targets": [ "TROP2" ], "modality": "antibody-drug conjugate", "label": "TROP2-directed antibody-drug conjugate", "mechanism": "The antibody binds TROP2 on tumour cells and is internalised; released DXd inhibits topoisomerase I, causing DNA damage and apoptotic cell death.", "quote": "The antibody binds to TROP2 expressed on the surface of certain tumour cells." }, "decision": null }, "degarelix__firmagon": { "url": "https://www.ema.europa.eu/en/documents/product-information/firmagon-epar-product-information_en.pdf", "text": "Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and\nreversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins,\nluteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of\ntestosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to\ntreatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a\nLH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the\ninitiation of treatment.\nA single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a\ndecrease in the concentrations of LH, FSH and subsequently testosterone. The serum concentration of\ndihydrotestosterone (DHT) decreases in a similar manner to testosterone.\nDegarelix is effective in achieving and maintaining testosterone suppression well below medical castration\nlevel of 0.5 ng/ml. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in\n97% of patients for at least one year. No testosterone microsurges were observed after re-injection during\ndegarelix treatment. Median testosterone levels after one year of treatment were 0.087 ng/ml (interquartile\nrange 0.06-0.15) N=167.\nResults of the confirmatory Phase III study\nThe efficacy and safety of degarelix was evaluated in an open-label, multi-centre, randomised, active\ncomparator controlled, parallel-group study. The study investigated the efficacy and safety of two different\ndegarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses\nsubcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly\n\n8\nintramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen\ndeprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504\n(81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) patients\ndiscontinued the study, as compared to 32 (16%) patients in the leuprorelin group.\nOf the 610 patients treated\n• 31% had localised prostate cancer\n• 29% had locally advanced prostate cancer\n• 20% had metastatic prostate cancer\n• 7% had an unknown metastatic status\n• 13% had previous curative intent surgery or radiation and a rising PSA\nBaseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years).\nThe primary objective was to demonstrate that degarelix is effective with respect to achieving and\nmaintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment.\nThe lowest effective maintenance dose of 80 mg degarelix was chosen.\nAttainment of serum testosterone (T) ≤0.5 ng/ml\nFIRMAGON is effective in achieving fast testosterone suppression, see Table 2.\nTable 2: Percentage of patients attaining T≤0.5 ng/ml after start of treatment.\nTime Degarelix 240/80 mg Leuprorelin 7.5 mg\nDay 1 52% 0%\nDay 3 96% 0%\nDay 7 99% 1%\nDay 14 100% 18%\nDay 28 100% 100%\nAvoidance of testosterone surge\nSurge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks.\nNone of the degarelix-treated patients experienced a testosterone surge; there was an average decrease of\n94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; there\nwas an average increase of 65% in testosterone at day 3. This difference was statistically significant\n(p<0.001).\nFigure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with\ninterquartile ranges).\n\n9\nThe primary end-point in the study was testosterone suppression rates after one year of treatment with\ndegarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti-androgen in the\ninitial phase of treatment has not been demonstrated.\nTestosterone Reversibility\nIn a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy and\nradiation) were administered FIRMAGON for seven months followed by a seven months monitoring period.\nThe median time to testosterone recovery (>0.5 ng/mL, above castrate level) after discontinuation of\ntreatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The median\ntime to testosterone >1.5 ng/mL (above lower limit of normal range) was 168 days.\nLong-term effect\nSuccessful response in the study was defined as attainment of medical castration at day 28 and maintenance\nthrough day 364 where no single testosterone concentration was greater than 0.5 ng/ml.\nTable 3: Cumulative probability of testosterone ≤0.5 ng/ml from Day 28 to Day 364.\nDegarelix 240/80 mg\nN=207\nLeuprorelin 7.5 mg\nN=201\nNo. of responders 202 194\nResponse Rate\n(confidence intervals)*\n97.2%\n(93.5; 98.8%)\n96.4%\n(92.5; 98.2%)\n* Kaplan Meier estimates within group\nAttainment of prostate specific antigen (PSA) reduction\nTumour size was not measured directly during the clinical trial programme, but there was an indirect\nbeneficial tumour response as shown by a 95% reduction after 12 months in median PSA for degarelix.\n\n10\nThe median PSA in the study at baseline was:\n• for the degarelix 240/80 mg treatment group 19.8 ng/ml (interquartile range: P25 9.4 ng/ml, P75\n46.4 ng/ml)\n• for the leuprorelin 7.5 mg treatment group 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P75\n56.5 ng/ml)\nFigure 2: Percentage change in PSA from baseline by treatment group until day 56 (median with interquartile\nranges).\nThis difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.\nProstate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85%\nafter one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one\nyear of treatment.\nFro", "a": { "targets": [ "GnRH receptor" ], "modality": "protein or peptide", "label": "GnRH receptor antagonist", "mechanism": "Competitively and reversibly binds pituitary GnRH receptors, rapidly decreasing LH and FSH release to suppress testicular testosterone secretion.", "quote": "Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes." }, "b": { "targets": [ "GnRH receptor (GNRHR)" ], "modality": "protein or peptide", "label": "GnRH receptor antagonist (peptide)", "mechanism": "Competitively and reversibly binds pituitary GnRH receptors, reducing LH and FSH release and consequently testosterone secretion by the testes.", "quote": "Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes." }, "decision": { "reason": "Both readings agree on substance; the text plainly states degarelix \"competitively and reversibly binds to the pituitary GnRH receptors\", so the target is unambiguous, and Reading 1's plain \"GnRH receptor\" matches the instructions' format for hormonal medicines.", "targets": [ "GnRH receptor" ], "modality": "protein or peptide", "label": "GnRH receptor antagonist", "mechanism": "Competitively and reversibly binds pituitary GnRH receptors, rapidly reducing LH and FSH release and thereby testicular testosterone secretion, without an initial testosterone surge.", "quote": "Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes.", "ambiguous": false } }, "dinutuximab-beta__qarziba-previously-dinutuximab-beta-eusa-and-dinutuximab-beta-apeiron-": { "url": "https://www.ema.europa.eu/en/documents/product-information/qarziba-epar-product-information_en.pdf", "text": "Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the\ncarbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells.", "a": { "targets": [ "GD2" ], "modality": "monoclonal antibody", "label": "Anti-GD2 monoclonal antibody", "mechanism": "Dinutuximab beta is a chimeric monoclonal IgG1 antibody specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2) overexpressed on neuroblastoma cells.", "quote": "Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells." }, "b": { "targets": [ "GD2" ], "modality": "monoclonal antibody", "label": "GD2-directed monoclonal antibody", "mechanism": "Dinutuximab beta binds the carbohydrate moiety of GD2, which is overexpressed on neuroblastoma cells.", "quote": "Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells." }, "decision": null }, "dostarlimab__jemperli": { "url": "https://www.ema.europa.eu/en/documents/product-information/jemperli-epar-product-information_en.pdf", "text": "Dostarlimab is a humanised mAb of the IgG4 isotype that binds to PD-1 receptors and blocks the\ninteractions of binding with its ligands PD-L1 and PD-L2. The inhibition of PD-1 pathway-mediated\nimmune response results in reactivation of T-cell function such as proliferation, cytokine production, and\ncytotoxic activity. Dostarlimab potentiates T-cell responses, including anti-tumour immuno responses\nthrough blockade of PD-1 binding to PD-L1 and PD-L2. In syngeneic mouse tumour models, blocking\nPD-1 activity resulted in decreased tumour growth.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Dostarlimab binds to PD-1 receptors and blocks interaction with PD-L1 and PD-L2, reactivating and potentiating anti-tumour T-cell responses.", "quote": "Dostarlimab is a humanised mAb of the IgG4 isotype that binds to PD-1 receptors and blocks the interactions of binding with its ligands PD-L1 and PD-L2." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds PD-1 and blocks its interactions with PD-L1 and PD-L2, reactivating T-cell function and potentiating anti-tumour immune responses.", "quote": "Dostarlimab is a humanised mAb of the IgG4 isotype that binds to PD-1 receptors and blocks the interactions of binding with its ligands PD-L1 and PD-L2." }, "decision": null }, "durvalumab__imfinzi": { "url": "https://www.ema.europa.eu/en/documents/product-information/imfinzi-epar-product-information_en.pdf", "text": "Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response that\nhelps tumours evade detection and elimination by the immune system. PD-L1 can be induced by\ninflammatory signals (e.g., IFN-gamma) and can be expressed on both tumour cells and\n\n31\ntumour-associated immune cells in tumour microenvironment. PD-L1 blocks T-cell function and\nactivation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces\ncytotoxic T-cell activity, proliferation and cytokine production.\nDurvalumab is a fully human, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that\nselectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Durvalumab does not induce\nantibody dependent cell-mediated cytotoxicity (ADCC). Selective blockade of PD-L1/PD-1 and\nPD-L1/CD80 interactions enhances antitumour immune responses and increases T-cell activation.\nThe combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor functions\nto enhance anti-tumour T-cell activation and function at multiple stages of the immune response\nresulting in improved anti-tumour responses. In murine syngeneic tumour models, dual blockade of\nPD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.", "a": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Durvalumab selectively blocks PD-L1 interaction with PD-1 and CD80, releasing inhibition of T-cell activation and enhancing antitumour immune responses.", "quote": "Durvalumab is a fully human, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1)." }, "b": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Durvalumab binds PD-L1 and blocks its interactions with PD-1 and CD80, enhancing antitumour immune responses and T-cell activation.", "quote": "Durvalumab is a fully human, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1)." }, "decision": null }, "elacestrant__orserdu": { "url": "https://www.ema.europa.eu/en/documents/product-information/orserdu-epar-product-information_en.pdf", "text": "Elacestrant, a tetrahydronaphthalene compound, is a potent, selective and orally active estrogen\nreceptor-α (ERα) antagonist and degrader.\n\n10", "a": { "targets": [ "estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Elacestrant is an orally active antagonist and degrader of estrogen receptor-α (ERα).", "quote": "Elacestrant, a tetrahydronaphthalene compound, is a potent, selective and orally active estrogen receptor-α (ERα) antagonist and degrader." }, "b": { "targets": [ "ESR1" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Elacestrant antagonizes and degrades estrogen receptor-α (ERα).", "quote": "Elacestrant, a tetrahydronaphthalene compound, is a potent, selective and orally active estrogen receptor-α (ERα) antagonist and degrader." }, "decision": { "reason": "The text names one target, \"estrogen receptor-α (ERα)\"; the readers differ only in naming it as \"ESR1\" versus \"estrogen receptor\", so it is listed here as ERα, the form the text uses.", "targets": [ "ERα" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Elacestrant is an oral, selective antagonist and degrader of estrogen receptor-α (ERα).", "quote": "Elacestrant, a tetrahydronaphthalene compound, is a potent, selective and orally active estrogen receptor-α (ERα) antagonist and degrader.", "ambiguous": false } }, "elotuzumab__empliciti": { "url": "https://www.ema.europa.eu/en/documents/product-information/empliciti-epar-product-information_en.pdf", "text": "Elotuzumab is an immunostimulatory humanised, IgG1 monoclonal antibody that specifically targets\nthe signaling lymphocyte activation molecule family member 7 (SLAMF7) protein. SLAMF7 is\nhighly expressed on multiple myeloma cells independent of cytogenetic abnormalities. SLAMF7 is\nalso expressed on natural killer cells (NK), normal plasma cells, and other immune cells including\nsome T cell subsets, monocytes, B cells, macrophages, and pDCs (plasmacytoid dendritic cells), but is\nnot detected on normal solid tissues or haematopoietic stem cells.\nElotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors\nenhancing anti-myeloma activity in vitro. Elotuzumab also targets SLAMF7 on myeloma cells and\nthrough interactions with Fc receptors on specific immune cells, promotes the killing of myeloma cells\nthrough NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and\nmacrophage-mediated antibody-dependant cellular phagocytosis (ADCP). In nonclinical models,\nelotuzumab has demonstrated synergistic activity when combined with lenalidomide, pomalidomide or\nbortezomib.", "a": { "targets": [ "SLAMF7" ], "modality": "monoclonal antibody", "label": "SLAMF7-directed monoclonal antibody", "mechanism": "It targets SLAMF7, directly activating natural killer cells and facilitating myeloma cell killing through antibody-dependent cellular cytotoxicity and phagocytosis.", "quote": "Elotuzumab is an immunostimulatory humanised, IgG1 monoclonal antibody that specifically targets the signaling lymphocyte activation molecule family member 7 (SLAMF7) protein." }, "b": { "targets": [ "SLAMF7" ], "modality": "monoclonal antibody", "label": "SLAMF7-directed monoclonal antibody", "mechanism": "Binds SLAMF7 and activates natural killer cells, promoting myeloma-cell killing through antibody-dependent cellular cytotoxicity and phagocytosis.", "quote": "Elotuzumab is an immunostimulatory humanised, IgG1 monoclonal antibody that specifically targets the signaling lymphocyte activation molecule family member 7 (SLAMF7) protein." }, "decision": null }, "elranatamab__elrexfio": { "url": "https://www.ema.europa.eu/en/documents/product-information/elrexfio-epar-product-information_en.pdf", "text": "Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T cells and B-cell\nmaturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells. Binding of\nelranatamab to BCMA on tumour cells and CD3 on T cells is independent of native T cell receptor\n(TCR) specificity or reliance on major histocompatibility (MHC) Class 1 molecules. Elranatamab\nactivated T cells, led to proinflammatory cytokine release, and resulted in multiple myeloma cell lysis.", "a": { "targets": [ "BCMA", "CD3" ], "modality": "bispecific antibody", "label": "BCMA × CD3 bispecific antibody", "mechanism": "Binds BCMA on myeloma cells and CD3 on T cells, activating T cells, releasing proinflammatory cytokines, and lysing multiple myeloma cells.", "quote": "Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T cells and B-cell maturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells." }, "b": { "targets": [ "BCMA", "CD3" ], "modality": "bispecific antibody", "label": "BCMA × CD3 bispecific antibody", "mechanism": "Binds BCMA on plasma cells and myeloma cells and CD3 on T cells, activating T cells to release proinflammatory cytokines and lyse myeloma cells.", "quote": "Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T cells and B-cell maturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells." }, "decision": null }, "encorafenib__braftovi": { "url": "https://www.ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf", "text": "Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor.\nThe half maximal inhibitory concentration (IC50) of encorafenib against BRAF V600E, BRAF and\nCRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively. The encorafenib\ndissociation half-life was >30 hours and resulted in prolonged pERK inhibition. Encorafenib\nsuppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF\nkinase (V600E, D and K). Specifically, encorafenib inhibits in vitro and in vivo BRAF V600E, D and\nK mutant melanoma cell growth and BRAF V600E mutant colorectal cancer cell growth. Encorafenib\ndoes not inhibit RAF/MEK/ERK signalling in cells expressing wild-type BRAF.\nCombination with binimetinib\n\n25\nEncorafenib and binimetinib (a MEK inhibitor, see section 5.1 of binimetinib SmPC) both inhibit the\nMAPK pathway, resulting in higher anti-tumour activity, compared to treatment with either drug\nalone.\nCombination with cetuximab with or without FOLFOX\nOne of the main mechanisms of resistance of BRAF-mutant CRC to RAF inhibitors has been\nidentified as the re-activation of EGFR with bypassing signal transduction via BRAF. Combinations of\na BRAF inhibitor, e.g. encorafenib and agents targeting EGFR, e.g. cetuximab have shown to improve\nanti-tumour efficacy in non-clinical models. The addition of a cytostatic agent, e.g. 5-fluorouracil and\na cytotoxic agent, e.g. oxaliplatin, have shown to improve anti-tumour efficacy in clinical studies.", "a": { "targets": [ "BRAF", "CRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Encorafenib is an ATP-competitive RAF kinase inhibitor that suppresses the RAF/MEK/ERK pathway in tumour cells expressing mutated BRAF, inhibiting tumour cell growth.", "quote": "Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor." }, "b": { "targets": [ "BRAF", "RAF1" ], "modality": "small molecule", "label": "RAF kinase inhibitor", "mechanism": "Encorafenib competitively inhibits RAF kinases, suppressing RAF/MEK/ERK signalling in tumour cells with mutated BRAF.", "quote": "The half maximal inhibitory concentration (IC50) of encorafenib against BRAF V600E, BRAF and CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively." }, "decision": { "reason": "Both readings agree on the substance and differ only in naming: the text says it is a \"highly selective ATP-competitive small molecule RAF kinase inhibitor\" with IC50 values against \"BRAF V600E, BRAF and CRAF\". I kept CRAF as written and the clinician label BRAF inhibitor, and the text is not ambiguous.", "targets": [ "BRAF V600E", "BRAF", "CRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "ATP-competitive RAF kinase inhibitor (BRAF V600E, BRAF, CRAF) that suppresses RAF/MEK/ERK signalling and growth of BRAF V600-mutant tumour cells; it does not inhibit signalling in wild-type BRAF cells.", "quote": "The half maximal inhibitory concentration (IC50) of encorafenib against BRAF V600E, BRAF and CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively.", "ambiguous": false } }, "enfortumab-vedotin__padcev": { "url": "https://www.ema.europa.eu/en/documents/product-information/padcev-epar-product-information_en.pdf", "text": "Enfortumab vedotin is an ADC targeting Nectin-4, an adhesion protein located on the surface of the\nurothelial cancer cells. It is comprised of a fully human IgG1-kappa antibody conjugated to the\nmicrotubule-disrupting agent MMAE via a protease-cleavable maleimidocaproyl valine-citrulline\nlinker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin is due to the binding\nof the ADC to Nectin-4-expressing cells, followed by internalisation of the ADC-Nectin-4 complex,\nand the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule\nnetwork within the cell, subsequently inducing cell cycle arrest, apoptosis and immunogenic cell\ndeath. MMAE released from enfortumab vedotin targeted cells can diffuse into nearby Nectin-4\nlow-expressing cells resulting in cytotoxic cell death. Combination of enfortumab vedotin with\nprogrammed death receptor 1 (PD-1) inhibitors results in enhanced anti-tumour activity, consistent\nwith the complementary mechanisms of MMAE induced cell cytotoxicity and induction of\nimmunogenic cell death, plus the up-regulation of immune function by PD-1 inhibition.", "a": { "targets": [ "Nectin-4" ], "modality": "antibody-drug conjugate", "label": "Nectin-4-directed antibody-drug conjugate", "mechanism": "Binds Nectin-4 on cancer cells, internalises, and releases MMAE to disrupt microtubules, causing cell cycle arrest and apoptosis.", "quote": "Enfortumab vedotin is an ADC targeting Nectin-4, an adhesion protein located on the surface of the urothelial cancer cells." }, "b": { "targets": [ "Nectin-4" ], "modality": "antibody-drug conjugate", "label": "Nectin-4-directed antibody-drug conjugate", "mechanism": "Binds Nectin-4 on urothelial cancer cells and delivers MMAE, which disrupts microtubules and induces cell-cycle arrest and cell death.", "quote": "Enfortumab vedotin is an ADC targeting Nectin-4, an adhesion protein located on the surface of the urothelial cancer cells." }, "decision": null }, "entrectinib__rozlytrek": { "url": "https://www.ema.europa.eu/en/documents/product-information/rozlytrek-epar-product-information_en.pdf", "text": "Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC\n(encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3,\nrespectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase\n(ALK), with IC50 values of 0.1 to 2 nM. The major active metabolite of entrectinib, M5, showed\nsimilar in vitro potency and activity against TRK, ROS1, and ALK.\nFusion proteins that include TRK, ROS1 or ALK kinase domains drive tumourigenic potential through\nhyperactivation of downstream signalling pathways leading to unconstrained cell proliferation.\nEntrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple\ntumour types, including subcutaneous and intracranial tumours, harbouring NTRK, ROS1, and ALK\nfusion genes.\nPrior treatments with other drugs that inhibit the same kinases may confer resistance to entrectinib.\nResistance mutations in the TRK kinase domain identified following entrectinib discontinuation\ninclude NTRK1 (G595R, G667C) and NTRK3 (G623R, G623E and G623K). Resistance mutations in\nthe ROS1 kinase domain identified following entrectinib discontinuation include G2032R, F2004C\nand F2004I.\nThe molecular causes for primary resistance to entrectinib are not known. It is therefore not known if\nthe presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy\nof TRK inhibition.", "a": { "targets": [ "TRKA", "TRKB", "TRKC", "ROS1", "ALK" ], "modality": "small molecule", "label": "TRK, ROS1, and ALK inhibitor", "mechanism": "Entrectinib inhibits TRKA, TRKB, TRKC, ROS1, and ALK tyrosine kinases, suppressing downstream signaling pathways and tumor cell proliferation driven by their fusion proteins.", "quote": "Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK), with IC50 values of 0.1 to 2 nM." }, "b": { "targets": [ "NTRK1", "NTRK2", "NTRK3", "ROS1", "ALK" ], "modality": "small molecule", "label": "TRK/ROS1/ALK inhibitor", "mechanism": "Entrectinib inhibits TRKA, TRKB, TRKC, ROS1 and ALK, blocking kinase signalling driven by fusion proteins.", "quote": "Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK), with IC50 values of 0.1 to 2 nM." }, "decision": { "reason": "The two readings differ only in naming the targets as genes (NTRK1-3) or as proteins (TRKA-C); the text says the drug inhibits the kinases TRKA, TRKB and TRKC, so the protein names fit and the text leaves nothing open.", "targets": [ "TRKA", "TRKB", "TRKC", "ROS1", "ALK" ], "modality": "small molecule", "label": "TRK/ROS1/ALK inhibitor", "mechanism": "Entrectinib inhibits the TRKA, TRKB, TRKC, ROS1 and ALK tyrosine kinases, blocking downstream signalling and cell proliferation driven by NTRK, ROS1 or ALK fusion proteins.", "quote": "Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK), with IC50 values of 0.1 to 2 nM.", "ambiguous": false } }, "enzalutamide__xtandi": { "url": "https://www.ema.europa.eu/en/documents/product-information/xtandi-epar-product-information_en.pdf", "text": "Prostate cancer is known to be androgen sensitive and responds to inhibition of androgen receptor\nsignalling. Despite low or even undetectable levels of serum androgen, androgen receptor signalling\ncontinues to promote disease progression. Stimulation of tumour cell growth via the androgen receptor\nrequires nuclear localization and DNA binding. Enzalutamide is a potent androgen receptor signalling\ninhibitor that blocks several steps in the androgen receptor signalling pathway. Enzalutamide\ncompetitively inhibits androgen binding to androgen receptors, and consequently; inhibits nuclear\ntranslocation of activated receptors and inhibits the association of the activated androgen receptor with\nDNA even in the setting of androgen receptor overexpression and in prostate cancer cells resistant to\nanti-androgens. Enzalutamide treatment decreases the growth of prostate cancer cells and can induce\ncancer cell death and tumour regression. In preclinical studies enzalutamide lacks androgen receptor\nagonist activity.", "a": { "targets": [ "androgen receptor" ], "modality": "small molecule", "label": "Androgen receptor signalling inhibitor", "mechanism": "Enzalutamide competitively inhibits androgen binding to androgen receptors, preventing nuclear translocation and DNA binding to suppress prostate cancer cell growth.", "quote": "Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway." }, "b": { "targets": [ "AR" ], "modality": "small molecule", "label": "Androgen receptor inhibitor", "mechanism": "Enzalutamide blocks androgen binding to the androgen receptor, receptor nuclear translocation, and receptor association with DNA, inhibiting androgen receptor signalling.", "quote": "Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway." }, "decision": { "reason": "Both readings agree on substance; the instructions ask hormonal medicines to name the receptor as \"androgen receptor\", and the text states enzalutamide \"competitively inhibits androgen binding to androgen receptors\", so the target is clear and not ambiguous.", "targets": [ "androgen receptor" ], "modality": "small molecule", "label": "Androgen receptor signalling inhibitor", "mechanism": "Competitively blocks androgen binding to the androgen receptor, inhibiting receptor nuclear translocation and DNA association, decreasing prostate cancer cell growth; no agonist activity.", "quote": "Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway.", "ambiguous": false } }, "epcoritamab__tepkinly": { "url": "https://www.ema.europa.eu/en/documents/product-information/tepkinly-epar-product-information_en.pdf", "text": "Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of\nCD20 on B cells and to CD3 on T cells. The activity of epcoritamab is dependent upon simultaneous\nengagement of CD20-expressing cancer cells and CD3-expressing endogenous T cells by epcoritamab\nthat induces specific T-cell activation and T-cell-mediated killing of CD20-expressing cells.\nEpcoritamab Fc region is silenced to prevent target-independent immune effector mechanisms, such as\nantibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC),\nand antibody-dependent cellular phagocytosis (ADCP).\nIn preclinical studies, the combination of epcoritamab and rituximab did not lead to functional\ninterference and results in complementary NK cell mediated antibody-dependent cellular cytotoxicity\n(ADCC) and T-cell mediated cytotoxicity.", "a": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Epcoritamab simultaneously binds CD20 on B cells and CD3 on T cells, inducing T-cell activation and T-cell-mediated killing of CD20-expressing cancer cells.", "quote": "Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of CD20 on B cells and to CD3 on T cells." }, "b": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Binds CD20 on B cells and CD3 on T cells, bringing them together to activate T cells and promote killing of CD20-expressing cells.", "quote": "Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of CD20 on B cells and to CD3 on T cells." }, "decision": null }, "erdafitinib__balversa": { "url": "https://www.ema.europa.eu/en/documents/product-information/balversa-epar-product-information_en.pdf", "text": "Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor.", "a": { "targets": [ "FGFR" ], "modality": "small molecule", "label": "Pan-FGFR tyrosine kinase inhibitor", "mechanism": "Erdafitinib acts as a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor.", "quote": "Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor." }, "b": { "targets": [ "FGFR" ], "modality": "small molecule", "label": "Pan-FGFR inhibitor", "mechanism": "Inhibits fibroblast growth factor receptor (FGFR) tyrosine kinases.", "quote": "Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor." }, "decision": null }, "erlotinib__tarceva": { "url": "https://www.ema.europa.eu/en/documents/product-information/tarceva-epar-product-information_en.pdf", "text": "Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1\n(EGFR also known as HER1) tyrosine kinase inhibitor. Erlotinib potently inhibits the intracellular\nphosphorylation of EGFR. EGFR is expressed on the cell surface of normal cells and cancer cells. In\nnon-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.\nEGFR mutations may lead to constitutive activation of anti-apoptotic and proliferation signaling\npathways. The potent effectiveness of erlotinib in blocking EGFR-mediated signalling in these EGFR\nmutation positive tumours is attributed to the tight binding of erlotinib to the ATP-binding site in the\nmutated kinase domain of the EGFR. Due to the blocking of downstream-signaling, the proliferation\nof cells is stopped, and cell death is induced through the intrinsic apoptotic pathway. Tumour\nregression is observed in mouse models of enforced expression of these EGFR activating mutations.", "a": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR tyrosine kinase inhibitor", "mechanism": "Erlotinib binds the ATP-binding site of EGFR, inhibiting its intracellular phosphorylation and downstream signaling to halt cell proliferation and induce apoptosis.", "quote": "Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor." }, "b": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR tyrosine kinase inhibitor", "mechanism": "Erlotinib binds the ATP-binding site of EGFR and inhibits its phosphorylation and downstream signalling, stopping cell proliferation and inducing cell death.", "quote": "Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor." }, "decision": null }, "everolimus__afinitor": { "url": "https://www.ema.europa.eu/en/documents/product-information/afinitor-epar-product-information_en.pdf", "text": "Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key\nserine-threonine kinase, the activity of which is known to be upregulated in a number of human\ncancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits\nmTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with\nthe translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase\n(S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved\nin the cell cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function\ndomain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation.\nEverolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour\nangiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells,\nendothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to\nreduce glycolysis in solid tumours in vitro and in vivo.", "a": { "targets": [ "mTOR" ], "modality": "small molecule", "label": "mTOR inhibitor", "mechanism": "Binds to intracellular FKBP-12 to form a complex that inhibits mTORC1 activity, reducing protein synthesis, cell cycle progression, and angiogenesis.", "quote": "Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor." }, "b": { "targets": [ "mTOR" ], "modality": "small molecule", "label": "mTOR inhibitor", "mechanism": "Everolimus binds FKBP-12, forming a complex that inhibits mTORC1 activity and interferes with protein translation and synthesis.", "quote": "Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor." }, "decision": null }, "everolimus__votubia": { "url": "https://www.ema.europa.eu/en/documents/product-information/votubia-epar-product-information_en.pdf", "text": "Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key\nserine-threonine kinase, the activity of which is known to be upregulated in a number of human\ncancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits\nmTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with\nthe translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase\n(S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved\nin the cell cycle, angiogenesis and glycolysis. Everolimus can reduce levels of vascular endothelial\ngrowth factor (VEGF). In patients with TSC, treatment with everolimus increases VEGF-A and\ndecreases VEGF-D levels. Everolimus is a potent inhibitor of the growth and proliferation of tumour\ncells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been\nshown to reduce glycolysis in solid tumours in vitro and in vivo.\nTwo primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis\ncomplexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a\nras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1\nactivation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In\nTSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation\nthroughout the body.", "a": { "targets": [ "mTOR" ], "modality": "small molecule", "label": "mTOR inhibitor", "mechanism": "Everolimus binds intracellular FKBP-12 to inhibit mTORC1 activity, blocking downstream signalling that regulates protein synthesis, the cell cycle, angiogenesis, and glycolysis.", "quote": "Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor." }, "b": { "targets": [ "mTOR" ], "modality": "small molecule", "label": "Selective mTOR inhibitor", "mechanism": "Everolimus binds intracellular FKBP-12; the resulting complex inhibits mTORC1, disrupting signalling involved in protein synthesis and cell growth.", "quote": "Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor." }, "decision": null }, "fedratinib__inrebic": { "url": "https://www.ema.europa.eu/en/documents/product-information/inrebic-epar-product-information_en.pdf", "text": "Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus\nAssociated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective\ninhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2.\nFedratinib reduced JAK2-mediated phosphorylation of signal transducer and activator of transcription\n(STAT3/5) proteins, inhibited malignant cell proliferation in vitro and in vivo.", "a": { "targets": [ "JAK2", "FLT3" ], "modality": "small molecule", "label": "JAK2 inhibitor", "mechanism": "Fedratinib selectively inhibits JAK2 and FLT3, reducing JAK2-mediated phosphorylation of STAT3 and STAT5 proteins and inhibiting malignant cell proliferation.", "quote": "Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3)." }, "b": { "targets": [ "JAK2", "FLT3" ], "modality": "small molecule", "label": "Kinase inhibitor (JAK2, FLT3)", "mechanism": "Inhibits JAK2 and FLT3, reducing JAK2-mediated STAT3/5 phosphorylation and malignant cell proliferation.", "quote": "Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3)." }, "decision": null }, "fruquintinib__fruzaqla": { "url": "https://www.ema.europa.eu/en/documents/product-information/fruzaqla-epar-product-information_en.pdf", "text": "Fruquintinib is a selective tyrosine kinase inhibitor of VEGFR-1, -2, and -3 with antitumor effects\nresulting from suppression of tumour angiogenesis.", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3" ], "modality": "small molecule", "label": "VEGFR tyrosine kinase inhibitor", "mechanism": "Fruquintinib selectively inhibits VEGFR-1, -2, and -3 tyrosine kinases, producing antitumor effects by suppressing tumour angiogenesis.", "quote": "Fruquintinib is a selective tyrosine kinase inhibitor of VEGFR-1, -2, and -3 with antitumor effects resulting from suppression of tumour angiogenesis." }, "b": { "targets": [ "VEGFR-1", "VEGFR-2", "VEGFR-3" ], "modality": "small molecule", "label": "VEGFR-1/2/3 inhibitor", "mechanism": "Fruquintinib inhibits VEGFR-1, -2, and -3, suppressing tumour angiogenesis and producing antitumour effects.", "quote": "Fruquintinib is a selective tyrosine kinase inhibitor of VEGFR-1, -2, and -3 with antitumor effects resulting from suppression of tumour angiogenesis." }, "decision": null }, "fulvestrant__faslodex": { "url": "https://www.ema.europa.eu/en/documents/product-information/faslodex-epar-product-information_en.pdf", "text": "Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol.\nFulvestrant blocks the trophic actions of estrogens without any partial agonist (estrogen-like) activity.\nThe mechanism of action is associated with downregulation of estrogen receptor protein levels.\nClinical studies in postmenopausal women with primary breast cancer have shown that fulvestrant\nsignificantly downregulates ER protein in ER positive tumours compared with placebo. There was also\na significant decrease in progesterone receptor expression consistent with a lack of intrinsic estrogen\nagonist effects. It has also been shown that fulvestrant 500 mg downregulates ER and the proliferation\nmarker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours in postmenopausal\nneoadjuvant setting.\nClinical efficacy and safety in advanced breast cancer\nMonotherapy\nA Phase 3 clinical study was completed in 736 postmenopausal women with advanced breast cancer\nwho had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine\ntherapy for advanced disease. The study included 423 patients whose disease had recurred or\nprogressed during antiestrogen therapy (AE subgroup) and 313 patients whose disease had recurred or\nprogressed during aromatase inhibitor therapy (AI subgroup). This study compared the efficacy and\n\n9\nsafety of Faslodex 500 mg (n=362) with Faslodex 250 mg (n=374). Progression-free survival (PFS)\nwas the primary endpoint; key secondary efficacy endpoints included objective response rate (ORR),\nclinical benefit rate (CBR) and overall survival (OS). Efficacy results for the CONFIRM study are\nsummarized in Table 3.\nTable 3 Summary of results of the primary efficacy endpoint (PFS) and key secondary\nefficacy endpoints in the CONFIRM study\nVariable Type of\nestimate;\ntreatment\ncomparison\nFaslodex\n500 mg\n(N=362)\nFaslodex\n250 mg\n(N=374)\nComparison between groups\n(Faslodex 500 mg/Faslodex 250 mg)\nHazard ratio 95% CI p-value\nPFS K-M median\nin months;\nhazard ratio\nAll Patients 6.5 5.5 0.80 0.68, 0.94 0.006\n-AE subgroup (n=423) 8.6 5.8 0.76 0.62, 0.94 0.013\n-AI subgroup (n=313)a 5.4 4.1 0.85 0.67, 1.08 0.195\nOSb K-M median\nin months;\nhazard ratio\nAll Patients 26.4 22.3 0.81 0.69, 0.96 0.016c\n-AE subgroup (n=423) 30.6 23.9 0.79 0.63, 0.99 0.038c\n-AI subgroup (n=313)a 24.1 20.8 0.86 0.67, 1.11 0.241c\nVariable Type of\nestimate;\ntreatment\ncomparison\nFaslodex\n500 mg\n(N=362)\nFaslodex\n250 mg\n(N=374)\nComparison between groups\n(Faslodex 500 mg/Faslodex 250 mg)\nAbsolute\ndifference in %\n95% CI\nORRd % of patients\nwith OR;\nabsolute\ndifference in\n%\nAll Patients 13.8 14.6 -0.8 -5.8, 6.3\n-AE subgroup (n=296) 18.1 19.1 -1.0 -8.2, 9.3\n-AI subgroup (n=205)a 7.3 8.3 -1.0 -5.5, 9.8\nCBRe % of patients\nwith CB;\nabsolute\ndifference in\n%\nAll Patients 45.6 39.6 6.0 -1.1, 13.3\n-AE subgroup (n=423) 52.4 45.1 7.3 -2.2, 16.6\n-AI subgroup (n=313)a 36.2 32.3 3.9 -6.1, 15.2\na Faslodex is indicated in patients whose disease had recurred or progressed on an antiestrogen therapy.\nThe results in the AI subgroup are inconclusive.\nb OS is presented for the final survival analyses at 75% maturity.\nc Nominal p-value with no adjustments made for multiplicity between the initial overall survival analyses at\n50% maturity and the updated survival analyses at 75% maturity.\nd ORR was assessed in patients who were evaluable for response at baseline (i.e. those with measurable\ndisease at baseline: 240 patients in the Faslodex 500 mg group and 261 patients in the Faslodex 250 mg\ngroup).\ne Patients with a best objective response of complete response, partial response or stable disease ≥24 weeks.\nPFS:Progression-free survival; ORR:Objective response rate; OR:Objective response; CBR:Clinical benefit rate; CB:Clinical\nbenefit; OS:Overall survival; K-M:Kaplan-Meier; CI:Confidence interval; AI:Aromatase inhibitor; AE:Antiestrogen.\n\n10\nA Phase 3, randomised, double-blind, double-dummy, multicentre study of Faslodex 500 mg versus\nanastrozole 1 mg was conducted in postmenopausal women with ER-positive and/or PgR-positive\nlocally advanced or metastatic breast cancer who had not previously been treated with any hormonal\ntherapy. A total of 462 patients were randomised 1:1 sequentially to receive either fulvestrant 500 mg\nor anastrozole 1 mg. Randomisation was stratified by disease setting (locally advanced or metastatic),\nprior chemotherapy for advanced disease, and measurable disease.\nThe primary efficacy endpoint of the study was investigator assessed progression-free survival (PFS)\nevaluated according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumours). Key secondary\nefficacy endpoints included overall survival (OS) and objective response rate (ORR).\nPatients enrolled in this study had a median age of 63 years (range 36-90). The majority of patients\n(87.0%) had metastatic disease at baseline. Fifty-five percent (55.0%) of patients had visceral\nmetastasis at baseline. A total of 17.1% of patients received a prior chemotherapy regimen for\nadvanced disease; 84.2% of patients had measurable disease.\nConsistent results were observed across the majority of pre-specified patient subgroups. For the\nsubgroup of patients with disease limited to non-visceral metastasis (n=208), the HR was 0.592 (95%\nCI: 0.419, 0.837) for the Faslodex arm compared to the anastrozole arm. For the subgroup of patients\nwith visceral metastasis (n=254), the HR was 0.993 (95% CI: 0.740, 1.331) for the Faslodex arm\ncompared to the anastrozole arm. The efficacy results of the FALCON study are presented in Table 4\nand Figure 1.\nTable 4 Summary of results of the primary efficacy endpoint (PFS) and key secondary\nefficacy endpoints (Investigator Assessment, Intent-To-Treat Population) ─ FALCON study\nFaslodex\n500 mg\n(N=230)\nAnastrozole\n1 mg\n(N=232)\nProgression-Free Survival\nNumber of PFS Events (%) 143 (62.2%) 166 (71.6%)\nPFS Hazard Ratio (95% CI) and\np-value\nHR 0.797 (0.637 - 0.999)\np = 0.0486\nPFS Median [months (95% CI)] 16.6 (13.8", "a": { "targets": [ "estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "A competitive estrogen receptor antagonist that blocks estrogen-mediated trophic actions and downregulates estrogen receptor protein levels without intrinsic agonist activity.", "quote": "Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol." }, "b": { "targets": [ "ER (estrogen receptor)" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Fulvestrant competitively antagonizes estrogen receptors, blocks estrogen trophic effects without partial agonist activity, and downregulates estrogen receptor protein levels.", "quote": "Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol." }, "decision": { "reason": "Both readings agree on substance; the text plainly names the target: \"Fulvestrant is a competitive estrogen receptor (ER) antagonist\" whose action is \"associated with downregulation of estrogen receptor protein levels,\" so the only difference is formatting, and \"estrogen receptor\" is the cleaner symbol.", "targets": [ "estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Competitive estrogen receptor antagonist that blocks the trophic actions of estrogens without partial agonist activity and downregulates estrogen receptor protein levels.", "quote": "Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol.", "ambiguous": false } }, "futibatinib__lytgobi": { "url": "https://www.ema.europa.eu/en/documents/product-information/lytgobi-epar-product-information_en.pdf", "text": "Constitutive fibroblast growth factor receptor (FGFR) signalling can support the proliferation and\nsurvival of malignant cells. Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits FGFR 1,\n2, 3, and 4 by covalent binding. Futibatinib exhibited in vitro inhibitory activity against FGFR2\nresistance mutations (N550H, V565I, E566G, K660M).", "a": { "targets": [ "FGFR1", "FGFR2", "FGFR3", "FGFR4" ], "modality": "small molecule", "label": "Irreversible FGFR 1-4 inhibitor", "mechanism": "Futibatinib is a kinase inhibitor that irreversibly inhibits FGFR 1, 2, 3, and 4 by covalent binding, blocking constitutive FGFR signalling.", "quote": "Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits FGFR 1, 2, 3, and 4 by covalent binding." }, "b": { "targets": [ "FGFR1", "FGFR2", "FGFR3", "FGFR4" ], "modality": "small molecule", "label": "Irreversible FGFR1–4 inhibitor", "mechanism": "Futibatinib irreversibly inhibits FGFR1–4 by covalent binding.", "quote": "Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits FGFR 1, 2, 3, and 4 by covalent binding." }, "decision": null }, "gefitinib__iressa": { "url": "https://www.ema.europa.eu/en/documents/product-information/iressa-epar-product-information_en.pdf", "text": "The epidermal growth factor (EGF) and its receptor (EGFR [HER1; ErbB1]) have been identified as\nkey drivers in the process of cell growth and proliferation for normal and cancer cells. EGFR\nactivating mutation within a cancer cell is an important factor in promotion of tumour cell growth,\nblocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of\nmetastasis.\nGefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase\nand is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine\nkinase domain regardless of line of therapy. No clinically relevant activity has been shown in patients\nwith known EGFR mutation-negative tumours.\nThe common EGFR activating mutations (Exon 19 deletions; L858R) have robust response data\nsupporting sensitivity to gefitinib; for example a progression free survival HR (95% CI) of 0.489\n(0.336, 0.710) for gefitinib vs. doublet chemotherapy [WJTOG3405]. Gefitinib response data is more\nsparse in patients whose tumours contain the less common mutations; the available data indicates that\nG719X, L861Q and S7681 are sensitising mutations; and T790M alone or exon 20 insertions alone are\nresistance mechanisms.\nResistance\nMost NSCLC tumours with sensitising EGFR kinase mutations eventually develop resistance to\nIRESSA treatment, with a median time to disease progression of 1 year. In about 60% of cases,\nresistance is associated with a secondary T790M mutation for which T790M targeted EGFR TKIs may\n\nbe considered as a next line treatment option. Other potential mechanisms of resistance that have been\nreported following treatment with EGFR signal blocking agents include: bypass signalling such as\nHER2 and MET gene amplification and PIK3CA mutations. Phenotypic switch to small cell lung\ncancer has also been reported in 5-10% of cases.\nCirculating Tumour DNA (ctDNA)\nIn the IFUM trial, mutation status was assessed in tumour and ctDNA samples derived from plasma,\nusing the Therascreen EGFR RGQ PCR kit (Qiagen). Both ctDNA and tumour samples were evaluable\nfor 652 patients out of 1060 screened. The objective response rate (ORR) in those patients who were\ntumour and ctDNA mutation positive was 77% (95% CI: 66% to 86%) and in those who were tumour\nonly mutation positive 60% (95% CI: 44% to 74%).\nTable 2 Summary of baseline mutation status for tumour and ctDNA samples in all screened\npatients evaluable for both samples\nMeasure Definition IFUM rate\n% (CI)\nIFUM\nN\nSensitivity Proportion of tumour M+ that are\nM+ by ctDNA\n65.7 (55.8, 74.7) 105\nSpecificity Proportion of tumour M- that are M-\nby ctDNA)\n99.8 (99.0, 100.0) 547\nThese data are consistent with the pre-planned exploratory Japanese subgroup analysis in IPASS (Goto\n2012). In that study ctDNA derived from serum, not plasma was used for EGFR mutation analysis\nusing the EGFR Mutation Test Kit (DxS) (N= 86). In that study, sensitivity was 43.1%, specificity was\n100%.", "a": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR tyrosine kinase inhibitor", "mechanism": "Gefitinib is a selective small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase domain, inhibiting growth in tumours with sensitising EGFR mutations.", "quote": "Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy." }, "b": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR tyrosine kinase inhibitor", "mechanism": "Gefitinib selectively inhibits EGFR tyrosine kinase, treating tumours with activating EGFR tyrosine kinase domain mutations.", "quote": "Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy." }, "decision": null }, "gemtuzumab-ozogamicin__mylotarg": { "url": "https://www.ema.europa.eu/en/documents/product-information/mylotarg-epar-product-information_en.pdf", "text": "Gemtuzumab ozogamicin is a CD33-directed ADC. Gemtuzumab is a humanised immunoglobulin class G\nsubtype 4 (IgG4) antibody which specifically recognises human CD33. The antibody portion binds\nspecifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of myeloid\nleukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic\nstem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product.\nN-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4-(4-acetylphenoxy)\nbutanoic acid) linker. Non-clinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due\nto the binding of the ADC to CD33-expressing cancer cells, followed by internalisation of the ADC-CD33\ncomplex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic\n\n17\ncleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces\ndouble-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.\nSaturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of\ncalicheamicin to leukaemic blast cells. Several single agent studies measured CD33 saturation\npost-MYLOTARG dose in patients with relapsed and refractory AML. Across all studies, near maximal\nperipheral CD33 saturation was observed post-MYLOTARG dose at all dose levels of 2 mg/m² and above,\nsuggesting that a low dose of gemtuzumab ozogamicin is sufficient to bind all available CD33 sites.", "a": { "targets": [ "CD33" ], "modality": "antibody-drug conjugate", "label": "CD33-directed antibody-drug conjugate", "mechanism": "It binds CD33-expressing cells, internalises, and releases calicheamicin to induce double-stranded DNA breaks and apoptotic cell death.", "quote": "Gemtuzumab ozogamicin is a CD33-directed ADC." }, "b": { "targets": [ "CD33" ], "modality": "antibody-drug conjugate", "label": "CD33-directed antibody-drug conjugate", "mechanism": "The antibody binds CD33-expressing cells and is internalised; intracellular release of calicheamicin causes double-stranded DNA breaks, cell-cycle arrest and apoptosis.", "quote": "Gemtuzumab ozogamicin is a CD33-directed ADC." }, "decision": null }, "gilteritinib__xospata": { "url": "https://www.ema.europa.eu/en/documents/product-information/xospata-epar-product-information_en.pdf", "text": "Gilteritinib fumarate is a FLT3 and AXL inhibitor.\nGilteritinib inhibits FLT3 receptor signalling and proliferation in cells exogenously expressing FLT3\nincluding FLT3-ITD, FLT3-D835Y, and FLT3-ITD-D835Y, and it induces apoptosis in leukemic cells\nexpressing FLT3-ITD.", "a": { "targets": [ "FLT3", "AXL" ], "modality": "small molecule", "label": "FLT3 and AXL inhibitor", "mechanism": "Gilteritinib inhibits FLT3 and AXL, blocking FLT3 receptor signalling and cell proliferation, and inducing apoptosis in leukemic cells expressing FLT3-ITD.", "quote": "Gilteritinib fumarate is a FLT3 and AXL inhibitor." }, "b": { "targets": [ "FLT3", "AXL" ], "modality": "small molecule", "label": "Multikinase inhibitor (FLT3, AXL)", "mechanism": "Gilteritinib inhibits FLT3 receptor signalling and proliferation in cells expressing FLT3 variants, and induces apoptosis in leukemic cells expressing FLT3-ITD.", "quote": "Gilteritinib fumarate is a FLT3 and AXL inhibitor." }, "decision": null }, "glasdegib__daurismo": { "url": "https://www.ema.europa.eu/en/documents/product-information/daurismo-epar-product-information_en.pdf", "text": "Glasdegib is an inhibitor of the Hedgehog (Hh) signal transduction pathway that binds to Smoothened\n(SMO), a transmembrane protein, leading to decreased Glioma-Associated Oncogene (GLI)\ntranscription factor activity and downstream pathway signalling. Hh pathway signalling is required for\nmaintaining a leukaemic stem cell (LSC) population thus, glasdegib binding to and inhibiting SMO\nreduces GLI1 levels in AML cells and the leukaemic initiating potential of AML cells. Hh pathway\nsignalling is also implicated in resistance to chemotherapy and targeted therapy. In a preclinical model\nof AML, glasdegib in combination with low-dose cytarabine inhibited increases in tumour size to a\ngreater extent than glasdegib or low-dose cytarabine alone. However, mechanism of action of the\ncombination is not fully understood.", "a": { "targets": [ "SMO" ], "modality": "small molecule", "label": "Smoothened inhibitor", "mechanism": "Binds to Smoothened (SMO) to inhibit Hedgehog signal transduction, reducing GLI transcription factor activity and downstream pathway signalling.", "quote": "Glasdegib is an inhibitor of the Hedgehog (Hh) signal transduction pathway that binds to Smoothened (SMO), a transmembrane protein, leading to decreased Glioma-Associated Oncogene (GLI) transcription factor activity and downstream pathway signalling." }, "b": { "targets": [ "SMO" ], "modality": "small molecule", "label": "Hedgehog pathway inhibitor (SMO inhibitor)", "mechanism": "Glasdegib binds and inhibits SMO, reducing GLI transcription factor activity and downstream Hedgehog signalling.", "quote": "Glasdegib is an inhibitor of the Hedgehog (Hh) signal transduction pathway that binds to Smoothened (SMO), a transmembrane protein, leading to decreased Glioma-Associated Oncogene (GLI) transcription factor activity and downstream pathway signalling." }, "decision": null }, "glofitamab__columvi": { "url": "https://www.ema.europa.eu/en/documents/product-information/columvi-epar-product-information_en.pdf", "text": "Glofitamab is a bispecific monoclonal antibody that binds bivalently to CD20 expressed on the surface\nof B cells and monovalently to CD3 in the T-cell receptor complex expressed on the surface of T cells.\nBy simultaneous binding to CD20 on the B cell and CD3 on the T cell, glofitamab mediates the\nformation of an immunological synapse with subsequent T-cell activation and proliferation, secretion\nof cytokines and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.\nPharmacodynamics\nIn study NP30179, 84% (84/100) of patients were already B-cell depleted (< 70 cells/μL) before pre-\ntreatment with obinutuzumab. The proportion of patients with B-cell depletion increased to 100%\n(94/94) after obinutuzumab pre-treatment prior to Columvi treatment initiation, and B-cell counts\nremained low during Columvi treatment.\nDuring Cycle 1 (step-up dosing), transient increases in plasma IL-6 levels were observed at 6 hours\npost Columvi infusion, which remained elevated at 20 hours post-infusion and returned to baseline\nprior to the next infusion.\nIn study GO41944 (STARGLO), 63.9% (115/180) of patients were already B-cell depleted\n(< 70 cells/μL) before pre-treatment with obinutuzumab. The proportion of patients with B-cell\ndepletion increased to 79.4% (143/180) after obinutuzumab pre-treatment prior to Columvi treatment\ninitiation, and B-cell counts remained low during Columvi treatment.", "a": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Binds CD20 on B cells and CD3 on T cells to induce an immunological synapse, leading to T-cell activation and targeted lysis of CD20-expressing B cells.", "quote": "Glofitamab is a bispecific monoclonal antibody that binds bivalently to CD20 expressed on the surface of B cells and monovalently to CD3 in the T-cell receptor complex expressed on the surface of T cells." }, "b": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Binds CD20 on B cells and CD3 on T cells, bringing them together to activate T cells and cause lysis of CD20-expressing B cells.", "quote": "Glofitamab is a bispecific monoclonal antibody that binds bivalently to CD20 expressed on the surface of B cells and monovalently to CD3 in the T-cell receptor complex expressed on the surface of T cells." }, "decision": null }, "ibrutinib__imbruvica": { "url": "https://www.ema.europa.eu/en/documents/product-information/imbruvica-epar-product-information_en.pdf", "text": "Ibrutinib is a potent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a\ncovalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition\nof BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling\n\n15\nmolecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is\nimplicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell\nlymphoma (DLBCL), follicular lymphoma, and CLL. BTK’s pivotal role in signalling through the\nB-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis\nand adhesion. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell\nproliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.\nIn preclinical tumour models, the combination of ibrutinib and venetoclax resulted in increased\ncellular apoptosis and anti-tumour activity compared to either agent alone. BTK inhibition by ibrutinib\nincreases CLL cell dependence on BCL-2, a cell survival pathway, while venetoclax inhibits BCL-2\nleading to apoptosis.\nLymphocytosis\nUpon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from\nbaseline and an absolute count >5 000/mcL), often associated with reduction of lymphadenopathy, has\nbeen observed in about three fourths of patients with CLL treated with IMBRUVICA. This effect has\nalso been observed in about one third of patients with relapsed or refractory MCL treated with\nIMBRUVICA. This observed lymphocytosis is a pharmacodynamic effect and should not be\nconsidered progressive disease in the absence of other clinical findings. In both disease types,\nlymphocytosis typically occurs during the first month of IMBRUVICA therapy and typically resolves\nwithin a median of 8.0 weeks in patients with MCL and 14 weeks in patients with CLL. A large\nincrease in the number of circulating lymphocytes (e.g., >400 000/mcL) has been observed in some\npatients.\nLymphocytosis was not observed in patients with WM treated with IMBRUVICA.\nIn vitro platelet aggregation\nIn an in vitro study, ibrutinib demonstrated inhibition of collagen-induced platelet aggregation.\nIbrutinib did not show meaningful inhibition of platelet aggregation using other agonists of platelet\naggregation.\nEffect on QT/QTc interval and cardiac electrophysiology\nThe effect of ibrutinib on the QTc interval was evaluated in 20 healthy male and female subjects in a\nrandomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic\ndose of 1 680 mg, ibrutinib did not prolong the QTc interval to any clinically relevant extent. The\nlargest upper bound of the 2-sided 90% CI for the baseline adjusted mean differences between\nibrutinib and placebo was below 10 ms. In this same study, a concentration dependent shortening in\nthe QTc interval was observed (-5.3 ms [90% CI: -9.4, -1.1] at a Cmax of 719 ng/mL following the\nsupratherapeutic dose of 1 680 mg).", "a": { "targets": [ "BTK" ], "modality": "small molecule", "label": "BTK inhibitor", "mechanism": "Covalently binds to the active site of Bruton's tyrosine kinase (BTK) to sustain enzymatic inhibition, blocking B-cell receptor signalling and inhibiting malignant B-cell proliferation and survival.", "quote": "Ibrutinib is a potent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK)." }, "b": { "targets": [ "BTK" ], "modality": "small molecule", "label": "BTK inhibitor", "mechanism": "Ibrutinib covalently binds BTK at Cys-481, causing sustained inhibition of its enzymatic activity.", "quote": "Ibrutinib is a potent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK)." }, "decision": null }, "idecabtagene-vicleucel__abecma": { "url": "https://www.ema.europa.eu/en/documents/product-information/abecma-epar-product-information_en.pdf", "text": "Abecma is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation\nantigen (BCMA), which is expressed on the surface of normal and malignant plasma cells. The CAR\nconstruct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane\ndomain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific\nactivation of Abecma results in CAR-positive T cell proliferation, cytokine secretion and subsequent\ncytolytic killing of BCMA-expressing cells.", "a": { "targets": [ "BCMA" ], "modality": "cell therapy", "label": "BCMA-directed CAR T-cell therapy", "mechanism": "Binds BCMA on plasma cells to trigger CAR T-cell activation, proliferation, cytokine secretion, and cytolytic killing of BCMA-expressing cells.", "quote": "Abecma is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells." }, "b": { "targets": [ "BCMA" ], "modality": "cell therapy", "label": "BCMA-directed CAR T-cell therapy", "mechanism": "The CAR binds BCMA on plasma cells, activating T-cell proliferation and cytokine secretion that lead to cytolytic killing of BCMA-expressing cells.", "quote": "Abecma is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells." }, "decision": null }, "idelalisib__zydelig": { "url": "https://www.ema.europa.eu/en/documents/product-information/zydelig-epar-product-information_en.pdf", "text": "Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell\nmalignancies and is central to multiple signalling pathways that drive proliferation, survival, homing,\nand retention of malignant cells in lymphoid tissues and bone marrow. Idelalisib is a selective inhibitor\nof adenosine-5’-triphosphate (ATP) binding to the catalytic domain of PI3Kδ, resulting in inhibition of\n\n14\nthe phosphorylation of the key lipid second messenger phosphatidylinositol and prevention of Akt\n(protein kinase B) phosphorylation.\nIdelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B-cells and\nin primary tumour cells. Through inhibition of chemokine receptors CXCR4 and CXCR5 signalling\ninduced by the chemokines CXCL12 and CXCL13, respectively, idelalisib inhibits homing and\nretention of malignant B-cells in the tumour microenvironment including lymphoid tissues and the\nbone marrow.\nNo mechanistic explanations for the development of resistance to treatment with idelalisib have been\nidentified from clinical studies. Further investigation of this topic in current B-cell malignancy studies\nis not planned.", "a": { "targets": [ "PI3Kδ" ], "modality": "small molecule", "label": "PI3Kδ inhibitor", "mechanism": "Idelalisib selectively inhibits PI3Kδ by blocking ATP binding to its catalytic domain, preventing Akt phosphorylation and inducing apoptosis in malignant B-cells.", "quote": "Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signalling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow." }, "b": { "targets": [ "PI3Kδ" ], "modality": "small molecule", "label": "PI3Kδ inhibitor", "mechanism": "Idelalisib selectively inhibits ATP binding to PI3Kδ, blocking downstream signalling that supports malignant B-cell proliferation, survival, homing and retention.", "quote": "Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signalling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow." }, "decision": null }, "imatinib__glivec": { "url": "https://www.ema.europa.eu/en/documents/product-information/glivec-epar-product-information_en.pdf", "text": "Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the\nBcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor\n(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the\ncolony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and\nbeta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation\nof these receptor kinases.", "a": { "targets": [ "BCR-ABL", "KIT", "PDGFRA", "PDGFRB", "CSF-1R", "DDR1" ], "modality": "small molecule", "label": "BCR-ABL and receptor tyrosine kinase inhibitor", "mechanism": "Imatinib potently inhibits Bcr-Abl tyrosine kinase, Kit, DDR1/2, CSF-1R, and PDGFR-alpha/beta, suppressing cellular events mediated by activation of these receptor kinases.", "quote": "Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta)." }, "b": { "targets": [ "BCR-ABL", "KIT", "DDR1", "DDR2", "CSF1R", "PDGFRA/PDGFRB" ], "modality": "small molecule", "label": "Multikinase inhibitor (BCR-ABL, KIT, PDGFR)", "mechanism": "Imatinib inhibits BCR-ABL and several receptor tyrosine kinases, including KIT, DDR1/DDR2, CSF-1R and PDGFRα/β, and can inhibit cellular events mediated by their activation.", "quote": "Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta)." }, "decision": { "reason": "The text plainly names Bcr-Abl, Kit, DDR1/DDR2, CSF-1R and PDGFR-alpha/beta (\"potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs\"), so the readings differ only in how they order and format these targets. I kept the clinically central BCR-ABL, KIT and PDGFR first, within the six-target limit.", "targets": [ "BCR-ABL", "KIT", "PDGFRA", "PDGFRB", "DDR1/DDR2", "CSF1R" ], "modality": "small molecule", "label": "BCR-ABL tyrosine kinase inhibitor", "mechanism": "Imatinib inhibits the BCR-ABL tyrosine kinase and the receptor kinases KIT, PDGFRα/β, DDR1/DDR2 and CSF-1R, blocking cellular events driven by their activation.", "quote": "Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta).", "ambiguous": false } }, "imetelstat__rytelo": { "url": "https://www.ema.europa.eu/en/documents/product-information/rytelo-epar-product-information_en.pdf", "text": "Imetelstat is an oligonucleotide telomerase inhibitor that binds to the template region of the RNA\ncomponent of human telomerase (hTR), which prevents telomere binding.\nTelomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression are known\nto be significantly increased in MDS and malignant stem and progenitor cells. Imetelstat treatment\nleads to reduction of telomere length, inhibition of malignant stem and progenitor cell proliferation\nand induction of apoptotic cell death leading to reduction of malignant clones.", "a": { "targets": [ "telomerase", "hTR" ], "modality": "other", "label": "Oligonucleotide telomerase inhibitor", "mechanism": "Binds the template region of the RNA component of human telomerase (hTR), preventing telomere binding, reducing telomere length, and inducing apoptosis in malignant cells.", "quote": "Imetelstat is an oligonucleotide telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), which prevents telomere binding." }, "b": { "targets": [ "TERC" ], "modality": "other", "label": "Telomerase inhibitor (oligonucleotide)", "mechanism": "Binds the template region of the telomerase RNA component, preventing telomere binding and reducing telomere length.", "quote": "Imetelstat is an oligonucleotide telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), which prevents telomere binding." }, "decision": { "reason": "The text plainly names the target as \"the RNA component of human telomerase (hTR)\", so the answer is not open; telomerase (hTR) is used rather than the gene symbol TERC, which the text does not use, and hTERT is mentioned only as overexpressed, not as the binding site.", "targets": [ "telomerase RNA component (hTR)" ], "modality": "other", "label": "Oligonucleotide telomerase inhibitor", "mechanism": "Oligonucleotide that binds the template region of telomerase's RNA component (hTR), blocking telomere binding; shortens telomeres and causes apoptosis of malignant stem and progenitor cells.", "quote": "Imetelstat is an oligonucleotide telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), which prevents telomere binding.", "ambiguous": false } }, "imlunestrant__inluriyo": { "url": "https://www.ema.europa.eu/en/documents/product-information/inluriyo-epar-product-information_en.pdf", "text": "Imlunestrant is an antagonist and degrader of wild-type and mutant oestrogen receptor-α (ERα),\nleading to inhibition of oestrogen receptor-dependent gene transcription and cellular proliferation in\nER-positive breast cancer cells.", "a": { "targets": [ "estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Imlunestrant antagonises and degrades wild-type and mutant ERα, inhibiting estrogen receptor-dependent gene transcription and cell proliferation in ER-positive breast cancer.", "quote": "Imlunestrant is an antagonist and degrader of wild-type and mutant oestrogen receptor-α (ERα), leading to inhibition of oestrogen receptor-dependent gene transcription and cellular proliferation in ER-positive breast cancer cells." }, "b": { "targets": [ "ERα (ESR1)" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Imlunestrant antagonises and degrades wild-type and mutant ERα, inhibiting oestrogen receptor-dependent gene transcription and cellular proliferation in ER-positive breast cancer cells.", "quote": "Imlunestrant is an antagonist and degrader of wild-type and mutant oestrogen receptor-α (ERα), leading to inhibition of oestrogen receptor-dependent gene transcription and cellular proliferation in ER-positive breast cancer cells." }, "decision": { "reason": "The two readings differ only in how the target is written; the text names it precisely as \"oestrogen receptor-α (ERα)\", so \"ERα\" is the faithful target name and nothing is left open.", "targets": [ "ERα" ], "modality": "small molecule", "label": "Selective estrogen receptor degrader", "mechanism": "Imlunestrant antagonises and degrades wild-type and mutant ERα, inhibiting oestrogen receptor-dependent gene transcription and cell proliferation in ER-positive breast cancer cells.", "quote": "Imlunestrant is an antagonist and degrader of wild-type and mutant oestrogen receptor-α (ERα), leading to inhibition of oestrogen receptor-dependent gene transcription and cellular proliferation in ER-positive breast cancer cells.", "ambiguous": false } }, "inavolisib__itovebi": { "url": "https://www.ema.europa.eu/en/documents/product-information/itovebi-epar-product-information_en.pdf", "text": "Inavolisib is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic\nsubunit alpha isoform protein (p110α; encoded by the PIK3CA gene). In addition, inavolisib promotes\nthe degradation of mutated p110α (mutant degrader). The PI3K signalling pathway is commonly\ndysregulated in HR-positive breast cancer, often due to activating PIK3CA mutations. With its dual\nmechanism of action, inavolisib inhibits the activity of downstream PI3K pathway targets, including\nAKT, resulting in reduced cellular proliferation and induction of apoptosis in PIK3CA-mutated breast\ncancer cell lines.", "a": { "targets": [ "PI3Kα" ], "modality": "small molecule", "label": "PI3Kα inhibitor and mutant degrader", "mechanism": "Inavolisib inhibits the PI3K catalytic subunit alpha isoform (p110α) and degrades mutated p110α, blocking downstream PI3K pathway signaling to reduce cell proliferation and induce apoptosis.", "quote": "Inavolisib is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha isoform protein (p110α; encoded by the PIK3CA gene)." }, "b": { "targets": [ "PI3Kα (p110α; PIK3CA)", "AKT" ], "modality": "small molecule", "label": "PI3Kα inhibitor and mutant p110α degrader", "mechanism": "Inavolisib inhibits PI3Kα and promotes degradation of mutated p110α, reducing downstream PI3K pathway activity, including AKT, and suppressing cancer cell proliferation.", "quote": "Inavolisib is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha isoform protein (p110α; encoded by the PIK3CA gene)." }, "decision": { "reason": "The text names only p110α as the direct target (\"an inhibitor of the ... PI3K catalytic subunit alpha isoform protein (p110α...)\"); AKT is mentioned only as a downstream pathway component, not a target, so Reading 2 is correct.", "targets": [ "PI3Kα" ], "modality": "small molecule", "label": "PI3Kα inhibitor and mutant degrader", "mechanism": "Inavolisib inhibits the PI3K catalytic subunit alpha (p110α) and degrades mutated p110α, reducing downstream PI3K/AKT signalling, cell proliferation and survival.", "quote": "Inavolisib is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha isoform protein (p110α; encoded by the PIK3CA gene).", "ambiguous": false } }, "inotuzumab-ozogamicin__besponsa": { "url": "https://www.ema.europa.eu/en/documents/product-information/besponsa-epar-product-information_en.pdf", "text": "Inotuzumab ozogamicin is an ADC composed of a CD22-directed monoclonal antibody that is\ncovalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inotuzumab is a humanised\nimmunoglobulin class G subtype 4 (IgG4) antibody that specifically recognises human CD22. The\nsmall molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic product.\nN-acetyl-gamma-calicheamicin is covalently attached to the antibody via an acid-cleavable linker.\nNonclinical data suggest that the anticancer activity of BESPONSA is due to the binding of the ADC\nto CD22-expressing tumour cells, followed by internalisation of the ADC-CD22 complex, and the\nintracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of\nthe linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-stranded\nDNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.", "a": { "targets": [ "CD22" ], "modality": "antibody-drug conjugate", "label": "CD22-directed antibody-drug conjugate", "mechanism": "Binds CD22-expressing tumour cells and internalises to intracellularly release calicheamicin, which induces double-stranded DNA breaks and apoptotic cell death.", "quote": "Inotuzumab ozogamicin is an ADC composed of a CD22-directed monoclonal antibody that is covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide." }, "b": { "targets": [ "CD22" ], "modality": "antibody-drug conjugate", "label": "CD22-directed antibody-drug conjugate", "mechanism": "The ADC binds CD22-expressing tumour cells and is internalised; intracellular release of calicheamicin causes double-stranded DNA breaks, cell-cycle arrest and apoptotic cell death.", "quote": "Inotuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody that specifically recognises human CD22." }, "decision": null }, "ipilimumab__yervoy": { "url": "https://www.ema.europa.eu/en/documents/product-information/yervoy-epar-product-information_en.pdf", "text": "Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab is\na CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4\npathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell\nimmune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function,\nwhich may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete\nT-regulatory cells at the tumour site, leading to an increase in the intratumoural T-effector/\nT-regulatory cell ratio which drives tumour cell death.", "a": { "targets": [ "CTLA-4" ], "modality": "monoclonal antibody", "label": "CTLA-4 immune checkpoint inhibitor", "mechanism": "Ipilimumab blocks CTLA-4-induced inhibitory signals, increasing reactive T-effector cells and reducing regulatory T-cell function to drive an immune attack against tumour cells.", "quote": "Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell immune attack against tumour cells." }, "b": { "targets": [ "CTLA-4" ], "modality": "monoclonal antibody", "label": "CTLA-4 inhibitor (antibody)", "mechanism": "Blocks inhibitory signals through CTLA-4, increasing reactive T-effector cells and promoting an anti-tumour immune response.", "quote": "Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell immune attack against tumour cells." }, "decision": null }, "isatuximab__sarclisa": { "url": "https://www.ema.europa.eu/en/documents/product-information/sarclisa-epar-product-information_en.pdf", "text": "Isatuximab is an IgG1-derived monoclonal antibody that binds to a specific extracellular epitope of\nCD38 receptor. CD38 is a transmembrane glycoprotein that is highly expressed on multiple myeloma\ncells.\nIn vitro, isatuximab acts through IgG Fc-dependent mechanisms including: antibody dependent cell\nmediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement\ndependent cytotoxicity (CDC). Furthermore, isatuximab can also trigger tumour cell death by\ninduction of apoptosis via an Fc-independent mechanism.\nIn vitro, isatuximab blocks the enzymatic activity of CD38 which catalyses the synthesis and\nhydrolysis of cyclic ADP-ribose (cADPR), a calcium mobilizing agent. Isatuximab inhibits the\ncADPR production from extracellular nicotinamide adenine dinucleotide (NAD) in multiple myeloma\ncells.\nIn vitro, isatuximab can activate NK cells in the absence of CD38 positive target tumour cells.\nIn vivo, a decrease in absolute counts of total CD16+ and CD56+ NK cells, CD19+ B-cells, CD4+\nT- cells and TREG (CD3+, CD4+, CD25+, CD127-) was observed in peripheral blood of patients\ntreated with isatuximab monotherapy.\nIn multiple myeloma patients, isatuximab monotherapy induced clonal expansion of the T-cell\nreceptor repertoire indicating an adaptive immune response.\nThe combination of isatuximab and pomalidomide in vitro enhances cell lysis of CD38 expressing\nmultiple myeloma cells by effector cells (ADCC), and by direct tumour cell killing compared to that\nof isatuximab alone. In vivo animal experiments using a human multiple myeloma xenograft model in\nmice demonstrated that the combination of isatuximab and pomalidomide results in enhanced\nantitumour activity compared to the activity of isatuximab or pomalidomide alone.", "a": { "targets": [ "CD38" ], "modality": "monoclonal antibody", "label": "CD38-directed monoclonal antibody", "mechanism": "Binds CD38 on myeloma cells to trigger tumour cell death via ADCC, ADCP, CDC, and apoptosis, while inhibiting CD38 enzymatic activity.", "quote": "Isatuximab is an IgG1-derived monoclonal antibody that binds to a specific extracellular epitope of CD38 receptor." }, "b": { "targets": [ "CD38" ], "modality": "monoclonal antibody", "label": "CD38-directed monoclonal antibody", "mechanism": "Binds an extracellular epitope of CD38 and can mediate tumour-cell killing through Fc-dependent mechanisms, induce apoptosis, and inhibit CD38 enzymatic activity.", "quote": "Isatuximab is an IgG1-derived monoclonal antibody that binds to a specific extracellular epitope of CD38 receptor." }, "decision": null }, "ivosidenib__tibsovo": { "url": "https://www.ema.europa.eu/en/documents/product-information/tibsovo-epar-product-information_en.pdf", "text": "Ivosidenib is an inhibitor of the mutant IDH1 enzyme. Mutant IDH1 converts alpha- ketoglutarate (α-\nKG) to 2-hydroxyglutarate (2-HG) which blocks cellular differentiation and promotes tumorigenesis\nin both hematologic and non-hematologic malignancies. The mechanism of action of ivosidenib\nbeyond its ability to reduce 2-HG and restore cellular differentiation is not fully understood across\nindications.", "a": { "targets": [ "IDH1" ], "modality": "small molecule", "label": "Mutant IDH1 inhibitor", "mechanism": "Ivosidenib inhibits the mutant IDH1 enzyme, reducing 2-hydroxyglutarate levels and restoring cellular differentiation.", "quote": "Ivosidenib is an inhibitor of the mutant IDH1 enzyme." }, "b": { "targets": [ "IDH1" ], "modality": "small molecule", "label": "Mutant IDH1 inhibitor", "mechanism": "Ivosidenib inhibits mutant IDH1, reducing 2-HG and restoring cellular differentiation.", "quote": "Ivosidenib is an inhibitor of the mutant IDH1 enzyme." }, "decision": null }, "ixazomib__ninlaro": { "url": "https://www.ema.europa.eu/en/documents/product-information/ninlaro-epar-product-information_en.pdf", "text": "Ixazomib citrate, a prodrug, is a substance that rapidly hydrolyses under physiological conditions to its\nbiologically active form, ixazomib.\nIxazomib is an oral, highly selective and reversible proteasome inhibitor. Ixazomib preferentially\nbinds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.\nIxazomib induced apoptosis of several tumour cell types in vitro. Ixazomib demonstrated in vitro\ncytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies,\nincluding bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and\nlenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo,\nixazomib demonstrated antitumour activity in various tumour xenograft models, including models of\nmultiple myeloma. In vitro, ixazomib affected cell types found in the bone marrow microenvironment\nincluding vascular endothelial cells, osteoclasts and osteoblasts.\n\n13", "a": { "targets": [ "20S proteasome" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Ixazomib selectively and reversibly binds and inhibits the chymotrypsin-like activity of the 20S proteasome beta 5 subunit, inducing tumour cell apoptosis.", "quote": "Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome." }, "b": { "targets": [ "PSMB5" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Ixazomib preferentially binds and reversibly inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.", "quote": "Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome." }, "decision": { "reason": "The text names a specific target, \"the beta 5 subunit of the 20S proteasome\", whose standard gene symbol is PSMB5, so Reading 1's target is more precise; Reading 2's mention of apoptosis is also supported by the text, so the mechanism combines both.", "targets": [ "PSMB5" ], "modality": "small molecule", "label": "Proteasome inhibitor", "mechanism": "Oral prodrug whose active form reversibly binds and inhibits the chymotrypsin-like activity of the 20S proteasome beta 5 subunit, inducing tumour cell apoptosis.", "quote": "Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.", "ambiguous": false } }, "lapatinib__tyverb": { "url": "https://www.ema.europa.eu/en/documents/product-information/tyverb-epar-product-information_en.pdf", "text": "Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both\nEGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Kiapp values of 3nM and 13nM,\nrespectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes).\nLapatinib inhibits ErbB-driven tumour cell growth in vitro and in various animal models.\nThe combination of lapatinib and trastuzumab may offer complementary mechanisms of action as well\nas possible non-overlapping mechanisms of resistance. The growth inhibitory effects of lapatinib were\nevaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against\nHER2-amplified breast cancer cell lines selected for long-term growth in trastuzumab-containing\nmedium in vitro and was synergistic in combination with trastuzumab in these cell lines.", "a": { "targets": [ "EGFR", "HER2" ], "modality": "small molecule", "label": "Dual EGFR and HER2 kinase inhibitor", "mechanism": "Lapatinib inhibits the intracellular tyrosine kinase domains of both EGFR and HER2 receptors, thereby inhibiting ErbB-driven tumour cell growth.", "quote": "Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes)." }, "b": { "targets": [ "EGFR", "HER2" ], "modality": "small molecule", "label": "EGFR/HER2 tyrosine kinase inhibitor", "mechanism": "Lapatinib inhibits the intracellular tyrosine kinase domains of EGFR and HER2 receptors, suppressing ErbB-driven tumour cell growth.", "quote": "Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes)." }, "decision": null }, "larotrectinib__vitrakvi": { "url": "https://www.ema.europa.eu/en/documents/product-information/vitrakvi-epar-product-information_en.pdf", "text": "Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor\nkinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target\nfor larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded\nby NTRK1, NTRK2 and NTRK3 genes, respectively. In a broad panel of purified enzyme assays,\nlarotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. The only other\nkinase activity occurred at 100-fold higher concentrations. In in vitro and in vivo tumour models,\nlarotrectinib demonstrated anti-tumour activity in cells with constitutive activation of TRK proteins\nresulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein\noverexpression.\nIn-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1,\nNTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel\nchimeric oncogenic proteins are aberrantly expressed, driving constitutive kinase activity subsequently\nactivating downstream cell signalling pathways involved in cell proliferation and survival leading to\nTRK fusion-positive cancer.\nAcquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib\nhad minimal activity in cell lines with point mutations in the TRKA kinase domain, including the\nclinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain\nwith clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.\nThe molecular causes for primary resistance to larotrectinib are not known. It is therefore not known if\nthe presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy\nof TRK inhibition. The measured impact of any concomitant genomic alterations on larotrectinib\nefficacy is provided below (see clinical efficacy).\n\n13", "a": { "targets": [ "TRKA", "TRKB", "TRKC" ], "modality": "small molecule", "label": "TRK inhibitor", "mechanism": "Larotrectinib is a selective ATP-competitive inhibitor of TRKA, TRKB, and TRKC that blocks constitutive kinase activity driving cell proliferation and survival in TRK fusion-positive cancer.", "quote": "The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively." }, "b": { "targets": [ "NTRK1", "NTRK2", "NTRK3" ], "modality": "small molecule", "label": "Selective TRK inhibitor", "mechanism": "Larotrectinib competitively inhibits ATP binding to TRKA, TRKB and TRKC, suppressing TRK kinase activity and downstream signaling.", "quote": "The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively." }, "decision": { "reason": "The text plainly names the targets as proteins, \"the TRK family of proteins inclusive of TRKA, TRKB, and TRKC\", with NTRK1-3 given as the encoding genes, so the protein names fit the instruction better than the gene names in Reading 1; the answer is not open.", "targets": [ "TRKA", "TRKB", "TRKC" ], "modality": "small molecule", "label": "Selective TRK inhibitor", "mechanism": "Larotrectinib is a selective ATP-competitive inhibitor of TRKA, TRKB and TRKC that blocks constitutive kinase activity of oncogenic TRK fusion proteins driving proliferation and survival.", "quote": "The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively.", "ambiguous": false } }, "lazertinib__lazcluze": { "url": "https://www.ema.europa.eu/en/documents/product-information/lazcluze-epar-product-information_en.pdf", "text": "Lazertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI). It selectively inhibits both primary\nactivating EGFR mutations (exon 19 deletions and exon 21 L858R substitution mutations) and the\nEGFR T790M resistance mutation, while having less activity against wild-type EGFR.", "a": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR tyrosine kinase inhibitor", "mechanism": "Lazertinib is an irreversible EGFR tyrosine kinase inhibitor that selectively inhibits primary activating EGFR mutations and the T790M resistance mutation.", "quote": "Lazertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI)." }, "b": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR inhibitor (TKI)", "mechanism": "Irreversibly inhibits activating EGFR mutations and the EGFR T790M resistance mutation, with less activity against wild-type EGFR.", "quote": "Lazertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI)." }, "decision": null }, "lenalidomide__revlimid": { "url": "https://www.ema.europa.eu/en/documents/product-information/revlimid-epar-product-information_en.pdf", "text": "Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex\nthat includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and\nregulator of cullins 1 (Roc1). In haematopoietic cells, lenalidomide binding to cereblon recruits substrate\nproteins Aiolos and Ikaros, lymphoid transcriptional factors, leading to their ubiquitination and subsequent\ndegradation resulting in direct cytotoxic and immunomodulatory effects.\nSpecifically, lenalidomide inhibits proliferation and enhances apoptosis of certain haematopoietic tumour\ncells (including MM plasma tumour cells, follicular lymphoma tumour cells and those with deletions of\nchromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the number\nof NK, T and NK T cells. In MDS Del (5q), lenalidomide selectively inhibits the abnormal clone by\nincreasing the apoptosis of Del (5q) cells.\nThe combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular\nlymphoma cells.\nThe lenalidomide mechanism of action also includes additional activities such as anti-angiogenic and pro-\nerythropoietic properties. Lenalidomide inhibits angiogenesis by blocking the migration and adhesion of\nendothelial cells and the formation of microvessels, augments foetal haemoglobin production by CD34+\nhaematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by\nmonocytes.", "a": { "targets": [ "cereblon", "Aiolos", "Ikaros" ], "modality": "small molecule", "label": "Cereblon E3 ligase modulator", "mechanism": "Binds directly to cereblon to recruit and degrade transcription factors Aiolos and Ikaros, leading to direct cytotoxic, immunomodulatory, and anti-angiogenic effects.", "quote": "Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1)." }, "b": { "targets": [ "CRBN", "IKZF3", "IKZF1" ], "modality": "small molecule", "label": "Cereblon-modulating immunomodulatory agent", "mechanism": "Binds cereblon, recruiting Aiolos and Ikaros for ubiquitination and degradation, which produces direct cytotoxic and immunomodulatory effects.", "quote": "Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1)." }, "decision": { "reason": "The two readings agree on substance and differ only in naming style; the text plainly states \"Lenalidomide binds directly to cereblon\" and that this \"recruits substrate proteins Aiolos and Ikaros\" for degradation, so I used standard gene symbols (CRBN, IKZF3, IKZF1) and the label clinicians use.", "targets": [ "CRBN", "IKZF3", "IKZF1" ], "modality": "small molecule", "label": "Immunomodulatory agent (cereblon modulator)", "mechanism": "Binds cereblon in the CRL4 E3 ubiquitin ligase, recruiting Aiolos and Ikaros for ubiquitination and degradation, giving direct cytotoxic, immunomodulatory and anti-angiogenic effects.", "quote": "Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1).", "ambiguous": false } }, "lenvatinib__kisplyx": { "url": "https://www.ema.europa.eu/en/documents/product-information/kisplyx-epar-product-information_en.pdf", "text": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of\nvascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and\nVEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including\nfibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor\n(PDGF) receptor PDGFRα, KIT, and RET. In syngeneic mouse tumour models, lenvatinib decreased\ntumour-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater\nantitumour activity in combination with an anti-PD-1 monoclonal antibody compared to either\ntreatment alone.\nThe combination of lenvatinib and everolimus showed increased antiangiogenic and antitumour\nactivity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF\nsignalling in vitro and tumour volume in mouse xenograft models of human renal cell cancer greater\nthan each substance alone.\n\n22\nAlthough not studied directly with lenvatinib, the mechanism of action (MOA) for hypertension is\npostulated to be mediated by the inhibition of VEGFR2 in vascular endothelial cells. Similarly,\nalthough not studied directly, the MOA for proteinuria is postulated to be mediated by downregulation\nof VEGFR1 and VEGFR2 in the podocytes of the glomerulus.\nThe mechanism of action for hypothyroidism is not fully elucidated.\nThe mechanism of action for the worsening of hypercholesterolaemia with the combination of\nlenvatinib and everolimus has not been studied directly and is not fully elucidated.\nAlthough not studied directly, the MOA for the worsening of diarrhoea with the combination of\nlenvatinib and everolimus is postulated to be mediated by the impairment of intestinal function related\nto the MOAs for the individual agents – VEGF/VEGFR and c-KIT inhibition by lenvatinib coupled\nwith mTOR/NHE3 inhibition by everolimus.", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "PDGFRA", "KIT", "RET" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, FGFR, RET)", "mechanism": "Lenvatinib selectively inhibits VEGFR1, VEGFR2, and VEGFR3 kinase activity, as well as FGFR1-4, PDGFRα, KIT, and RET, suppressing proangiogenic and oncogenic signalling pathways.", "quote": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET." }, "b": { "targets": [ "FLT1 (VEGFR1)", "KDR (VEGFR2)", "FLT4 (VEGFR3)", "FGFR1/2/3/4", "PDGFRA", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, FGFR, PDGFR, KIT, RET)", "mechanism": "Lenvatinib inhibits kinase activity of VEGFR1–3 and other proangiogenic and oncogenic pathway-related RTKs, including FGFR1–4, PDGFRα, KIT and RET.", "quote": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET." }, "decision": { "reason": "The text names the targets plainly: \"selectively inhibits the kinase activities of ... VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to ... FGFR1, 2, 3, and 4 ... PDGFRα, KIT, and RET\". Reading 1 leaves out FGFR, which the text names second, and Reading 2's label runs past seven words and its list drops RET, so a combined list within six entries is used.", "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "FGFR1-4", "PDGFRA", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, FGFR, PDGFRα, KIT, RET)", "mechanism": "Small-molecule RTK inhibitor that blocks the kinase activity of VEGFR1–3 and also FGFR1–4, PDGFRα, KIT and RET, suppressing proangiogenic and oncogenic signalling.", "quote": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET.", "ambiguous": false } }, "lenvatinib__lenvima": { "url": "https://www.ema.europa.eu/en/documents/product-information/lenvima-epar-product-information_en.pdf", "text": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of\nvascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and\nVEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including\nfibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor\n(PDGF) receptor PDGFRα, KIT, and RET.\nIn addition, lenvatinib had selective, direct antiproliferative activity in hepatocellular cell lines\ndependent on activated FGFR signalling, which is attributed to the inhibition of FGFR signalling by\nlenvatinib.\nIn syngeneic mouse tumour models, lenvatinib decreased tumour-associated macrophages, increased\nactivated cytotoxic T cells, and demonstrated greater antitumour activity in combination with an anti-\nPD-1 monoclonal antibody compared to either treatment alone.\nAlthough not studied directly with lenvatinib, the mechanism of action (MOA) for hypertension is\npostulated to be mediated by the inhibition of VEGFR2 in vascular endothelial cells. Similarly,\nalthough not studied directly, the MOA for proteinuria is postulated to be mediated by downregulation\nof VEGFR1 and VEGFR2 in the podocytes of the glomerulus.\nThe mechanism of action for hypothyroidism is not fully elucidated.\n\n30", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "FGFR1", "FGFR2", "PDGFRA" ], "modality": "small molecule", "label": "Multikinase inhibitor", "mechanism": "Lenvatinib is a receptor tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, FGFR1–4, PDGFRα, KIT, and RET kinase activities, suppressing proangiogenic and oncogenic signaling pathways.", "quote": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET." }, "b": { "targets": [ "VEGFR1 (FLT1)", "VEGFR2 (KDR)", "VEGFR3 (FLT4)", "FGFR1", "FGFR2", "FGFR3" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, FGFR, PDGFRα, KIT, RET)", "mechanism": "Lenvatinib selectively inhibits VEGFR1–3 and other proangiogenic and oncogenic receptor tyrosine kinases, including FGFRs, PDGFRα, KIT and RET.", "quote": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET." }, "decision": { "reason": "The text plainly calls lenvatinib a small-molecule RTK inhibitor of \"VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to… FGFR1, 2, 3, and 4, the… PDGFRα, KIT, and RET\"; with a six-target cap I kept the first-named VEGFRs and FGFRs, using standard symbols.", "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "FGFR1", "FGFR2", "FGFR3" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, FGFR, PDGFRα, KIT, RET)", "mechanism": "Small-molecule inhibitor of VEGFR1–3 kinases and other proangiogenic and oncogenic RTKs (FGFR1–4, PDGFRα, KIT, RET), blocking tumour angiogenesis and FGFR-driven proliferation.", "quote": "Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET.", "ambiguous": false } }, "leuprorelin__camcevi": { "url": "https://www.ema.europa.eu/en/documents/product-information/camcevi-epar-product-information_en.pdf", "text": "Leuprorelin mesilate is a synthetic nonapeptide agonist of naturally occurring GnRH that, when\ngiven continuously, inhibits pituitary gonadotropin secretion and suppresses testicular\nsteroidogenesis in males. This effect is reversible upon discontinuation of medicinal product\ntherapy. However, the agonist possesses greater potency than the natural hormone and the time\nto recovery of testosterone levels may vary between patients.", "a": { "targets": [ "GnRH receptor" ], "modality": "protein or peptide", "label": "GnRH receptor agonist", "mechanism": "Leuprorelin is a synthetic GnRH agonist that, when administered continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis.", "quote": "Leuprorelin mesilate is a synthetic nonapeptide agonist of naturally occurring GnRH that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males." }, "b": { "targets": [ "GnRH" ], "modality": "protein or peptide", "label": "GnRH agonist (peptide)", "mechanism": "When given continuously, leuprorelin inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males.", "quote": "Leuprorelin mesilate is a synthetic nonapeptide agonist of naturally occurring GnRH that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males." }, "decision": { "reason": "The instructions say a hormonal medicine's target is named as the receptor, and the text calls leuprorelin \"a synthetic nonapeptide agonist of naturally occurring GnRH\", which means it acts at the GnRH receptor rather than on the hormone itself, so Reading 1 is right.", "targets": [ "GnRH receptor" ], "modality": "protein or peptide", "label": "GnRH receptor agonist", "mechanism": "Synthetic nonapeptide GnRH agonist that, given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis (testosterone production), reversibly.", "quote": "Leuprorelin mesilate is a synthetic nonapeptide agonist of naturally occurring GnRH that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males.", "ambiguous": false } }, "linvoseltamab__lynozyfic": { "url": "https://www.ema.europa.eu/en/documents/product-information/lynozyfic-epar-product-information_en.pdf", "text": "Linvoseltamab is a human IgG4-based bispecific antibody that binds to cluster of differentiation 3\n(CD3), a T-cell antigen associated with the T-cell receptor complex, and B-cell maturation antigen\n(BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as\nlate-stage B cells and plasma cells. Simultaneous engagement of both arms of linvoseltamab results in\nformation of a synapse between the T-cell and the BCMA-expressing cell, resulting in T-cell\nactivation and generation of polyclonal cytotoxic T-cell response, which result in redirected lysis of\nthe targeted cells, including malignant multiple myeloma B-lineage cells. This effect occurs without\nregard to T-cell receptor specificity or reliance on major histocompatibility complex (MHC) Class I\nmolecules on the surface of antigen-presenting cells.", "a": { "targets": [ "BCMA", "CD3" ], "modality": "bispecific antibody", "label": "BCMA × CD3 bispecific antibody", "mechanism": "It binds CD3 on T cells and BCMA on malignant myeloma cells, triggering T-cell activation and redirected lysis of BCMA-expressing cells.", "quote": "Linvoseltamab is a human IgG4-based bispecific antibody that binds to cluster of differentiation 3 (CD3), a T-cell antigen associated with the T-cell receptor complex, and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells." }, "b": { "targets": [ "CD3", "BCMA" ], "modality": "bispecific antibody", "label": "BCMA × CD3 bispecific antibody", "mechanism": "It binds CD3 on T cells and BCMA on malignant and late-stage B cells and plasma cells, bringing them together to activate T cells and redirect cell lysis.", "quote": "Linvoseltamab is a human IgG4-based bispecific antibody that binds to cluster of differentiation 3 (CD3), a T-cell antigen associated with the T-cell receptor complex, and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells." }, "decision": null }, "lisocabtagene-maraleucel__breyanzi": { "url": "https://www.ema.europa.eu/en/documents/product-information/breyanzi-epar-product-information_en.pdf", "text": "Breyanzi is a CD19-directed genetically modified autologous cellular immunotherapy administered as\na defined composition to reduce variability in CD8+ and CD4+ T-cell dose. The CAR is comprised of\na murine FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge\nregion, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation\ndomain. CD3 zeta signalling is critical for initiating T-cell activation and antitumour activity, while\n4- 1BB (CD137) signalling enhances the expansion and persistence of Breyanzi (see section 5.2).\nCAR binding to CD19 expressed on the cell surface of tumour and normal B-cells induces activation\nand proliferation of CAR T-cells, release of pro-inflammatory cytokines, and cytotoxic killing of\ntarget cells.", "a": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "CAR binding to CD19 on tumour and normal B cells activates CAR T cells, inducing proliferation, cytokine release, and cytotoxic killing of target cells.", "quote": "CAR binding to CD19 expressed on the cell surface of tumour and normal B-cells induces activation and proliferation of CAR T-cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells." }, "b": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "CAR binding to CD19 on tumour and normal B-cells activates and expands CAR T-cells, leading to cytokine release and cytotoxic killing of target cells.", "quote": "CAR binding to CD19 expressed on the cell surface of tumour and normal B-cells induces activation and proliferation of CAR T-cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells." }, "decision": null }, "loncastuximab-tesirine__zynlonta": { "url": "https://www.ema.europa.eu/en/documents/product-information/zynlonta-epar-product-information_en.pdf", "text": "Loncastuximab tesirine is an antibody-drug conjugate (ADC) targeting CD19. The monoclonal IgG1\nkappa antibody component binds to human CD19, a transmembrane protein expressed on the surface\nof cells of B-lineage origin. The small molecule component is SG3199, a PBD dimer and alkylating\nagent.\nUpon binding to CD19, loncastuximab tesirine is internalised followed by release of SG3199 via\nproteolytic cleavage. The released SG3199 binds to the DNA minor groove and forms highly\ncytotoxic DNA interstrand crosslinks, subsequently inducing cell death.", "a": { "targets": [ "CD19" ], "modality": "antibody-drug conjugate", "label": "CD19-directed antibody-drug conjugate", "mechanism": "Binds to CD19 on B-lineage cells, is internalised, and releases SG3199 which forms cytotoxic DNA interstrand crosslinks to induce cell death.", "quote": "Loncastuximab tesirine is an antibody-drug conjugate (ADC) targeting CD19." }, "b": { "targets": [ "CD19" ], "modality": "antibody-drug conjugate", "label": "CD19-directed antibody-drug conjugate", "mechanism": "It binds CD19 and is internalised, releasing SG3199, which binds the DNA minor groove and forms cytotoxic interstrand crosslinks that induce cell death.", "quote": "Loncastuximab tesirine is an antibody-drug conjugate (ADC) targeting CD19." }, "decision": null }, "lorlatinib__lorviqua": { "url": "https://www.ema.europa.eu/en/documents/product-information/lorviqua-epar-product-information_en.pdf", "text": "15\nLorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-ros\noncogene 1 (ROS1) tyrosine kinases.\nIn non-clinical studies, lorlatinib inhibited catalytic activities of non-mutated ALK and clinically\nrelevant ALK mutant kinases in recombinant enzyme and cell-based assays. Lorlatinib demonstrated\nmarked antitumour activity in mice bearing tumour xenografts that express echinoderm\nmicrotubule-associated protein-like 4 (EML4) fusions with ALK variant 1 (v1), including ALK\nmutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T,\nare known to confer resistance to alectinib, brigatinib, ceritinib, and crizotinib. Lorlatinib was also\ncapable of penetrating the blood-brain barrier. Lorlatinib demonstrated activity in mice bearing\northotopic EML4-ALK or EML4-ALKL1196M brain tumour implants.", "a": { "targets": [ "ALK", "ROS1" ], "modality": "small molecule", "label": "ALK and ROS1 inhibitor", "mechanism": "Lorlatinib is an ATP-competitive tyrosine kinase inhibitor that selectively inhibits non-mutated ALK, clinically relevant ALK mutant kinases, and ROS1.", "quote": "Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-ros oncogene 1 (ROS1) tyrosine kinases." }, "b": { "targets": [ "ALK", "ROS1" ], "modality": "small molecule", "label": "ALK/ROS1 inhibitor", "mechanism": "Lorlatinib competitively inhibits the ATP-binding sites of ALK and ROS1 tyrosine kinases.", "quote": "Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-ros oncogene 1 (ROS1) tyrosine kinases." }, "decision": null }, "lurbinectedin__zepzelca": { "url": "https://www.ema.europa.eu/en/documents/product-information/zepzelca-epar-product-information_en.pdf", "text": "Lurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequences\nof DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcription\nfactors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specific\ndegradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cell\ncycle arrest and tumour cell apoptosis.\nLurbinectedin suppresses the expression of inflammatory and motility-related genes at non-toxic\nnanomolar concentrations in vitro, while also inhibiting cell migration and adhesion. At higher\nconcentrations, it induces apoptosis in monocytes and macrophages through caspase-8 activation. In\nvivo (murine models), antitumour dosing (0.18–0.20 mg/kg) restricts tumour growth, reduces specific\nimmune cell populations, and decreases tumour vascularity.", "a": { "targets": [ "DNA" ], "modality": "small molecule", "label": "DNA-binding transcription inhibitor", "mechanism": "Lurbinectedin binds CG-rich DNA promoter sequences, evicts oncogenic transcription factors, stalls and degrades elongating RNA polymerase II, and triggers apoptosis.", "quote": "Lurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequences of DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specific degradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cell cycle arrest and tumour cell apoptosis." }, "b": { "targets": [ "DNA (CG-rich sequences)", "RNA polymerase II" ], "modality": "small molecule", "label": "DNA-binding transcription inhibitor", "mechanism": "Binds CG-rich DNA sequences, displaces oncogenic transcription factors, and stalls elongating RNA polymerase II, leading to its degradation and tumour cell apoptosis.", "quote": "Lurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequences of DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specific degradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cell cycle arrest and tumour cell apoptosis." }, "decision": { "reason": "The text names one binding target, \"its binding to CG-rich sequences of DNA\"; RNA polymerase II is stalled and degraded as a downstream effect rather than bound, so Reading 1's single target fits the text better.", "targets": [ "DNA (CG-rich promoter sequences)" ], "modality": "small molecule", "label": "DNA-binding transcription inhibitor", "mechanism": "Binds CG-rich DNA sequences in gene promoters, evicts oncogenic transcription factors and stalls elongating RNA polymerase II, causing its degradation, cell cycle arrest and tumour cell apoptosis.", "quote": "Lurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequences of DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specific degradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cell cycle arrest and tumour cell apoptosis.", "ambiguous": false } }, "lutetium-177lu-oxodotreotide__lutathera": { "url": "https://www.ema.europa.eu/en/documents/product-information/lutathera-epar-product-information_en.pdf", "text": "Lutetium (177Lu) oxodotreotide has a high affinity for subtype 2 somatostatin receptors (SSTR2). It\nbinds to malignant cells which overexpress SSTR2.\nLutetium-177 is a β- emitting radionuclide with a maximum penetration range in tissue of 2.2 mm\n(mean penetration range of 0.67 mm), causing death of the targeted tumour cells with a limited effect\non neighbouring normal cells.", "a": { "targets": [ "SSTR2" ], "modality": "radioligand", "label": "SSTR2-targeted radioligand", "mechanism": "Binds to subtype 2 somatostatin receptors on tumour cells and delivers beta-minus radiation to cause targeted cell death.", "quote": "Lutetium (177Lu) oxodotreotide has a high affinity for subtype 2 somatostatin receptors (SSTR2)." }, "b": { "targets": [ "SSTR2" ], "modality": "radioligand", "label": "SSTR2-targeted radioligand", "mechanism": "It binds SSTR2 on malignant cells and delivers beta radiation that kills targeted tumour cells, with limited effect on neighbouring normal cells.", "quote": "Lutetium (177Lu) oxodotreotide has a high affinity for subtype 2 somatostatin receptors (SSTR2)." }, "decision": null }, "lutetium-177lu-vipivotide-tetraxetan__pluvicto": { "url": "https://www.ema.europa.eu/en/documents/product-information/pluvicto-epar-product-information_en.pdf", "text": "The active moiety of Pluvicto is the radionuclide lutetium-177 which is linked to a small-molecule\nligand that targets and binds with high affinity to PSMA, a transmembrane protein that is highly\nexpressed in prostate cancer, including mCRPC. Upon the binding of Pluvicto to PSMA-expressing\ncancer cells, the beta-minus emission from lutetium-177 delivers therapeutic radiation to the targeted\ncell, as well as to surrounding cells, and induces DNA damage which can lead to cell death.", "a": { "targets": [ "PSMA" ], "modality": "radioligand", "label": "PSMA-directed radioligand therapy", "mechanism": "Binds to PSMA on prostate cancer cells to deliver targeted beta-minus radiation from lutetium-177, causing DNA damage and cell death.", "quote": "The active moiety of Pluvicto is the radionuclide lutetium-177 which is linked to a small-molecule ligand that targets and binds with high affinity to PSMA, a transmembrane protein that is highly expressed in prostate cancer, including mCRPC." }, "b": { "targets": [ "PSMA" ], "modality": "radioligand", "label": "PSMA-targeted radioligand therapy", "mechanism": "The ligand binds PSMA on cancer cells, delivering lutetium-177 beta-minus radiation that damages DNA and can lead to cell death.", "quote": "The active moiety of Pluvicto is the radionuclide lutetium-177 which is linked to a small-molecule ligand that targets and binds with high affinity to PSMA, a transmembrane protein that is highly expressed in prostate cancer, including mCRPC." }, "decision": null }, "midostaurin__rydapt": { "url": "https://www.ema.europa.eu/en/documents/product-information/rydapt-epar-product-information_en.pdf", "text": "Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin\ninhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukaemic cells\nexpressing FLT3 ITD or TKD mutant receptors or over-expressing FLT3 wild type receptors. In vitro\ndata indicate that midostaurin inhibits D816V mutant KIT receptors at exposure levels achieved in\npatients (average achieved exposure higher than IC50). In vitro data indicate that KIT wild type\nreceptors are inhibited to a much lesser extent at these concentrations (average achieved exposure\nlower than IC50). Midostaurin interferes with aberrant KIT D816V-mediated signalling and inhibits\nmast cell proliferation, survival and histamine release.\nIn addition, midostaurin inhibits several other receptor tyrosine kinases such as PDGFR\n(platelet-derived growth factor receptor) or VEGFR2 (vascular endothelial growth factor receptor 2),\nas well as members of the serine/threonine kinase family PKC (protein kinase C). Midostaurin binds to\nthe catalytic domain of these kinases and inhibits the mitogenic signalling of the respective growth\nfactors in cells, resulting in growth arrest.\nMidostaurin in combination with chemotherapeutic agents (cytarabine, doxorubicin, idarubicin and\ndaunorubicin) resulted in synergistic growth inhibition in FLT3-ITD expressing AML cell lines.", "a": { "targets": [ "FLT3", "KIT", "PDGFR", "VEGFR2", "PKC" ], "modality": "small molecule", "label": "Multikinase inhibitor (FLT3, KIT)", "mechanism": "Midostaurin binds the catalytic domain of receptor tyrosine kinases including FLT3 and KIT, inhibiting downstream signalling to cause cell cycle arrest and apoptosis.", "quote": "Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase." }, "b": { "targets": [ "FLT3", "KIT", "PDGFR", "VEGFR2", "PKC" ], "modality": "small molecule", "label": "Multikinase inhibitor (FLT3, KIT, PDGFR, VEGFR2)", "mechanism": "Midostaurin binds kinase catalytic domains and inhibits FLT3 and KIT signalling, causing cell-cycle arrest and apoptosis in leukaemic cells and inhibiting mast-cell proliferation and survival.", "quote": "Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase." }, "decision": null }, "mirdametinib__ezmekly": { "url": "https://www.ema.europa.eu/en/documents/product-information/ezmekly-epar-product-information_en.pdf", "text": "Mirdametinib is a selective, non‑competitive inhibitor of mitogen‑activated protein kinase kinases\n1 and 2 (MEK1/2). Mirdametinib blocks MEK activity and the rat sarcoma (RAS)‑rapidly accelerated\nfibrosarcoma (RAF)‑MEK pathway. Therefore, MEK inhibition blocks proliferation and survival of\ntumour cells in which the RAF‑MEK‑extracellular related kinase (ERK) pathway is activated.", "a": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Mirdametinib selectively and non-competitively inhibits MEK1/2, blocking downstream signaling to inhibit tumour cell proliferation and survival.", "quote": "Mirdametinib is a selective, non‑competitive inhibitor of mitogen‑activated protein kinase kinases 1 and 2 (MEK1/2)." }, "b": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Mirdametinib selectively inhibits MEK1/2, blocking MEK activity and the RAS-RAF-MEK pathway, which can block tumour-cell proliferation and survival when the RAF-MEK-ERK pathway is activated.", "quote": "Mirdametinib is a selective, non‑competitive inhibitor of mitogen‑activated protein kinase kinases 1 and 2 (MEK1/2)." }, "decision": null }, "mirvetuximab-soravtansine__elahere": { "url": "https://www.ema.europa.eu/en/documents/product-information/elahere-epar-product-information_en.pdf", "text": "Mirvetuximab soravtansine is an antibody-drug conjugate. The antibody is an engineered IgG1\ndirected against folate receptor alpha (FRα). The function of the antibody portion is to bind to FRα\nexpressed on the surface of ovarian cancer cells. DM4 is a microtubule inhibitor attached to the\n\n12\nantibody via a cleavable linker. Upon binding to FRα, mirvetuximab soravtansine is internalised\nfollowed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule\nnetwork within the cell, resulting in cell cycle arrest and apoptotic cell death.", "a": { "targets": [ "FRα" ], "modality": "antibody-drug conjugate", "label": "FRα-directed antibody-drug conjugate", "mechanism": "Binds FRα on cancer cells and internalises, releasing the microtubule inhibitor DM4 to disrupt the microtubule network and trigger cell cycle arrest and apoptosis.", "quote": "The antibody is an engineered IgG1 directed against folate receptor alpha (FRα)." }, "b": { "targets": [ "FOLR1 (FRα)" ], "modality": "antibody-drug conjugate", "label": "FRα-directed antibody-drug conjugate", "mechanism": "The antibody binds FRα on ovarian cancer cells, enabling internalisation and release of DM4, which disrupts microtubules and causes cell-cycle arrest and apoptosis.", "quote": "The antibody is an engineered IgG1 directed against folate receptor alpha (FRα)." }, "decision": { "reason": "Both readings agree on FRα as the target; the instructions list \"FRα\" as the standard symbol, so Reading 2's form is used, and the text is clear that the antibody is \"directed against folate receptor alpha (FRα)\".", "targets": [ "FRα" ], "modality": "antibody-drug conjugate", "label": "FRα-directed antibody-drug conjugate", "mechanism": "Binds FRα on ovarian cancer cells and is internalised, releasing the microtubule inhibitor DM4, which disrupts microtubules and causes cell cycle arrest and apoptosis.", "quote": "The antibody is an engineered IgG1 directed against folate receptor alpha (FRα).", "ambiguous": false } }, "mogamulizumab__poteligeo": { "url": "https://www.ema.europa.eu/en/documents/product-information/poteligeo-epar-product-information_en.pdf", "text": "Mogamulizumab is a defucosylated, humanised IgG1 kappa immunoglobulin that selectively binds to\nCCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking of\nlymphocytes to various organs including the skin, resulting in depletion of the target cells. CCR4 is\nexpressed on the surface of some cancer cells including T cell malignancies, such as MF and SS in\nwhich CCR4 expression is inherent.", "a": { "targets": [ "CCR4" ], "modality": "monoclonal antibody", "label": "CCR4-directed monoclonal antibody", "mechanism": "Selectively binds to CCR4 on lymphocytes and T-cell malignancies, resulting in depletion of the target cells.", "quote": "Mogamulizumab is a defucosylated, humanised IgG1 kappa immunoglobulin that selectively binds to CCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking of lymphocytes to various organs including the skin, resulting in depletion of the target cells." }, "b": { "targets": [ "CCR4" ], "modality": "monoclonal antibody", "label": "CCR4-targeting monoclonal antibody", "mechanism": "Binds CCR4, a chemokine receptor involved in lymphocyte trafficking, and depletes the target cells.", "quote": "Mogamulizumab is a defucosylated, humanised IgG1 kappa immunoglobulin that selectively binds to CCR4, a G protein-coupled receptor for CC chemokines that is involved in the trafficking of lymphocytes to various organs including the skin, resulting in depletion of the target cells." }, "decision": null }, "momelotinib__omjjara": { "url": "https://www.ema.europa.eu/en/documents/product-information/omjjara-epar-product-information_en.pdf", "text": "Momelotinib and its major human circulating metabolite (M21), are inhibitors of wild type Janus\nKinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F, which contribute to signalling of a number of\ncytokines and growth factors that are important for haematopoiesis and immune function. JAK1 and\nJAK2 recruit and activate STAT (signal transducer and activator of transcription) proteins that\ncontrol gene transcription impacting inflammation, haematopoiesis, and immune regulation.\nMyelofibrosis is a myeloproliferative neoplasm associated with constitutive activation and\ndysregulated JAK signalling that contributes to elevated inflammation and hyperactivation of activin\nA receptor type 1 (ACVR1), also known as activin receptor-like kinase 2 (ALK-2). Additionally,\nmomelotinib and M21 are direct inhibitors of ACVR1, which further down regulates liver hepcidin\nexpression resulting in increased iron availability and red blood cell production. Momelotinib and\nM21 potentially inhibit additional kinases, such as other JAK family members, inhibitor of κB kinase\n(IKK), interleukin-1 receptor-associated kinase 1 (IRAK1), and others.", "a": { "targets": [ "JAK1", "JAK2", "ACVR1" ], "modality": "small molecule", "label": "JAK1, JAK2, and ACVR1 inhibitor", "mechanism": "Momelotinib inhibits JAK1, JAK2, and ACVR1, reducing dysregulated cytokine and STAT signalling while down-regulating hepcidin expression to increase iron availability and red blood cell production.", "quote": "Momelotinib and its major human circulating metabolite (M21), are inhibitors of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F, which contribute to signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function." }, "b": { "targets": [ "JAK1", "JAK2", "JAK2 V617F", "ACVR1" ], "modality": "small molecule", "label": "JAK1/JAK2 and ACVR1 inhibitor", "mechanism": "Inhibits JAK1, JAK2 and mutant JAK2 V617F signalling, and directly inhibits ACVR1, lowering hepcidin and increasing iron availability and red blood cell production.", "quote": "Additionally, momelotinib and M21 are direct inhibitors of ACVR1, which further down regulates liver hepcidin expression resulting in increased iron availability and red blood cell production." }, "decision": { "reason": "The text names \"wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F\" and \"direct inhibitors of ACVR1\", so JAK1, JAK2 and ACVR1 are the main targets, with the V617F mutant as a variant of JAK2 that can be noted; the targets are clear and the readings differ only in granularity.", "targets": [ "JAK1", "JAK2", "ACVR1" ], "modality": "small molecule", "label": "JAK1/JAK2 and ACVR1 inhibitor", "mechanism": "Inhibits JAK1, JAK2 (including mutant JAK2 V617F) and STAT signalling, and directly inhibits ACVR1, lowering hepcidin and increasing iron availability and red blood cell production.", "quote": "Momelotinib and its major human circulating metabolite (M21), are inhibitors of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F, which contribute to signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function.", "ambiguous": false } }, "mosunetuzumab__lunsumio": { "url": "https://www.ema.europa.eu/en/documents/product-information/lunsumio-epar-product-information_en.pdf", "text": "Mosunetuzumab is an anti-CD20/CD3 T-cell engaging bispecific antibody targeting CD20-expressing\nB-cells. It is a conditional agonist; targeted B-cell killing is observed only upon simultaneous binding\nto CD20 on B-cells and CD3 on T-cells. Engagement of both arms of mosunetuzumab results in the\nformation of an immunologic synapse between a target B cell and a cytotoxic T cell leading to T-cell\n\n16\nactivation. Subsequent directed release of perforin and granzymes from T-cell activation through the\nimmunologic synapsis induce B-cell lysis leading to cell death.\nLunsumio caused B-cell depletion (defined as CD19 B-cell counts < 5 cells/uL) after the initial cycle\nof administration (by Cycle 2 Day 1) by both intravenous and subcutaneous administration routes in a\nmajority of patients (95.2% and 94.1% respectively) and depletion was maintained throughout the\nduration of treatment.", "a": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Simultaneously engages CD20 on B-cells and CD3 on T-cells, forming an immunological synapse that activates T-cells to induce B-cell lysis via perforin and granzymes.", "quote": "Mosunetuzumab is an anti-CD20/CD3 T-cell engaging bispecific antibody targeting CD20-expressing B-cells." }, "b": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "It binds CD20 on B cells and CD3 on T cells, forming an immunologic synapse that activates T cells to release perforin and granzymes and lyse B cells.", "quote": "Mosunetuzumab is an anti-CD20/CD3 T-cell engaging bispecific antibody targeting CD20-expressing B-cells." }, "decision": null }, "nadofaragene-firadenovec__adstiladrin": { "url": "https://www.ema.europa.eu/en/documents/product-information/adstiladrin-epar-product-information_en.pdf", "text": "ADSTILADRIN is a non-replicating recombinant type 5 adenovirus vector-based gene therapy\ncontaining the human IFNα2b transgene. Intravesical administration of ADSTILADRIN results in the\nentry of viral particles into the tumour cells and the urothelium that make up the luminal surface of the\nbladder, leading to the expression of IFNα2b protein by those cells. In the transduced cells, the viral\nDNA does not integrate into the genome. Treatment with nadofaragene firadenovec has shown anti-\ntumour effects in mice with bladder (cancer cell) xenografts.", "a": { "targets": [ "IFNα2b" ], "modality": "other", "label": "IFNα2b-expressing adenoviral gene therapy", "mechanism": "An adenoviral vector that enters bladder urothelial and tumour cells to drive local expression of IFNα2b protein, producing anti-tumour effects.", "quote": "ADSTILADRIN is a non-replicating recombinant type 5 adenovirus vector-based gene therapy containing the human IFNα2b transgene." }, "b": { "targets": [], "modality": "other", "label": "Intravesical adenoviral gene therapy", "mechanism": "The adenovirus vector enters tumour cells and bladder urothelium, causing them to express IFNα2b; the text does not name a molecular target.", "quote": "Intravesical administration of ADSTILADRIN results in the entry of viral particles into the tumour cells and the urothelium that make up the luminal surface of the bladder, leading to the expression of IFNα2b protein by those cells." }, "decision": { "reason": "The text describes a non-replicating adenoviral vector that makes cells express IFNα2b, but it names no receptor or molecular target. IFNα2b is the expressed transgene product, not a target, so targets stay empty and the text is not ambiguous on this.", "targets": [], "modality": "other", "label": "IFNα2b-expressing intravesical adenoviral gene therapy", "mechanism": "A non-replicating adenovirus vector enters bladder tumour cells and urothelium, causing them to express IFNα2b protein without integrating into the genome; the text names no molecular target.", "quote": "ADSTILADRIN is a non-replicating recombinant type 5 adenovirus vector-based gene therapy containing the human IFNα2b transgene.", "ambiguous": false } }, "neratinib__nerlynx": { "url": "https://www.ema.europa.eu/en/documents/product-information/nerlynx-epar-product-information_en.pdf", "text": "Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine\nkinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high\naffinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR\n(encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active\nheterodimers with HER3 (encoded by ERBB3). This results in sustained inhibition of these growth\npromoting pathways with HER2-amplified or over-expressed, or HER2-mutant breast cancers.\nNeratinib binds to the HER2 receptor, reduces EGFR and HER2 autophosphorylation, downstream\nMAPK and AKT signaling pathways, and potently inhibits tumour cell proliferation in vitro.\nNeratinib inhibited EGFR and/or HER2-expressing carcinoma cell lines with a cellular IC50\n<100 nM.", "a": { "targets": [ "HER2", "EGFR", "HER4", "HER3" ], "modality": "small molecule", "label": "Pan-HER tyrosine kinase inhibitor", "mechanism": "Irreversibly binds EGFR, HER2, and HER4 to inhibit receptor autophosphorylation and downstream MAPK and AKT pathways, blocking tumor cell proliferation.", "quote": "Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine kinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high affinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active heterodimers with HER3 (encoded by ERBB3)." }, "b": { "targets": [ "EGFR", "HER2", "HER4" ], "modality": "small molecule", "label": "Pan-ERBB tyrosine kinase inhibitor", "mechanism": "Neratinib covalently binds the ATP-binding sites of EGFR, HER2 and HER4, inhibiting their signaling pathways and tumour cell proliferation.", "quote": "Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine kinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high affinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active heterodimers with HER3 (encoded by ERBB3)." }, "decision": { "reason": "The text names three directly bound receptors, \"EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4)\", and mentions HER3 only as a heterodimer partner. So HER3 is not a direct target, and HER2 comes first given the HER2-driven breast cancer focus.", "targets": [ "HER2", "EGFR", "HER4" ], "modality": "small molecule", "label": "Irreversible pan-HER tyrosine kinase inhibitor", "mechanism": "Covalently and irreversibly binds the ATP site of EGFR, HER2 and HER4, reducing receptor autophosphorylation and downstream MAPK/AKT signalling and inhibiting tumour cell proliferation.", "quote": "Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine kinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high affinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active heterodimers with HER3 (encoded by ERBB3).", "ambiguous": false } }, "nilotinib__tasigna": { "url": "https://www.ema.europa.eu/en/documents/product-information/tasigna-epar-product-information_en.pdf", "text": "Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in\ncell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance binds with\nhigh affinity to the ATP-binding site in such a manner that it is a potent inhibitor of wild-type\nBCR-ABL and maintains activity against 32/33 imatinib-resistant mutant forms of BCR-ABL. As a\nconsequence of this biochemical activity, nilotinib selectively inhibits the proliferation and induces\napoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML\npatients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs\nsurvival following oral administration.", "a": { "targets": [ "BCR-ABL" ], "modality": "small molecule", "label": "BCR-ABL tyrosine kinase inhibitor", "mechanism": "Nilotinib binds the ATP-binding site of the BCR-ABL oncoprotein, inhibiting its kinase activity to block proliferation and induce apoptosis in Philadelphia-chromosome positive leukaemia cells.", "quote": "Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukaemia cells." }, "b": { "targets": [ "BCR-ABL" ], "modality": "small molecule", "label": "BCR-ABL tyrosine kinase inhibitor", "mechanism": "Nilotinib binds the ATP-binding site of BCR-ABL and inhibits its tyrosine kinase activity, suppressing proliferation and inducing apoptosis in Philadelphia-chromosome-positive leukaemia cells.", "quote": "Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukaemia cells." }, "decision": null }, "nintedanib__vargatef": { "url": "https://www.ema.europa.eu/en/documents/product-information/vargatef-epar-product-information_en.pdf", "text": "Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors\n(VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor\nreceptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate\n(ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the\nproliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth\nmuscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specific\ntyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "PDGFRA", "PDGFRB", "FGFR1" ], "modality": "small molecule", "label": "Triple angiokinase inhibitor", "mechanism": "Competitively binds the ATP-binding pocket of VEGFR 1-3, PDGFR α/ß, and FGFR 1-3, blocking downstream signaling essential for proliferation and survival of endothelial and perivascular cells.", "quote": "Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity." }, "b": { "targets": [ "VEGFR1-3", "PDGFRA", "PDGFRB", "FGFR1-3", "FLT3", "LCK" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, PDGFR, FGFR)", "mechanism": "Nintedanib competitively blocks the ATP-binding pockets of VEGFR1-3, PDGFRA/B and FGFR1-3, inhibiting intracellular signalling crucial for endothelial and perivascular cell proliferation and survival.", "quote": "Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity." }, "decision": { "reason": "The text plainly names the main targets first as \"VEGFR 1-3\", \"PDGFR α and ß\" and \"FGFR 1-3\", with Flt-3, Lck and Src as secondary, so it is not ambiguous. Reading 2 truncates FGFR to FGFR1 only, and Reading 1 adds secondary kinases instead of grouping the three main families, so the grouped main families are the better list.", "targets": [ "VEGFR1-3", "PDGFRA", "PDGFRB", "FGFR1-3" ], "modality": "small molecule", "label": "Triple angiokinase inhibitor (VEGFR, PDGFR, FGFR)", "mechanism": "Binds the ATP pocket of VEGFR1-3, PDGFRα/β and FGFR1-3, blocking signalling needed for endothelial and perivascular cell proliferation and survival; also inhibits FLT3, LCK and SRC.", "quote": "Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity.", "ambiguous": false } }, "niraparib-abiraterone-acetate__akeega": { "url": "https://www.ema.europa.eu/en/documents/product-information/akeega-epar-product-information_en.pdf", "text": "Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and\nabiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic\ndependencies in patients with metastatic prostate cancer and HRR gene mutations.\n\n15\nNiraparib\nNiraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2,\nwhich play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may\ninvolve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes,\nresulting in DNA damage, apoptosis and cell death.\nAbiraterone acetate\nAbiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor.\nSpecifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This\nenzyme is expressed in, and is required for, androgen biosynthesis in testicular, adrenal and prostatic\ntumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone\nprecursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the\nC17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals\n(see section 4.4).\nAndrogen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.\nAndrogen deprivation therapies, such as treatment with luteinising hormone releasing hormone\n(LHRH) analogues or orchiectomy, decrease androgen production in the testes but do not affect\nandrogen production by the adrenals or in the tumour. Treatment with abiraterone acetate decreases\nserum testosterone to undetectable levels (using commercial assays) when given with LHRH\nanalogues (or orchiectomy).", "a": { "targets": [ "PARP1", "PARP2", "CYP17A1" ], "modality": "small molecule", "label": "PARP and CYP17 inhibitor combination", "mechanism": "Niraparib inhibits PARP-1 and PARP-2 to impair DNA repair and trigger cell death, while abiraterone inhibits CYP17 to block androgen biosynthesis in testicular, adrenal, and prostatic tissues.", "quote": "Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and abiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic dependencies in patients with metastatic prostate cancer and HRR gene mutations." }, "b": { "targets": [ "PARP-1", "PARP-2", "CYP17A1" ], "modality": "small molecule", "label": "PARP and CYP17 inhibitor combination", "mechanism": "Niraparib inhibits PARP-1 and PARP-2, impairing DNA repair; abiraterone inhibits CYP17, decreasing androgen biosynthesis.", "quote": "Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and abiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic dependencies in patients with metastatic prostate cancer and HRR gene mutations." }, "decision": null }, "niraparib__zejula": { "url": "https://www.ema.europa.eu/en/documents/product-information/zejula-epar-product-information_en.pdf", "text": "Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2,\nwhich play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may\ninvolve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes\nresulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was\nobserved in tumour cell lines with or without deficiencies in the BReast CAncer (BRCA) 1 and 2\ntumour suppressor genes. In orthotopic high-grade serous ovarian cancer patient-derived xenograft\ntumours (PDX) grown in mice, niraparib has been shown to reduce tumour growth in BRCA 1 and 2\nmutant, BRCA wild-type but homologous recombination (HR) deficient, and in tumours that are BRCA\nwild-type and without detectable HR deficiency.", "a": { "targets": [ "PARP1", "PARP2" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Inhibits PARP-1 and PARP-2 enzymes and increases formation of PARP-DNA complexes, leading to DNA damage, apoptosis, and cell death.", "quote": "Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair." }, "b": { "targets": [ "PARP1", "PARP2" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Inhibits PARP-1 and PARP-2, which play a role in DNA repair; this may cause DNA damage, apoptosis and cell death.", "quote": "Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair." }, "decision": null }, "nirogacestat__ogsiveo": { "url": "https://www.ema.europa.eu/en/documents/product-information/ogsiveo-epar-product-information_en.pdf", "text": "Nirogacestat is a reversible and non‑competitive inhibitor of gamma secretase that blocks proteolytic\nactivation of the Notch receptor.", "a": { "targets": [ "gamma secretase" ], "modality": "small molecule", "label": "Gamma secretase inhibitor", "mechanism": "Reversibly and non-competitively inhibits gamma secretase, blocking the proteolytic activation of Notch receptors.", "quote": "Nirogacestat is a reversible and non‑competitive inhibitor of gamma secretase that blocks proteolytic activation of the Notch receptor." }, "b": { "targets": [ "gamma-secretase" ], "modality": "small molecule", "label": "Gamma-secretase inhibitor", "mechanism": "Nirogacestat reversibly and non-competitively inhibits gamma-secretase, blocking proteolytic activation of the Notch receptor.", "quote": "Nirogacestat is a reversible and non‑competitive inhibitor of gamma secretase that blocks proteolytic activation of the Notch receptor." }, "decision": null }, "nivolumab__opdivo": { "url": "https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf", "text": "Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to\nthe programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1\nreceptor is a negative regulator of T-cell activity that has been shown to be involved in the control of\nT-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are\nexpressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour\nmicroenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab\npotentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to\nPD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased\ntumour growth.\nCombined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in\nimproved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual\nblockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, potentiating anti-tumour T-cell responses.", "quote": "Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Nivolumab binds PD-1 and blocks its interaction with PD-L1 and PD-L2, potentiating T-cell responses, including anti-tumour responses.", "quote": "Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2." }, "decision": null }, "nogapendekin-alfa-inbakicept__anktiva": { "url": "https://www.ema.europa.eu/en/documents/product-information/anktiva-epar-product-information_en.pdf", "text": "Nogapendekin alfa inbakicept is an IL-15 receptor agonist. IL-15 signals through a heterotrimeric\nreceptor that is composed of the common gamma chain (γc) subunit, the beta chain (βc) subunit, and\nthe IL-15-specific alpha subunit, IL-15 receptor α. IL-15 is trans-presented by the IL-15 receptor α to\nthe shared IL-2/IL-15 receptor (βc and γc) on the surface of CD4+ and CD8+ T cells and NK cells.\nBinding of nogapendekin alfa inbakicept to its receptor results in proliferation and activation of NK,\nCD4+, CD8+, and memory T cells without proliferation of immuno-suppressive Treg cells.", "a": { "targets": [ "IL-15 receptor" ], "modality": "protein or peptide", "label": "IL-15 receptor agonist", "mechanism": "Binds the IL-15 receptor to stimulate proliferation and activation of NK, CD4+, CD8+, and memory T cells without expanding immunosuppressive Treg cells.", "quote": "Nogapendekin alfa inbakicept is an IL-15 receptor agonist." }, "b": { "targets": [ "IL15RA", "IL2RB", "IL2RG" ], "modality": "protein or peptide", "label": "IL-15 receptor agonist", "mechanism": "Binding to the IL-15 receptor promotes proliferation and activation of NK, CD4+, CD8+, and memory T cells without proliferating immunosuppressive Treg cells.", "quote": "Nogapendekin alfa inbakicept is an IL-15 receptor agonist." }, "decision": { "reason": "The text calls the drug \"an IL-15 receptor agonist\" and says IL-15 is trans-presented \"to the shared IL-2/IL-15 receptor (βc and γc)\". So the target is the IL-15 receptor, signalling through its βc and γc subunits. Listing IL-15Rα as a separate target goes beyond the text, which describes it as the presenting subunit rather than what the drug binds.", "targets": [ "IL-15 receptor", "IL-2/IL-15Rβ (CD122)", "γc (CD132)" ], "modality": "protein or peptide", "label": "IL-15 receptor agonist", "mechanism": "Binds the IL-15 receptor (shared IL-2/IL-15 βc/γc) to drive proliferation and activation of NK, CD4+, CD8+ and memory T cells without expanding immunosuppressive Treg cells.", "quote": "Nogapendekin alfa inbakicept is an IL-15 receptor agonist.", "ambiguous": false } }, "obecabtagene-autoleucel__aucatzyl": { "url": "https://www.ema.europa.eu/en/documents/product-information/aucatzyl-epar-product-information_en.pdf", "text": "Obecabtagene autoleucel is an autologous immunotherapy consisting of the patient’s own T cells\nengineered to express a CAR that recognises CD19 on-target cells via the murine CAT13.1E10\nhybridoma (CAT) binding domain. Engagement of anti-CD19 (CAT) CAR-positive T cells with\nCD19-expressed on-target cells, such as cancer cells and normal B cells, leads to activation of the\nanti-CD19 (CAT) CAR-positive T cells and downstream signalling through the CD3-zeta domain.\nProliferation and persistence by the anti-CD19 (CAT) CAR-positive T cells following activation are\nenhanced by the presence of the 4-1BB co-stimulatory domain. This binding to CD19 results in\nanti-tumour activity and killing of CD19-expressing target cells.\nStudies demonstrate obecabtagene autoleucel has a fast off-rate of 3.1 × 10-3s-1 of its CD19 binding\ndomain.", "a": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "Autologous CAR T cells bind CD19 on target cells, leading to CAR T-cell activation, proliferation, and anti-tumour killing of CD19-expressing cells.", "quote": "Obecabtagene autoleucel is an autologous immunotherapy consisting of the patient’s own T cells engineered to express a CAR that recognises CD19 on-target cells via the murine CAT13.1E10 hybridoma (CAT) binding domain." }, "b": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "The patient’s T cells are engineered to recognize CD19; engagement activates them and leads to killing of CD19-expressing target cells.", "quote": "Obecabtagene autoleucel is an autologous immunotherapy consisting of the patient’s own T cells engineered to express a CAR that recognises CD19 on-target cells via the murine CAT13.1E10 hybridoma (CAT) binding domain." }, "decision": null }, "obinutuzumab__gazyvaro": { "url": "https://www.ema.europa.eu/en/documents/product-information/gazyvaro-epar-product-information_en.pdf", "text": "Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II anti-CD20\nantibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembrane\nantigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on\nhaematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineering\n\n27\nof the Fc part of obinutuzumab results in higher affinity for FcɣRIII receptors on immune effector\ncells such as natural killer (NK) cells, macrophages and monocytes as compared to\nnon-glycoengineered antibodies.\nIn nonclinical studies, obinutuzumab induces direct cell death and mediates antibody dependent\ncellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) through\nrecruitment of FcɣRIII positive immune effector cells. In addition, in vivo, obinutuzumab mediates a\nlow degree of complement dependent cytotoxicity (CDC). Compared to Type I antibodies,\nobinutuzumab, a Type II antibody, is characterised by an enhanced direct cell death induction with a\nconcomitant reduction in CDC at an equivalent dose. Obinutuzumab, as a glycoengineered antibody, is\ncharacterised by enhanced ADCC and ADCP compared to non-glycoengineered antibodies at an\nequivalent dose. In animal models obinutuzumab mediates potent B-cell depletion and antitumour\nefficacy.\nIn the pivotal clinical study in patients with CLL (BO21004/CLL11), 91% (40 out of 44) of evaluable\npatients treated with Gazyvaro were B-cell depleted (defined as CD19+ B-cell counts < 0.07 x 109/L)\nat the end of treatment period and remained depleted during the first 6 months of follow up. Recovery\nof B-cells was observed within 12-18 months of follow up in 35% (14 out of 40) of patients without\nprogressive disease and 13% (5 out of 40) with progressive disease.\nIn the pivotal clinical study in patients with iNHL (GAO4753/GADOLIN), 97% (171 out of 176) of\nevaluable patients treated with Gazyvaro were B-cell depleted at the end of the treatment period, and\n97% (61 out of 63) remained depleted for more than 6 months from the last dose. Recovery of B-cells\nwas observed within 12-18 months of follow-up in 11% (5 out of 46) of evaluable patients.\nIn the pivotal clinical study in patients with LN (CA41705/REGENCY), 99.2% (127 out of 128) of\nevaluable patients treated with Gazyvaro were B-cell depleted (defined as CD19+ B-cell counts\n< 10 cells/μl) at Week 4 and 95% (117 out of 123) were B cell depleted at Week 76.\nReductions in circulating naïve B, memory B, and plasmablasts/plasma cells were observed by\nWeek 4 and remained low through Week 76 after treatment initiation.", "a": { "targets": [ "CD20" ], "modality": "monoclonal antibody", "label": "Anti-CD20 monoclonal antibody", "mechanism": "Binds to CD20 on B-lymphocytes to induce direct cell death and mediate enhanced ADCC and ADCP via FcγRIII-bearing effector cells, leading to potent B-cell depletion.", "quote": "It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue." }, "b": { "targets": [ "CD20" ], "modality": "monoclonal antibody", "label": "CD20-directed monoclonal antibody", "mechanism": "Binds CD20 on B-lymphocytes and induces direct cell death while recruiting immune effector cells to mediate antibody-dependent cellular cytotoxicity and phagocytosis.", "quote": "It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue." }, "decision": null }, "odronextamab__ordspono": { "url": "https://www.ema.europa.eu/en/documents/product-information/ordspono-epar-product-information_en.pdf", "text": "Odronextamab is a human IgG4-based bispecific antibody that binds to CD20, a B-cell surface antigen\npresent on normal and malignant B cells and CD3, a T-cell antigen associated with the T-cell receptor\ncomplex. Simultaneous engagement of both arms of odronextamab results in formation of a synapse\nbetween the T cell and the CD20-expressing cell, resulting in T-cell activation and generation of\npolyclonal cytotoxic T-cell response, which result in redirected lysis of the targeted cells, including\nmalignant B cells.", "a": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Odronextamab binds CD20 on B cells and CD3 on T cells, creating an immune synapse that induces T-cell activation and redirected lysis of CD20-expressing cells.", "quote": "Odronextamab is a human IgG4-based bispecific antibody that binds to CD20, a B-cell surface antigen present on normal and malignant B cells and CD3, a T-cell antigen associated with the T-cell receptor complex." }, "b": { "targets": [ "CD20", "CD3" ], "modality": "bispecific antibody", "label": "CD20 × CD3 bispecific antibody", "mechanism": "Odronextamab binds CD20 on B cells and CD3 on T cells, bringing them together to activate T cells and redirect lysis of CD20-expressing cells.", "quote": "Odronextamab is a human IgG4-based bispecific antibody that binds to CD20, a B-cell surface antigen present on normal and malignant B cells and CD3, a T-cell antigen associated with the T-cell receptor complex." }, "decision": null }, "olaparib__lynparza": { "url": "https://www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf", "text": "Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2,\nand PARP-3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and\ntumour growth in vivo either as a standalone treatment or in combination with established\nchemotherapies or new hormonal agents (NHA).\nPARPs are required for the efficient repair of DNA single strand breaks and an important aspect of\nPARP-induced repair requires that after chromatin modification, PARP auto-modifies itself and\ndissociates from the DNA to facilitate access for base excision repair (BER) enzymes. When olaparib\nis bound to the active site of DNA-associated PARP it prevents the dissociation of PARP and traps it\non the DNA, thus blocking repair. In replicating cells this also leads to the formation of DNA\ndouble-strand breaks (DSBs) when replication forks meet the PARP-DNA adducts. In normal cells,\nhomologous recombination repair (HRR) pathway is effective at repairing these DNA DSBs. In cancer\n\n18\ncells lacking critical functional components for efficient HRR such as BRCA1 or 2, DNA DSBs\ncannot be repaired accurately or effectively, leading to substantial homologous recombination\ndeficiency (HRD). Instead, alternative and error-prone pathways are activated, such as the classical\nnon-homologous end joining (NHEJ) pathway, leading to a high degree of genomic instability. After a\nnumber of rounds of replication, genomic instability can reach insupportable levels and result in\ncancer cell death, as cancer cells already have a high DNA damage load relative to normal cells. HRR\npathway may be compromised by other mechanisms, although the causative aberrancy and penetrance\nare not fully elucidated. Absence of fully functional HRR pathway is one of the key determinants of\nplatinum sensitivity in ovarian and possibly other cancers.\nIn BRCA1/2-deficient in vivo models, olaparib given after platinum treatment resulted in a delay in\ntumour progression and an increase in overall survival compared to platinum treatment alone that\ncorrelated with the period of olaparib maintenance treatment.\nCombined anti-tumour effect with NHAs\nPre-clinical studies in prostate cancer models reported a combined anti-tumour effect when PARP\ninhibitors and next-generation hormonal agents are administered together. PARP is involved in\npositive co-regulation of androgen receptor (AR) signalling, which leads to enhanced AR target gene\nsuppression when PARP/AR signalling is co-inhibited. Other pre-clinical studies reported that\ntreatment with NHAs inhibit the transcription of some HRR genes, therefore, inducing HRR\ndeficiency and increased sensitivity to PARP inhibitors via non-genetic mechanisms.\nDetection of BRCA1/2 mutations\nGenetic testing should be conducted by an experienced laboratory using a validated test. Local or\ncentral testing of blood and/or tumour samples for germline and/or somatic BRCA1/2 mutations have\nbeen used in different studies. DNA obtained from a tissue or blood sample has been tested in most of\nthe studies, with testing of ctDNA being used for exploratory purposes. Depending on the test used\nand the international classification consensus, the BRCA1/2 mutations have been classified as\ndeleterious/suspected deleterious or pathogenic/likely pathogenic. Homologous recombination\ndeficiency (HRD) positive status can be defined by detection of a BRCA1/2 mutation classified as\ndeleterious/suspected deleterious or pathogenic/likely pathogenic. Detection of these mutations could\nbe combined with positive HRD score (below) to determine HRD positive status.\nDetection of genomic instability\nHR deficiency-associated genomic alterations that have been investigated in Paola-1 include genome-\nwide loss of heterozygosity, telomeric allelic imbalance and large-scale transition, which are\ncontinuous measures with pre-defined criteria and score. Composite genomic instability score (GIS,\nalso called HRD score) is determined when the combined measures and respective scores are used to\nassess the extent of specific genomic aberrations accumulated in tumour cells. Lower score defines\nlower likelihood of HR deficiency of tumour cells and higher score determines higher likelihood of\nHR deficiency of tumour cells at the time of the sample collection relative to exposure to DNA\ndamaging agents. Validated cut-offs should be used to determine GIS positive status.\nHRD positive status can be defined by a composite GIS score for HR deficiency-associated genomic\nalterations tested by an experienced laboratory using a validated test.", "a": { "targets": [ "PARP-1", "PARP-2", "PARP-3" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Olaparib inhibits PARP-1, PARP-2, and PARP-3 and traps PARP on DNA, blocking single-strand break repair and inducing double-strand breaks that lead to cell death in homologous recombination-deficient tumour cells.", "quote": "Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo either as a standalone treatment or in combination with established chemotherapies or new hormonal agents (NHA)." }, "b": { "targets": [ "PARP1", "PARP2", "PARP3" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Olaparib binds the active site of DNA-associated PARP, trapping it on DNA and blocking repair; this can lead to DNA double-strand breaks and cancer cell death.", "quote": "Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo either as a standalone treatment or in combination with established chemotherapies or new hormonal agents (NHA)." }, "decision": null }, "osimertinib__tagrisso": { "url": "https://www.ema.europa.eu/en/documents/product-information/tagrisso-epar-product-information_en.pdf", "text": "Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of EGFRs harboring\nsensitising-mutations (EGFRm) and TKI-resistance mutation T790M.", "a": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "EGFR tyrosine kinase inhibitor", "mechanism": "Osimertinib is an irreversible inhibitor of epidermal growth factor receptors (EGFR) harboring sensitising mutations and the T790M resistance mutation.", "quote": "It is an irreversible inhibitor of EGFRs harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M." }, "b": { "targets": [ "EGFR" ], "modality": "small molecule", "label": "Irreversible EGFR inhibitor (TKI)", "mechanism": "Irreversibly inhibits EGFRs with sensitising mutations or the TKI-resistance mutation T790M.", "quote": "It is an irreversible inhibitor of EGFRs harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M." }, "decision": null }, "palbociclib__ibrance": { "url": "https://www.ema.europa.eu/en/documents/product-information/ibrance-epar-product-information_en.pdf", "text": "Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6.\nCyclin D1 and CDK4/6 are downstream of multiple signalling pathways which lead to cellular\nproliferation.\n\n13", "a": { "targets": [ "CDK4", "CDK6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Palbociclib is a selective, reversible inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), which act downstream of multiple signalling pathways leading to cellular proliferation.", "quote": "Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6." }, "b": { "targets": [ "CDK4", "CDK6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Palbociclib reversibly inhibits CDK4 and CDK6, kinases downstream of signalling pathways that lead to cellular proliferation.", "quote": "Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6." }, "decision": null }, "panitumumab__vectibix": { "url": "https://www.ema.europa.eu/en/documents/product-information/vectibix-epar-product-information_en.pdf", "text": "Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity\nand specificity to the human EGFR. EGFR is a transmembrane glycoprotein that is a member of a\nsubfamily of type I receptor tyrosine kinases including EGFR (HER1/c-ErbB-1), HER2, HER3, and\nHER4. EGFR promotes cell growth in normal epithelial tissues, including the skin and hair follicle,\nand is expressed on a variety of tumour cells.\nPanitumumab binds to the ligand binding domain of EGFR and inhibits receptor autophosphorylation\ninduced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalisation of\nthe receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascular\nendothelial growth factor production.\nKRAS and NRAS are highly related members of the RAS oncogene family. KRAS and NRAS genes\nencode small, GTP-binding proteins involved in signal transduction. A variety of stimuli, including\nthat from the EGFR activate KRAS and NRAS which in turn stimulate other intracellular proteins to\npromote cell proliferation, cell survival and angiogenesis.\n\n12\nActivating mutations in the RAS genes occur frequently in a variety of human tumours and have been\nimplicated in both oncogenesis and tumour progression.", "a": { "targets": [ "EGFR" ], "modality": "monoclonal antibody", "label": "EGFR-directed monoclonal antibody", "mechanism": "Panitumumab binds to the ligand-binding domain of EGFR, inhibiting ligand-induced receptor autophosphorylation and cell growth, while inducing receptor internalization and apoptosis.", "quote": "Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to the human EGFR." }, "b": { "targets": [ "EGFR" ], "modality": "monoclonal antibody", "label": "EGFR-directed monoclonal antibody", "mechanism": "Binds the EGFR ligand-binding domain, inhibiting ligand-induced receptor autophosphorylation and leading to receptor internalisation, inhibition of cell growth, and induction of apoptosis.", "quote": "Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to the human EGFR." }, "decision": null }, "panobinostat__farydak": { "url": "https://www.ema.europa.eu/en/documents/product-information/farydak-epar-product-information_en.pdf", "text": "Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at\nnanomolar concentrations. HDACs catalyse the removal of acetyl groups from the lysine residues of\nhistones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation\nof histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to\ntranscriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and\nother proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels\nof acetylated histones were observed in xenografts from mice that were treated with panobinostat.\nPanobinostat shows more cytotoxicity towards tumour cells compared to normal cells.", "a": { "targets": [ "HDAC" ], "modality": "small molecule", "label": "Histone deacetylase (HDAC) inhibitor", "mechanism": "Inhibits histone deacetylase enzymatic activity, increasing histone acetylation and relaxing chromatin to induce cell cycle arrest and apoptosis.", "quote": "Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations." }, "b": { "targets": [ "HDACs" ], "modality": "small molecule", "label": "HDAC inhibitor", "mechanism": "Panobinostat inhibits HDAC enzymatic activity, increasing histone acetylation and causing chromatin relaxation and transcriptional activation.", "quote": "Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations." }, "decision": { "reason": "The two readings agree in substance; the text plainly names the target (\"Farydak is a histone deacetylase (HDAC) inhibitor\"), so the only differences are wording, and the standard symbol is HDAC.", "targets": [ "HDAC" ], "modality": "small molecule", "label": "Histone deacetylase (HDAC) inhibitor", "mechanism": "Inhibits HDAC enzymatic activity, increasing acetylation of histones and other proteins, relaxing chromatin and inducing cell cycle arrest and/or apoptosis of transformed cells.", "quote": "Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations.", "ambiguous": false } }, "pazopanib__votrient": { "url": "https://www.ema.europa.eu/en/documents/product-information/votrient-epar-product-information_en.pdf", "text": "Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of vascular\nendothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor\n(PDGFR) -α and –β, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and\n74 nM, respectively. In preclinical experiments, pazopanib dose-dependently inhibited ligand-induced\nauto-phosphorylation of VEGFR-2, c-Kit and PDGFR- receptors in cells. In vivo, pazopanib\ninhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal\nmodels, and the growth of multiple human tumour xenografts in mice.\nPharmacogenomics\nIn a pharmacogenetic meta-analysis of data from 31 clinical studies of pazopanib administered either\nas monotherapy or in combination with other agents, ALT >5 x ULN (NCI CTC Grade 3) occurred in\n19% of HLA-B*57:01 allele carriers and in 10% of non-carriers. In this dataset, 133/2235 (6%) of the\npatients carried the HLA-B*57:01 allele (see section 4.4).\nClinical studies\nRenal cell carcinoma (RCC)\nThe safety and efficacy of pazopanib in RCC were evaluated in a randomised, double-blind,\nplacebo-controlled multicentre study. Patients (N = 435) with locally advanced and/or metastatic RCC\nwere randomised to receive pazopanib 800 mg once daily or placebo. The primary objective of the\nstudy was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the\nprinciple secondary endpoint was overall survival (OS). The other objectives were to evaluate the\noverall response rate and duration of response.\nFrom the total of 435 patients in this study, 233 patients were treatment-naïve and 202 were\nsecond-line patients who had received one prior IL-2 or INF-based therapy. The performance status\n(ECOG) was similar between the pazopanib and placebo groups (ECOG 0: 42% vs. 41%, ECOG 1:\n58% vs. 59%). The majority of patients had either favourable (39%) or intermediate (54%), MSKCC\n(Memorial Sloan Kettering Cancer Centre) / Motzer prognostic factors. All patients had clear cell\nhistology or predominantly clear cell histology. Approximately half of all patients had 3 or more\norgans involved in their disease and most patients had the lung (74%), and/or lymph nodes (54%) as a\nmetastatic location for disease at baseline.\nA similar proportion of patients in each arm were treatment-naïve and cytokine pre-treated (53% and\n47% in pazopanib arm, 54% and 46% in placebo arm). In the cytokine pre-treated subgroup, the\nmajority (75%) had received interferon-based treatment.\n\n22\nSimilar proportions of patients in each arm had prior nephrectomy (89% and 88% in the pazopanib\nand placebo arms, respectively) and/or prior radiotherapy (22% and 15% in the pazopanib and placebo\narms, respectively.\nThe primary analysis of the primary endpoint PFS is based on disease assessment by independent\nradiological review in the entire study population (treatment-naïve and cytokine pre-treated).\nTable 4 Overall efficacy results in RCC by independent assessment (VEG105192)\nEndpoints/Study population Pazopanib Placebo HR (95% CI)\nP value\n(one-sided)\nPFS\nOverall* ITT N = 290 N = 145\nMedian (months) 9.2 4.2 0.46 (0.34, 0.62) <0.0000001\nResponse rate N = 290 N = 145\n% (95% CI) 30 (25.1,35.6) 3 (0.5, 6.4) – <0.001\nHR = hazard ratio; ITT = intent to treat; PFS = progression-free survival. * - treatment-naïve and cytokine\npre-treated populations\nFigure 1 Kaplan-Meier curve for progression-free survival by independent assessment for the\noverall population (treatment-naïve and cytokine pre-treated populations)\n(VEG105192)\nx axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 290) Median 9.2 months; Placebo --\n------ (N = 145) Median 4.2 months; Hazard Ratio = 0.46, 95% CI (0.34, 0.62), P <0.0000001\n\n23\nFigure 2 Kaplan-Meier curve for progression-free survival by independent assessment for the\ntreatment-naïve population (VEG105192)\nx axis; Months, y axis; Proportion Progression Free, Pazopanib —―— (N = 155) Median 11.1 months; Placebo\n-------- (N = 78) Median 2.8 months; Hazard Ratio = 0.40, 95% CI (0.27, 0.60), P <0.0000001\nFigure 3 Kaplan-Meier Curve for progression-free survival by independent assessment for\nthe cytokine pre-treated population (VEG105192)\nx axis; Months, y\naxis; Proportion Progression Free, Pazopanib —―— (N = 135) Median 7.4 months; Placebo -------- (N = 67)\nMedian 4.2 months; Hazard Ratio = 0.54, 95% CI (0.35, 0.84), P <0.001\nFor patients who responded to treatment, the median time to response was 11.9 weeks and the median\nduration of response was 58.7 weeks as per independent review (VEG105192).\nThe median overall survival (OS) data at the protocol-specified final survival analysis were\n22.9 months and 20.5 months [HR = 0.91 (95% CI: 0.71, 1.16; p = 0.224)] for patients randomised to\nthe pazopanib and placebo arms, respectively. The OS results are subject to potential bias as 54% of\npatients in the placebo arm also received pazopanib in the extension part of this study following\ndisease progression. Sixty-six per cent of placebo patients received post-study therapy compared to\n30% of pazopanib patients.\nNo statistical differences were observed between treatment groups for Global Quality of Life using\nEORTC QLQ-C30 and EuroQoL EQ-5D.\nIn a Phase II study of 225 patients with locally recurrent or metastatic clear cell renal cell carcinoma,\nobjective response rate was 35% and median duration of response was 68 weeks, as per independent\n\n24\nreview. Median PFS was 11.9 months.\nThe safety, efficacy and quality of life of pazopanib versus sunitinib was evaluated in a randomised,\nopen-label, parallel group Phase III non-inferiority study (VEG108844).\nIn VEG108844, patients (N = 1110) with locally advanced and/or metastatic RCC who had not\nreceived prior systemic therapy, were randomised to receive either pazopanib 800 mg once daily\ncontinuously or sunitinib 50 mg once daily in 6-week cycles of dosing with 4 weeks on treatment\nfollowed by 2 w", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "PDGFRA", "PDGFRB", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, PDGFR, KIT)", "mechanism": "Pazopanib inhibits VEGFR-1/-2/-3, PDGFR-α/-β, and c-KIT receptor tyrosine kinases, blocking ligand-induced phosphorylation and suppressing tumor angiogenesis and growth.", "quote": "Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor (PDGFR) -α and –β, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively." }, "b": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "PDGFRA", "PDGFRB", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, PDGFR, KIT)", "mechanism": "Pazopanib inhibits VEGFR-1, -2 and -3, PDGFR-α and -β, and c-Kit tyrosine kinase activity, blocking receptor phosphorylation.", "quote": "Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor (PDGFR) -α and –β, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively." }, "decision": null }, "peginterferon-alfa-2a__pegasys": { "url": "https://www.ema.europa.eu/en/documents/product-information/pegasys-epar-product-information_en.pdf", "text": "The conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms a\npegylated interferon alfa-2a (Pegasys). Pegasys possesses the in vitro antiviral and antiproliferative\nactivities that are characteristic of interferon alfa-2a.\nInterferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of\nsubstitution of one mole of polymer/mole of protein. The average molecular mass is approximately\n60 000 of which the protein moiety constitutes approximately 20 000.", "a": { "targets": [], "modality": "protein or peptide", "label": "Pegylated interferon alfa", "mechanism": "Pegylated interferon alfa-2a provides antiviral and antiproliferative activities characteristic of interferon alfa-2a.", "quote": "Pegasys possesses the in vitro antiviral and antiproliferative activities that are characteristic of interferon alfa-2a." }, "b": { "targets": [], "modality": "protein or peptide", "label": "Pegylated interferon alfa", "mechanism": "PEG-conjugated interferon alfa-2a retains the in vitro antiviral and antiproliferative activities characteristic of interferon alfa-2a.", "quote": "Pegasys possesses the in vitro antiviral and antiproliferative activities that are characteristic of interferon alfa-2a." }, "decision": null }, "pembrolizumab__keytruda": { "url": "https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_en.pdf", "text": "KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1\n(PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a\nnegative regulator of T-cell activity that has been shown to be involved in the control of T-cell\nimmune responses. KEYTRUDA potentiates T-cell responses, including anti-tumour responses,\nthrough blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting\ncells and may be expressed by tumours or other cells in the tumour microenvironment.\nThe anti-angiogenic effect of lenvatinib (multi-TKI) in combination with the immune-stimulatory\neffect of pembrolizumab (anti-PD-1) results in a tumour microenvironment with greater T-cell\nactivation to help overcome primary and acquired resistance to immunotherapy and may improve\ntumour responses compared to either treatment alone. In preclinical murine models, PD-1 plus TKI\ninhibitors have demonstrated enhanced anti-tumour activity compared to either agent alone.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Pembrolizumab binds to the PD-1 receptor, blocking interaction with PD-L1 and PD-L2 to potentiate T-cell anti-tumour immune responses.", "quote": "KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, potentiating T-cell responses, including anti-tumour responses.", "quote": "KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2." }, "decision": null }, "pemigatinib__pemazyre": { "url": "https://www.ema.europa.eu/en/documents/product-information/pemazyre-epar-product-information_en.pdf", "text": "Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EN02\nPemigatinib is a kinase inhibitor of FGFR1, 2 and 3 which inhibits FGFR phosphorylation and\nsignalling and decreases cell viability in cells expressing FGFR genetic alterations, including point\nmutations, amplifications, and fusions or rearrangements. FGFR2 fusions/rearrangements are strong\noncogenic drivers and are the most common FGFR alteration occurring, almost exclusively, in 10-\n16 % of intrahepatic cholangiocarcinoma (CCA).\nPharmacodynamic effects\nSerum phosphate\nPemigatinib increased serum phosphate level as a consequence of FGFR inhibition. In pemigatinib\nclinical studies, phosphate-lowering therapy and dose modifications were permitted to manage\nhyperphosphataemia (see sections 4.2, 4.4 and 4.8).\nClinical studies\nFIGHT-202 was a multicentre, open-label, single-arm study to evaluate the efficacy and safety of\nPemazyre in previously treated patients with locally advanced/metastatic or surgically unresectable\ncholangiocarcinoma. The efficacy population consists of 108 patients (107 patients with intrahepatic\ndisease) that had progressed after at least 1 prior therapy and who had FGFR2 fusion or\nrearrangement, as determined by the test performed at a central laboratory.\nPatients received Pemazyre in 21-days cycles consisting of 13.5 mg once daily oral dosing for 14 days,\nfollowed by 7 days off therapy. Pemazyre was administered until disease progression or unacceptable\ntoxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of\nresponse (DoR), as determined by independent review committee (IRC) according to RECIST v1.1.\nThe median age was 55.5 years (range: 26 to 77 years), 23.1 % were ≥65 years, 61.1 % were female,\nand 73.1 % were Caucasian. Most (95.4 %) patients had a baseline Eastern Cooperative Oncology\nGroup (ECOG) performance status of 0 (42.6 %) or 1 (52.8 %). All patients had at least 1 prior line of\nsystemic therapy, 27.8 % had 2 prior lines of therapy, and 12.0 % had 3 or more prior lines of therapy.\nNinety-six percent of patients had received prior platinum-based therapy including 78 % with prior\ngemcitabine/cisplatin.\nEfficacy results are summarised in table 5.\nThe median time to response was 2.69 months (range 0.7 – 16.6 months).\n\n11\nTable 5: Efficacy results\nCohort A (FGFR2 fusion or rearrangement)\nEfficacy Evaluable Population\n(N = 108)\nORR (95 % CI) 37.0 % (27.94, 46.86)\nComplete response (N) 2.8 % (3)\nPartial response (N) 34.3 % (37)\nMedian duration of response (months) (95 %\nCI)a\n9.13 (6.01, 14.49)\nKaplan-Meier estimates of duration of\nresponse (95 % CI)\n3 months 100.0 (100.0, 100.0)\n6 months 67.8 (50.4, 80.3)\n9 months 50.5 (33.3, 65.4)\n12 months 41.2 (24.8, 56.8)\nORR- CR+PR\nCI= Confidence Interval\nNote: Data are from IRC per RECIST v1.1, and complete and partial responses are confirmed.\na The 95 % CI was calculated using the Brookmeyer and Crowley's method\nElderly patients\nIn the clinical st", "a": { "targets": [ "FGFR1", "FGFR2", "FGFR3" ], "modality": "small molecule", "label": "FGFR kinase inhibitor", "mechanism": "Inhibits FGFR1, 2, and 3 phosphorylation and signalling, decreasing cell viability in cells expressing FGFR genetic alterations.", "quote": "Pemigatinib is a kinase inhibitor of FGFR1, 2 and 3 which inhibits FGFR phosphorylation and signalling and decreases cell viability in cells expressing FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements." }, "b": { "targets": [ "FGFR1", "FGFR2", "FGFR3" ], "modality": "small molecule", "label": "FGFR1-3 inhibitor", "mechanism": "Inhibits FGFR phosphorylation and signalling, decreasing cell viability in cells with FGFR genetic alterations.", "quote": "Pemigatinib is a kinase inhibitor of FGFR1, 2 and 3 which inhibits FGFR phosphorylation and signalling and decreases cell viability in cells expressing FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements." }, "decision": null }, "pertuzumab-trastuzumab__phesgo": { "url": "https://www.ema.europa.eu/en/documents/product-information/phesgo-epar-product-information_en.pdf", "text": "Phesgo contains pertuzumab and trastuzumab which provides the therapeutic effect of this medicinal\nproduct and vorhyaluronidase alfa, an enzyme used to increase the dispersion and absorption of\nco-formulated substances when administered subcutaneously.\nPertuzumab and trastuzumab are recombinant humanised IgG1 monoclonal antibodies which target\nthe human epidermal growth factor receptor 2 (HER2). Both substances bind to distinct HER2\nsubdomains without competing and have complementary mechanisms for disrupting HER2 signalling:\n• Pertuzumab specifically targets the extracellular dimerization domain (subdomain II) of HER2\nand thereby blocks ligand-dependent heterodimerization of HER2 with other HER family\nmembers, including epidermal growth factor receptor (EGFR), HER3 and HER4. As a result,\npertuzumab inhibits ligand-activated intracellular signalling through two major signalling\npathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K).\nInhibition of these signalling pathways can result in cell growth arrest and apoptosis,\nrespectively\n• Trastuzumab binds to sub-domain IV, of the extracellular domain of the HER2 protein to inhibit\nthe ligand-independent, HER2 mediated proliferation and survival signals in human tumour\ncells that over express HER2.\nAdditionally, both substances mediate antibody-dependent cell-mediated cytotoxicity (ADCC). In\nvitro, both pertuzumab and trastuzumab ADCC are exerted preferentially on HER2-overexpressing\ncancer cells compared with cancer cells that do not overexpress HER2.", "a": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "Dual HER2-directed monoclonal antibody combination", "mechanism": "Pertuzumab and trastuzumab bind distinct subdomains of HER2, blocking HER2 heterodimerization and signalling pathways to halt cell proliferation and mediate ADCC.", "quote": "Pertuzumab and trastuzumab are recombinant humanised IgG1 monoclonal antibodies which target the human epidermal growth factor receptor 2 (HER2)." }, "b": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2-targeting monoclonal antibody combination", "mechanism": "Pertuzumab and trastuzumab bind distinct HER2 subdomains, disrupting HER2 signalling and mediating antibody-dependent cellular cytotoxicity.", "quote": "Pertuzumab and trastuzumab are recombinant humanised IgG1 monoclonal antibodies which target the human epidermal growth factor receptor 2 (HER2)." }, "decision": null }, "pertuzumab__perjeta": { "url": "https://www.ema.europa.eu/en/documents/product-information/perjeta-epar-product-information_en.pdf", "text": "Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the extracellular\ndimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2),\nand thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members,\nincluding EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular\nsignalling through two major signal pathways, mitogen-activated protein (MAP) kinase and\nphosphoinositide 3-kinase (PI3K). Inhibition of these signalling pathways can result in cell growth\narrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated\ncytotoxicity (ADCC).\nWhile pertuzumab alone inhibited the proliferation of human tumour cells, the combination of\npertuzumab and trastuzumab significantly augmented antitumour activity in HER2-overexpressing\nxenograft models.", "a": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2-targeted monoclonal antibody", "mechanism": "Pertuzumab binds the dimerization domain of HER2, blocking heterodimerisation with other HER family receptors to inhibit downstream MAP kinase and PI3K signalling, while also mediating ADCC.", "quote": "Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2), and thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members, including EGFR, HER3 and HER4." }, "b": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2 dimerization inhibitor (antibody)", "mechanism": "Binds the HER2 extracellular dimerization domain, blocking ligand-dependent heterodimerisation with other HER family members and inhibiting downstream signalling.", "quote": "Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2), and thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members, including EGFR, HER3 and HER4." }, "decision": null }, "pirtobrutinib__jaypirca": { "url": "https://www.ema.europa.eu/en/documents/product-information/jaypirca-epar-product-information_en.pdf", "text": "Pirtobrutinib is a reversible, noncovalent inhibitor of BTK. BTK is a signalling protein of the B-cell\nantigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in\nactivation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.\nPirtobrutinib binds to wild type BTK as well as BTK harboring C481 mutations leading to inhibition\nof BTK kinase activity.\n\n9", "a": { "targets": [ "BTK" ], "modality": "small molecule", "label": "Noncovalent BTK inhibitor", "mechanism": "Pirtobrutinib reversibly binds wild-type and C481-mutant BTK, inhibiting its kinase activity to block BCR-mediated B-cell proliferation, trafficking, and survival pathways.", "quote": "Pirtobrutinib is a reversible, noncovalent inhibitor of BTK." }, "b": { "targets": [ "BTK" ], "modality": "small molecule", "label": "BTK inhibitor", "mechanism": "Pirtobrutinib reversibly and noncovalently binds wild-type and C481-mutated BTK, inhibiting its kinase activity.", "quote": "Pirtobrutinib is a reversible, noncovalent inhibitor of BTK." }, "decision": null }, "polatuzumab-vedotin__polivy": { "url": "https://www.ema.europa.eu/en/documents/product-information/polivy-epar-product-information_en.pdf", "text": "Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent\nanti-mitotic agent (monomethyl auristatin E, or MMAE) to B-cells, which results in the killing of\nmalignant B-cells. The polatuzumab vedotin molecule consists of MMAE covalently attached to a\nhumanised immunoglobulin G1 monoclonal antibody via a cleavable linker. The monoclonal antibody\nbinds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor.\nCD79b expression is restricted to normal cells within the B-cell lineage (with the exception of plasma\ncells) and malignant B-cells; it is expressed in  95% of diffuse large B-cell lymphoma. Upon binding\nCD79b, polatuzumab vedotin is rapidly internalised and the linker is cleaved by lysosomal proteases\nto enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by\ninhibiting cell division and inducing apoptosis.", "a": { "targets": [ "CD79b" ], "modality": "antibody-drug conjugate", "label": "CD79b-directed antibody-drug conjugate", "mechanism": "Binds CD79b on B-cells, undergoes internalisation, and releases MMAE to disrupt microtubules, inhibiting cell division and inducing apoptosis.", "quote": "The monoclonal antibody binds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor." }, "b": { "targets": [ "CD79b" ], "modality": "antibody-drug conjugate", "label": "CD79b-directed antibody-drug conjugate", "mechanism": "The antibody binds CD79b and delivers MMAE into cells, where MMAE binds microtubules, inhibits cell division and induces apoptosis.", "quote": "The monoclonal antibody binds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor." }, "decision": null }, "pomalidomide__imnovid-previously-pomalidomide-celgene-": { "url": "https://www.ema.europa.eu/en/documents/product-information/imnovid-epar-product-information_en.pdf", "text": "Pomalidomide has direct anti-myeloma tumoricidal activity, immunomodulatory activities and inhibits\nstromal cell support for multiple myeloma tumour cell growth. Specifically, pomalidomide inhibits\nproliferation and induces apoptosis of haematopoietic tumour cells. Additionally, pomalidomide\ninhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergises with\ndexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumour\ncell apoptosis. Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity and\ninhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.\nPomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells.\nPomalidomide binds directly to the protein cereblon (CRBN), which is part of an E3 ligase complex\nthat includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and\nregulator of cullins-1 (Roc1), and can inhibit the auto-ubiquitination of CRBN within the complex. E3\nubiquitin ligases are responsible for the poly-ubiquitination of a variety of substrate proteins, and may\npartially explain the pleiotropic cellular effects observed with pomalidomide treatment.\n\n20\nIn the presence of pomalidomide in vitro, substrate proteins Aiolos and Ikaros are targeted for\nubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.\nIn vivo, pomalidomide therapy led to reduction in the levels of Ikaros in patients with relapsed\nlenalidomide-refractory multiple myeloma.", "a": { "targets": [ "CRBN", "IKZF1", "IKZF3" ], "modality": "small molecule", "label": "Immunomodulatory agent", "mechanism": "Pomalidomide binds cereblon to recruit and degrade substrate proteins Aiolos and Ikaros, causing direct myeloma cell apoptosis, anti-angiogenic effects, and immune activation.", "quote": "Pomalidomide binds directly to the protein cereblon (CRBN), which is part of an E3 ligase complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins-1 (Roc1), and can inhibit the auto-ubiquitination of CRBN within the complex." }, "b": { "targets": [ "CRBN", "IKZF3", "IKZF1" ], "modality": "small molecule", "label": "Cereblon-binding immunomodulatory agent", "mechanism": "Binds cereblon (CRBN) and promotes ubiquitination and degradation of Aiolos and Ikaros, producing cytotoxic and immunomodulatory effects.", "quote": "Pomalidomide binds directly to the protein cereblon (CRBN), which is part of an E3 ligase complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins-1 (Roc1), and can inhibit the auto-ubiquitination of CRBN within the complex." }, "decision": null }, "ponatinib__iclusig": { "url": "https://www.ema.europa.eu/en/documents/product-information/iclusig-epar-product-information_en.pdf", "text": "Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon\ntriple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL\nkinase.", "a": { "targets": [ "BCR-ABL", "ABL" ], "modality": "small molecule", "label": "Pan BCR-ABL tyrosine kinase inhibitor", "mechanism": "Binds with high affinity to native BCR-ABL and mutant forms of the ABL kinase to inhibit their activity.", "quote": "Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase." }, "b": { "targets": [ "BCR-ABL", "ABL1" ], "modality": "small molecule", "label": "BCR-ABL tyrosine kinase inhibitor", "mechanism": "Ponatinib binds native BCR-ABL and mutant forms of the ABL kinase with high affinity, inhibiting their activity.", "quote": "Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase." }, "decision": { "reason": "The readings differ only in symbol (ABL1 vs ABL) and label wording; the text clearly names \"native BCR-ABL and mutant forms of the ABL kinase\", so the target is not ambiguous, and I use BCR-ABL with the mutant ABL forms noted in the mechanism.", "targets": [ "BCR-ABL" ], "modality": "small molecule", "label": "Pan BCR-ABL tyrosine kinase inhibitor", "mechanism": "Binds with high affinity to native BCR-ABL and mutant forms of the ABL kinase, inhibiting their kinase activity.", "quote": "Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase.", "ambiguous": false } }, "quizartinib__vanflyta": { "url": "https://www.ema.europa.eu/en/documents/product-information/vanflyta-epar-product-information_en.pdf", "text": "Quizartinib is an inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major metabolite\nAC886 competitively bind to the adenosine triphosphate (ATP) binding pocket of FLT3 with high\naffinity. Quizartinib and AC886 inhibit FLT3 kinase activity, preventing autophosphorylation of the\nreceptor, thereby inhibiting further downstream FLT3 receptor signalling and blocking FLT3-ITD-\ndependent cell proliferation.", "a": { "targets": [ "FLT3" ], "modality": "small molecule", "label": "FLT3 inhibitor", "mechanism": "Quizartinib competitively binds the ATP-binding pocket of FLT3 to inhibit kinase activity, preventing autophosphorylation, downstream receptor signalling, and FLT3-ITD-dependent proliferation.", "quote": "Quizartinib is an inhibitor of the receptor tyrosine kinase FLT3." }, "b": { "targets": [ "FLT3" ], "modality": "small molecule", "label": "FLT3 inhibitor", "mechanism": "Quizartinib and its major metabolite AC886 bind the ATP-binding pocket of FLT3, inhibiting its kinase activity and downstream signalling.", "quote": "Quizartinib is an inhibitor of the receptor tyrosine kinase FLT3." }, "decision": null }, "radium-ra223-dichloride__xofigo": { "url": "https://www.ema.europa.eu/en/documents/product-information/xofigo-epar-product-information_en.pdf", "text": "Xofigo is a therapeutic alpha particle-emitting pharmaceutical.\nIts active moiety radium-223 (as radium-223 dichloride) mimics calcium and selectively targets bone,\nspecifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high\nlinear energy transfer of alpha emitters (80 keV/μm) leads to a high frequency of double-strand DNA breaks\nin adjacent tumour cells, resulting in a potent cytotoxic effect. Additional effects on the tumour\nmicroenvironment including osteoblasts and osteoclasts also contribute to the in vivo efficacy. The alpha\nparticle range from radium-223 is less than 100 μm (less than 10 cell diameters) which minimises damage to\nthe surrounding normal tissue.", "a": { "targets": [ "hydroxyapatite" ], "modality": "radioligand", "label": "Alpha particle-emitting radiopharmaceutical", "mechanism": "Mimics calcium to form complexes with hydroxyapatite in bone metastases, emitting high linear energy transfer alpha particles that cause lethal double-strand DNA breaks in adjacent tumor cells.", "quote": "Its active moiety radium-223 (as radium-223 dichloride) mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite." }, "b": { "targets": [ "Hydroxyapatite" ], "modality": "radioligand", "label": "Bone-targeting alpha-emitting radiopharmaceutical", "mechanism": "Radium-223 mimics calcium and forms complexes with hydroxyapatite in bone metastases, where alpha emission causes DNA breaks in adjacent tumour cells.", "quote": "Its active moiety radium-223 (as radium-223 dichloride) mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite." }, "decision": null }, "ramucirumab__cyramza": { "url": "https://www.ema.europa.eu/en/documents/product-information/cyramza-epar-product-information_en.pdf", "text": "Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF induced\nangiogenesis. Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF\nReceptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits\nligand stimulated activation of VEGF Receptor 2 and its downstream signalling components,\nincluding p44/p42 mitogen-activated protein kinases, neutralising ligand-induced proliferation and\nmigration of human endothelial cells.", "a": { "targets": [ "VEGFR2" ], "modality": "monoclonal antibody", "label": "VEGFR2 inhibitor antibody", "mechanism": "Ramucirumab binds VEGF Receptor 2 to block VEGF ligand binding and activation, inhibiting endothelial cell proliferation and migration.", "quote": "Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D." }, "b": { "targets": [ "VEGFR2" ], "modality": "monoclonal antibody", "label": "VEGFR2 inhibitor (antibody)", "mechanism": "Binds VEGFR2 and blocks VEGF-A, VEGF-C, and VEGF-D binding, inhibiting receptor activation and downstream signalling.", "quote": "Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D." }, "decision": null }, "regorafenib__stivarga": { "url": "https://www.ema.europa.eu/en/documents/product-information/stivarga-epar-product-information_en.pdf", "text": "Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases,\nincluding kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET,\n\n16\nRAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R).\nIn particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal\ntumours, and thereby blocks tumour cell proliferation. In preclinical studies regorafenib has\ndemonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal,\ngastrointestinal stromal and hepatocellular tumour models which is likely mediated by its\nanti-angiogenic and anti-proliferative effects. In addition, regorafenib reduced the levels of tumour\nassociated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2\nand M-5) exhibited similar efficacies, compared to regorafenib in in vitro and in vivo models.", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "TIE2", "KIT", "RET" ], "modality": "small molecule", "label": "Multikinase inhibitor", "mechanism": "Regorafenib is an oral multikinase inhibitor targeting VEGFR1-3, TIE2, KIT, and RET to inhibit tumour angiogenesis, oncogenesis, metastasis, and cell proliferation.", "quote": "Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R)." }, "b": { "targets": [ "VEGFR1 (FLT1)", "VEGFR2 (KDR)", "VEGFR3 (FLT4)", "TIE2 (TEK)", "KIT", "RET" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, TIE2, KIT, RET)", "mechanism": "Regorafenib blocks multiple kinases involved in angiogenesis, oncogenesis, metastasis and tumour immunity; inhibition of mutated KIT blocks tumour-cell proliferation.", "quote": "Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R)." }, "decision": { "reason": "Both readers agree on the substance. Reading 1 uses cleaner symbols, and Reading 2 has the more informative label and mentions mutated KIT. Neither is ambiguous: the text names the targets in order, 'angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF...'.", "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "TIE2", "KIT", "RET" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, TIE2, KIT, RET)", "mechanism": "Oral multikinase inhibitor blocking angiogenic (VEGFR1-3, TIE2), oncogenic (KIT, RET, RAF), metastatic (PDGFR, FGFR) and immune (CSF1R) kinases; inhibits mutated KIT to block tumour-cell proliferation.", "quote": "Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R).", "ambiguous": false } }, "relatlimab-nivolumab__opdualag": { "url": "https://www.ema.europa.eu/en/documents/product-information/opdualag-epar-product-information_en.pdf", "text": "Opdualag is a fixed-dose combination (FDC) of nivolumab, a programmed death-1 inhibitor\n(anti-PD-1) and relatlimab, a lymphocyte-activation gene-3 inhibitor (anti-LAG-3).\nBinding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell\nproliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumours, and\nsignalling through this pathway can contribute to inhibition of active T cell immune surveillance of\ntumours. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor, blocks\ninteraction with its ligands PD-L1 and PD-L2 and reduces PD-1 pathway-mediated inhibition of the\nimmune response, including the anti-tumour immune response. In syngeneic mouse tumour models,\nblocking PD-1 activity resulted in decreased tumour growth.\nRelatlimab is a human IgG4 monoclonal antibody that binds to the LAG-3 receptor, blocks its\ninteraction with ligands, including MHC II, and reduces LAG-3 pathway-mediated inhibition of the\nimmune response. Antagonism of this pathway promotes T cell proliferation and cytokine secretion.\nThe combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell\nactivation compared to the activity of either antibody alone. In murine syngeneic tumour models,\n\n15\nLAG-3 blockade potentiates the anti-tumour activity of PD-1 blockage, inhibiting tumour growth and\npromoting tumour regression.", "a": { "targets": [ "PD-1", "LAG-3" ], "modality": "monoclonal antibody", "label": "PD-1 and LAG-3 checkpoint inhibitor combination", "mechanism": "Binds PD-1 and LAG-3 receptors to block interaction with their ligands, reducing inhibitory signalling and enhancing T-cell activation and anti-tumour immune responses.", "quote": "Opdualag is a fixed-dose combination (FDC) of nivolumab, a programmed death-1 inhibitor (anti-PD-1) and relatlimab, a lymphocyte-activation gene-3 inhibitor (anti-LAG-3)." }, "b": { "targets": [ "PD-1", "LAG-3" ], "modality": "monoclonal antibody", "label": "Anti-PD-1 and anti-LAG-3 antibodies", "mechanism": "Nivolumab binds PD-1 and relatlimab binds LAG-3, reducing inhibitory immune signalling and increasing T-cell activation.", "quote": "Opdualag is a fixed-dose combination (FDC) of nivolumab, a programmed death-1 inhibitor (anti-PD-1) and relatlimab, a lymphocyte-activation gene-3 inhibitor (anti-LAG-3)." }, "decision": null }, "relugolix__orgovyx": { "url": "https://www.ema.europa.eu/en/documents/product-information/orgovyx-epar-product-information_en.pdf", "text": "Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRH\nreceptors in the anterior pituitary gland preventing native GnRH from binding and signalling\nthe secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).\nConsequently, the production of testosterone from the testes is reduced. In humans, FSH and\nLH concentrations rapidly decline upon initiating treatment with Orgovyx and testosterone\nconcentrations are suppressed to below physiologic concentrations. Treatment is not\nassociated with the initial increases in FSH and LH concentrations and subsequently\ntestosterone (“potential symptomatic flare”) observed upon initiation of treatment with a\nGnRH analogue. Following discontinuation of treatment, pituitary and gonadal hormone\nconcentrations return to physiologic concentrations.\n\n18", "a": { "targets": [ "GnRH receptor" ], "modality": "small molecule", "label": "GnRH receptor antagonist", "mechanism": "Competitively binds pituitary GnRH receptors, preventing native GnRH binding and suppressing LH, FSH, and testosterone production.", "quote": "Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland preventing native GnRH from binding and signalling the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)." }, "b": { "targets": [ "GNRHR" ], "modality": "small molecule", "label": "GnRH receptor antagonist", "mechanism": "Relugolix competitively binds GnRH receptors in the anterior pituitary, blocking GnRH signalling and reducing LH, FSH, and consequently testosterone production.", "quote": "Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland preventing native GnRH from binding and signalling the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)." }, "decision": { "reason": "Both readings agree on substance and differ only in how the target is written; the instructions ask for hormonal targets to be named as a receptor ('GnRH receptor'), and the text states plainly that relugolix 'competitively binds to GnRH receptors in the anterior pituitary gland', so it is not ambiguous.", "targets": [ "GnRH receptor" ], "modality": "small molecule", "label": "GnRH receptor antagonist", "mechanism": "Competitively binds pituitary GnRH receptors, blocking GnRH signalling so LH and FSH fall and testosterone is suppressed, without the initial flare seen with GnRH analogues.", "quote": "Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland preventing native GnRH from binding and signalling the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).", "ambiguous": false } }, "repotrectinib__augtyro": { "url": "https://www.ema.europa.eu/en/documents/product-information/augtyro-epar-product-information_en.pdf", "text": "Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin\nreceptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK) with\nIC50 values of 0.05 to 1.04 nM.\nFusion proteins that include ROS1 or TRK domains can drive tumourigenic potential through\nhyperactivation of downstream signalling pathways leading to unconstrained cell proliferation.\nRepotrectinib has demonstrated in vitro and in vivo inhibition of cell lines expressing the targeted\nfusion oncogenes ROS1, TRKA, TRKB, TRKC, and corresponding mutations (ROS1G2032R,\nROS1D2033N, TRKAG595R, TRKBG639R, TRKCG623R). Repotrectinib binds inside the boundary of the\nATP-binding pocket and avoids steric interference from both solvent front and gatekeeper mutations.", "a": { "targets": [ "ROS1", "TRKA", "TRKB", "TRKC", "ALK" ], "modality": "small molecule", "label": "ROS1 and TRK tyrosine kinase inhibitor", "mechanism": "Repotrectinib inhibits the tyrosine kinases ROS1, TRKA, TRKB, TRKC, and ALK, blocking downstream oncogenic signalling and tumour cell proliferation driven by fusion proteins and resistance mutations.", "quote": "Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK) with IC50 values of 0.05 to 1.04 nM." }, "b": { "targets": [ "ROS1", "NTRK1", "NTRK2", "NTRK3", "ALK" ], "modality": "small molecule", "label": "Multikinase inhibitor (ROS1, TRK, ALK)", "mechanism": "Repotrectinib inhibits ROS1, TRKA, TRKB, TRKC and ALK by binding inside their ATP-binding pockets.", "quote": "Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK) with IC50 values of 0.05 to 1.04 nM." }, "decision": { "reason": "The text plainly names the targets: \"Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK)\". Reading 1 uses the protein symbols the text gives and a clinically conventional label, so it is preferred over Reading 2's gene symbols and \"multikinase\" label.", "targets": [ "ROS1", "TRKA", "TRKB", "TRKC", "ALK" ], "modality": "small molecule", "label": "ROS1 and TRK tyrosine kinase inhibitor", "mechanism": "Binds the ATP-binding pocket of ROS1, TRKA/B/C and ALK and inhibits these kinases, including solvent-front and gatekeeper resistance mutants, blocking fusion-driven signalling and proliferation.", "quote": "Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK) with IC50 values of 0.05 to 1.04 nM.", "ambiguous": false } }, "retifanlimab__zynyz": { "url": "https://www.ema.europa.eu/en/documents/product-information/zynyz-epar-product-information_en.pdf", "text": "Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed\ndeath receptor-1 (PD-1) and blocks its interaction with its ligands PD-L1 and PD-L2. Engagement of\nPD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may be\nexpressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of\nT-cell function such as proliferation, cytokine secretion and cytotoxic activity. Retifanlimab binds to\nthe PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and potentiates T-cell\nactivity.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Retifanlimab is a monoclonal antibody that binds the PD-1 receptor and blocks interaction with PD-L1 and PD-L2, potentiating T-cell anti-tumour activity.", "quote": "Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed death receptor-1 (PD-1) and blocks its interaction with its ligands PD-L1 and PD-L2." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds PD-1, blocks its interaction with PD-L1 and PD-L2, and potentiates T-cell activity.", "quote": "Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed death receptor-1 (PD-1) and blocks its interaction with its ligands PD-L1 and PD-L2." }, "decision": null }, "ribociclib__kisqali": { "url": "https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf", "text": "Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50%\ninhibition (IC50) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays,\nrespectively. These kinases are activated upon binding to D-cyclins and play a crucial role in\nsignalling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-\nCDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma\nprotein (pRb).\nIn vitro, ribociclib decreased pRb phosphorylation, resulting in arrest in the G1 phase of the cell cycle,\nreduced proliferation and a senescent phenotype in breast cancer derived models. In vivo, treatment\nwith single-agent ribociclib led to tumour regressions which correlated with inhibition of pRb\nphosphorylation.\nIn vivo studies using patient-derived oestrogen receptor-positive breast cancer xenograft model\ncombinations of ribociclib and antioestrogens (i.e. letrozole) resulted in superior tumour growth\ninhibition with sustained tumour regression and delayed tumour regrowth after stopping dosing\ncompared to each substance alone. When administered to patients ribociclib can also be\nimmunomodulatory, decreasing regulatory T-cells and relative levels of CD3+ T-cells. Additionally,\nin vivo antitumour activity of ribociclib in combination with fulvestrant was assessed in immune-\ndeficient mice bearing the ZR751 ER+ human breast cancer xenografts and the combination with\nfulvestrant resulted in complete tumour growth inhibition.\nWhen tested in a panel of breast cancer cell lines with known ER status, ribociclib demonstrated to be\nmore efficacious in ER+ breast cancer cell lines than in the ER- ones. In the preclinical models tested\nso far, intact pRb was required for ribociclib activity.", "a": { "targets": [ "CDK4/6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Ribociclib selectively inhibits CDK4 and CDK6, decreasing retinoblastoma protein phosphorylation and causing G1 cell cycle arrest to reduce tumor cell proliferation.", "quote": "Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% inhibition (IC50) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays, respectively." }, "b": { "targets": [ "CDK4", "CDK6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Ribociclib inhibits CDK4 and CDK6, reducing retinoblastoma protein phosphorylation and arresting cells in the G1 phase of the cell cycle.", "quote": "Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% inhibition (IC50) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays, respectively." }, "decision": { "reason": "The two readings differ only in format; the instructions' example list uses \"CDK4/6\" as the standard symbol, and the text unambiguously names \"cyclin-dependent kinase (CDK) 4 and 6\" as the targets.", "targets": [ "CDK4/6" ], "modality": "small molecule", "label": "CDK4/6 inhibitor", "mechanism": "Ribociclib selectively inhibits CDK4 and CDK6, decreasing retinoblastoma protein phosphorylation and causing G1 cell cycle arrest and reduced proliferation.", "quote": "Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% inhibition (IC50) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays, respectively.", "ambiguous": false } }, "ripretinib__qinlock": { "url": "https://www.ema.europa.eu/en/documents/product-information/qinlock-epar-product-information_en.pdf", "text": "Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine\nkinase and PDGFRA kinase, including wild type, primary, and secondary mutations. Ripretinib also\ninhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF.", "a": { "targets": [ "KIT", "PDGFRA", "PDGFRB", "TIE2", "VEGFR2", "BRAF" ], "modality": "small molecule", "label": "KIT and PDGFRA kinase inhibitor", "mechanism": "Ripretinib is a tyrosine kinase inhibitor that inhibits wild-type and mutant KIT and PDGFRA kinases, as well as other kinases including PDGFRB, TIE2, VEGFR2, and BRAF.", "quote": "Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase and PDGFRA kinase, including wild type, primary, and secondary mutations." }, "b": { "targets": [ "KIT", "PDGFRA", "PDGFRB", "TEK", "KDR", "BRAF" ], "modality": "small molecule", "label": "Multikinase inhibitor (KIT, PDGFRA, PDGFRB, TEK, KDR, BRAF)", "mechanism": "Ripretinib inhibits KIT and PDGFRA, including wild-type and mutated forms, and also inhibits PDGFRB, TIE2, VEGFR2, and BRAF in vitro.", "quote": "Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase and PDGFRA kinase, including wild type, primary, and secondary mutations." }, "decision": { "reason": "The text names KIT and PDGFRA as the primary targets (\"inhibits KIT proto-oncogene receptor tyrosine kinase and PDGFRA kinase\") and lists the others only as in vitro activity, so Reading 2's label and symbols (TIE2, VEGFR2, as the instructions use) fit best, though its mechanism should keep the in vitro qualifier.", "targets": [ "KIT", "PDGFRA", "PDGFRB", "TIE2", "VEGFR2", "BRAF" ], "modality": "small molecule", "label": "KIT and PDGFRA kinase inhibitor", "mechanism": "Tyrosine kinase inhibitor of KIT and PDGFRA, including wild-type, primary and secondary mutant forms; also inhibits PDGFRB, TIE2, VEGFR2 and BRAF in vitro.", "quote": "Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase and PDGFRA kinase, including wild type, primary, and secondary mutations.", "ambiguous": false } }, "rituximab__mabthera": { "url": "https://www.ema.europa.eu/en/documents/product-information/mabthera-epar-product-information_en.pdf", "text": "Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein,\nlocated on pre-B and mature B lymphocytes. The antigen is expressed on >95% of all B-cell\nnon-Hodgkin’s lymphomas.\nCD20 is found on both normal and malignant B-cells, but not on haematopoietic stem cells, pro-B-cells,\nnormal plasma cells or other normal tissue. This antigen does not internalise upon antibody binding and\nis not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, does\nnot compete for antibody binding.\nThe Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can\nrecruit immune effector functions to mediate B-cell lysis. Possible mechanisms of effector-mediated cell\nlysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and\nantibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the\nsurface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B\nlymphocytes has also been demonstrated to induce cell death via apoptosis.", "a": { "targets": [ "CD20" ], "modality": "monoclonal antibody", "label": "Anti-CD20 monoclonal antibody", "mechanism": "Binds specifically to CD20 on B lymphocytes, recruiting immune effector functions to mediate B-cell lysis via CDC, ADCC, and induction of apoptosis.", "quote": "Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes." }, "b": { "targets": [ "CD20" ], "modality": "monoclonal antibody", "label": "CD20-directed monoclonal antibody", "mechanism": "Rituximab binds CD20 on B lymphocytes and promotes B-cell lysis through immune effector functions, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity; it can also induce apoptosis.", "quote": "Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes." }, "decision": null }, "ropeginterferon-alfa-2b__besremi": { "url": "https://www.ema.europa.eu/en/documents/product-information/besremi-epar-product-information_en.pdf", "text": "Interferon alfa belongs to the class of type I interferons which exhibit their cellular effects by binding\nto a transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates a\ndownstream signalling cascade through the activation of kinases, particularly Janus kinase 1 (JAK1)\nsignal transducer and activator of transcription (STAT) proteins.\nNuclear translocation of STAT proteins controls distinct gene-expression programs and exhibits\nvarious cellular effects. Interferon alfa was shown to have an inhibitory effect on the proliferation of\nhematopoietic and bone marrow fibroblast progenitor cells and antagonised the action of growth\nfactors and other cytokines that have a role in the development of myelofibrosis. These actions may be\ninvolved in the therapeutic effects of interferon alfa in polycythaemia vera.\nFurther, it was demonstrated that interferon alfa is able to decrease the mutated JAK2V617F allele\nburden in patients with polycythaemia vera (a V617F point mutation in the JAK2 kinase is a hallmark\nof polycythaemia vera and is present in approximately 95% of patients).", "a": { "targets": [ "IFNAR" ], "modality": "protein or peptide", "label": "Interferon alfa receptor agonist", "mechanism": "Binds to the interferon alfa receptor (IFNAR), activating downstream JAK/STAT signaling to inhibit proliferation of hematopoietic progenitor cells and reduce JAK2V617F allele burden.", "quote": "Interferon alfa belongs to the class of type I interferons which exhibit their cellular effects by binding to a transmembrane receptor termed interferon alfa receptor (IFNAR)." }, "b": { "targets": [ "IFNAR" ], "modality": "protein or peptide", "label": "Type I interferon (IFNAR-binding)", "mechanism": "Binds IFNAR and activates downstream JAK1/STAT signalling and gene-expression programs; it also inhibits proliferation of hematopoietic and bone marrow fibroblast progenitor cells.", "quote": "Interferon alfa belongs to the class of type I interferons which exhibit their cellular effects by binding to a transmembrane receptor termed interferon alfa receptor (IFNAR)." }, "decision": null }, "rucaparib__rubraca": { "url": "https://www.ema.europa.eu/en/documents/product-information/rubraca-epar-product-information_en.pdf", "text": "Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XK03\nMechanism of action and pharmacodynamics effects\nRucaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1,\nPARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-\ninduced cytotoxicity involves inhibition of PARP enzymatic activity and the trapping of PARP-DNA\ncomplexes resulting in increased DNA damage, apoptosis, and cell death.\nRucaparib has been shown to have in vitro and in vivo anti-tumour activity in BRCA mutant cell lines\nthrough a mechanism known as synthetic lethality, whereby the loss of two DNA repair pathways is\nrequired for cell death. Increased rucaparib-induced cytotoxicity and anti-tumour activity was\nobserved in tumour cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib\nhas been shown to decrease tumour growth in mouse xenograft models of human cancer with or\nwithout deficiencies in BRCA.\nClinical efficacy\nFirst-Line maintenance treatment of advanced ovarian cancer\nThe efficacy of rucaparib was evaluated in ATHENA, a Phase 3, double-blind, multicentre trial in\nwhich 538 patients with advanced ovarian (EOC), fallopian tube (FTC), or primary peritoneal cancer\n(PPC) who were in response to first-line platinum-based chemotherapy and surgery were enrolled.\nResponse was defined as no evidence of disease progression radiologically or through rising CA-125\n(per Gynecological Cancer Intergroup (GCIG) guidelines) at any time during first-line treatment; and\neither no evidence of measurable disease by RECIST v1.1, if complete resection after surgery, or a\nresponse (complete or partial) if measurable disease was present after surgery and prior to\nchemotherapy, or a GCIG CA-125 response if non-measurable disease was present in the same\nsituation.\nAll patients had received between 4 to 8 cycles of platinum-doublet treatment (including ≥ 4 cycles of\nplatinum/taxane combination). Bevacizumab treatment was allowed during first-line chemotherapy,\nbut not during the maintenance rucaparib treatment. All patients were randomised within 8 weeks of\nthe first day of the last cycle of chemotherapy.\nPatients were randomised (4:1) to receive rucaparib tablets 600 mg orally twice daily (n=427) or\nplacebo (n=111). Treatment was continued until disease progression or unacceptable toxicity or for up\nto 2 years. Randomisation was stratified by disease status post-chemotherapy (residual disease vs. no\nresidual disease), timing of surgery (primary surgery vs. interval debulking), and biomarker status.\nBiomarker status was determined using the homologous recombination deficiency (HRD) test where\nbiomarker-positive was a tumour with HRD defined by the presence of a deleterious tumour BRCA\n\n12\n(tBRCA) mutation or tBCRA wild type (tBRCAwt) / high genomic loss of heterozygosity (LOHhigh),\nand biomarker-negative was a tumour without HRD, defined by tBRCAwt / low genomic LOH\n(LOHlow).\nThe major effi", "a": { "targets": [ "PARP1", "PARP2", "PARP3" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Inhibits PARP enzymatic activity and traps PARP-DNA complexes, resulting in increased DNA damage, apoptosis, and cell death.", "quote": "Rucaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair." }, "b": { "targets": [ "PARP1", "PARP2", "PARP3" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Rucaparib inhibits PARP enzymatic activity and traps PARP-DNA complexes, increasing DNA damage and leading to apoptosis and cell death.", "quote": "Rucaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair." }, "decision": null }, "ruxolitinib-hemifumarate__ruxolitinib-viatris": { "url": "https://www.ema.europa.eu/en/documents/product-information/ruxolitinib-viatris-epar-product-information_en.pdf", "text": "Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50\nvalues of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the\nsignalling of a number of cytokines and growth factors that are important for haematopoiesis and\nimmune function.\nMF and PV are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and\nJAK2 signalling. The basis for the dysregulation is believed to include high levels of circulating\ncytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and\nsilencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signalling\nregardless of JAK2V617F mutation status. Activating mutations in JAK2 (V617F or exon 12) are\nfound in >95% of PV patients.\nRuxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models\nof haematological malignancies, as well as of Ba/F3 cells rendered cytokine-independent by\nexpressing the JAK2V617F mutated protein, with IC50 ranging from 80 to 320 nM.\nJAK-STAT signalling pathways play a role in regulating the development, proliferation, and activation\nof several immune cell types important for GvHD pathogenesis.", "a": { "targets": [ "JAK1", "JAK2" ], "modality": "small molecule", "label": "JAK1 and JAK2 inhibitor", "mechanism": "Ruxolitinib selectively inhibits the Janus Associated Kinases JAK1 and JAK2, blocking downstream JAK-STAT signalling and cell proliferation.", "quote": "Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively)." }, "b": { "targets": [ "JAK1", "JAK2" ], "modality": "small molecule", "label": "JAK1/2 inhibitor", "mechanism": "Ruxolitinib selectively inhibits JAK1 and JAK2, suppressing JAK-STAT signalling and cell proliferation in cytokine-dependent models.", "quote": "Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively)." }, "decision": null }, "ruxolitinib__jakavi": { "url": "https://www.ema.europa.eu/en/documents/product-information/jakavi-epar-product-information_en.pdf", "text": "Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50\nvalues of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the\nsignalling of a number of cytokines and growth factors that are important for haematopoiesis and\nimmune function.\nMF and PV are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and\nJAK2 signalling. The basis for the dysregulation is believed to include high levels of circulating\n\n23\ncytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and\nsilencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signalling\nregardless of JAK2V617F mutation status. Activating mutations in JAK2 (V617F or exon 12) are\nfound in >95% of PV patients.\nRuxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models\nof haematological malignancies, as well as of Ba/F3 cells rendered cytokine-independent by\nexpressing the JAK2V617F mutated protein, with IC50 ranging from 80 to 320 nM.\nJAK-STAT signalling pathways play a role in regulating the development, proliferation, and activation\nof several immune cell types important for GvHD pathogenesis.", "a": { "targets": [ "JAK1", "JAK2" ], "modality": "small molecule", "label": "JAK1 and JAK2 inhibitor", "mechanism": "Ruxolitinib selectively inhibits JAK1 and JAK2, blocking downstream JAK-STAT signaling and the proliferation of cytokine-dependent malignant cells.", "quote": "Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively)." }, "b": { "targets": [ "JAK1", "JAK2" ], "modality": "small molecule", "label": "Selective JAK1/JAK2 inhibitor", "mechanism": "Ruxolitinib inhibits JAK1 and JAK2, blocking JAK-STAT signalling and the proliferation of cytokine-dependent cellular models.", "quote": "Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively)." }, "decision": null }, "sacituzumab-govitecan__trodelvy": { "url": "https://www.ema.europa.eu/en/documents/product-information/trodelvy-epar-product-information_en.pdf", "text": "Sacituzumab govitecan binds to Trop-2-expressing tumour cells and is internalised with the\nsubsequent release of SN-38 from a hydrolysable linker. SN-38 interacts with topoisomerase I and\nprevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads\nto apoptosis and cell death.", "a": { "targets": [ "TROP2" ], "modality": "antibody-drug conjugate", "label": "TROP2-directed antibody-drug conjugate", "mechanism": "Binds Trop-2-expressing tumour cells and internalises to release SN-38, which inhibits topoisomerase I, causing DNA damage and cell death.", "quote": "Sacituzumab govitecan binds to Trop-2-expressing tumour cells and is internalised with the subsequent release of SN-38 from a hydrolysable linker." }, "b": { "targets": [ "TROP2" ], "modality": "antibody-drug conjugate", "label": "TROP2-directed antibody-drug conjugate", "mechanism": "Sacituzumab govitecan binds TROP2-expressing tumour cells, is internalised and releases SN-38, which inhibits topoisomerase I, causing DNA damage and apoptosis.", "quote": "Sacituzumab govitecan binds to Trop-2-expressing tumour cells and is internalised with the subsequent release of SN-38 from a hydrolysable linker." }, "decision": null }, "selinexor__nexpovio": { "url": "https://www.ema.europa.eu/en/documents/product-information/nexpovio-epar-product-information_en.pdf", "text": "Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that\nspecifically blocks exportin 1 (XPO1). XPO1 is the major mediator of the nuclear export of many\ncargo proteins including tumour suppressor proteins (TSPs), growth regulators and mRNAs of growth\npromoting (oncogenic) proteins. XPO1 inhibition by selinexor leads to marked accumulation of TSPs\nin the nucleus, cell cycle arrest, reductions in several oncoproteins such as c-Myc and cyclin D1, and\napoptosis of cancer cells. The combination of selinexor and dexamethasone and/or bortezomib\ndemonstrated synergistic cytotoxic effects in multiple myeloma in vitro and increased anti‐tumour\nactivity in murine xenograft multiple myeloma models in vivo, including those resistant to proteasome\ninhibitors.", "a": { "targets": [ "XPO1" ], "modality": "small molecule", "label": "Exportin 1 (XPO1) inhibitor", "mechanism": "Selinexor selectively blocks exportin 1 (XPO1), leading to nuclear accumulation of tumour suppressor proteins, cell cycle arrest, down-regulation of oncoproteins, and cancer cell apoptosis.", "quote": "Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1)." }, "b": { "targets": [ "XPO1" ], "modality": "small molecule", "label": "Selective XPO1 nuclear export inhibitor", "mechanism": "Selinexor blocks XPO1, causing tumour suppressor proteins to accumulate in the nucleus and promoting cell-cycle arrest and cancer-cell apoptosis.", "quote": "Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1)." }, "decision": null }, "selpercatinib__retsevmo": { "url": "https://www.ema.europa.eu/en/documents/product-information/retsevmo-epar-product-information_en.pdf", "text": "Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase.\nSelpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and\nVEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib\nalso inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In a\nbinding assay at the concentration of 1 μM selpercatinib, significant antagonist binding activity\n(>50%) was observed for the 5-HT (serotonin) transporter (70.2% antagonist) and α2C adrenoreceptor\n(51.7% antagonist). The concentration of 1 μM is approximately 7-fold higher than the maximum\nunbound plasma concentration of at the efficacious dose of selpercatinib.\nCertain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET\nwith various partners can result in constitutively activated chimeric RET fusion proteins that can act as\noncogenic drivers by promoting cell proliferation of tumour cell lines. In in vitro and in vivo tumour\nmodels, selpercatinib demonstrated anti-tumour activity in cells harboring constitutive activation of\nRET protein resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET,\nRET V804M, and RET M918T. In addition, selpercatinib showed anti-tumour activity in mice\nintracranially implanted with a patient-derived RET fusion-positive tumour.\nPharmacodynamic properties", "a": { "targets": [ "RET", "VEGFR1", "VEGFR3", "FGFR1", "FGFR2", "FGFR3" ], "modality": "small molecule", "label": "RET kinase inhibitor", "mechanism": "Selpercatinib inhibits wild-type and mutant RET receptor tyrosine kinase isoforms and fusions, suppressing downstream oncogenic signalling and tumour cell proliferation.", "quote": "Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase." }, "b": { "targets": [ "RET", "VEGFR1", "VEGFR3", "FGFR1", "FGFR2", "FGFR3" ], "modality": "small molecule", "label": "Selective RET kinase inhibitor", "mechanism": "It inhibits RET, including wild-type and mutated isoforms, and also inhibits VEGFR1, VEGFR3 and FGFR1–3 at higher concentrations.", "quote": "Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase." }, "decision": null }, "selumetinib__koselugo": { "url": "https://www.ema.europa.eu/en/documents/product-information/koselugo-epar-product-information_en.pdf", "text": "Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK 1/2).\nSelumetinib blocks MEK activity and the RAF-MEK-ERK pathway. Therefore, MEK inhibition can\nblock the proliferation and survival of tumour cells in which the RAF-MEK-ERK pathway is\nactivated.", "a": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Selumetinib selectively inhibits MEK 1/2, blocking the RAF-MEK-ERK pathway and suppressing tumor cell proliferation and survival.", "quote": "Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK 1/2)." }, "b": { "targets": [ "MEK1", "MEK2" ], "modality": "small molecule", "label": "Selective MEK1/2 inhibitor", "mechanism": "Selumetinib selectively inhibits MEK1/2, blocking MEK activity and the RAF-MEK-ERK pathway, which can block proliferation and survival of tumour cells with an activated pathway.", "quote": "Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK 1/2)." }, "decision": { "reason": "The two readings differ only in format; the instructions' symbol list gives \"MEK1/2\", and the text clearly names one target class, \"mitogen activated protein kinase kinases 1 and 2 (MEK 1/2)\", so the answer is not ambiguous.", "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "Selective MEK1/2 inhibitor", "mechanism": "Selumetinib selectively inhibits MEK1/2, blocking MEK activity and the RAF-MEK-ERK pathway. This can block proliferation and survival of tumour cells in which that pathway is activated.", "quote": "Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK 1/2).", "ambiguous": false } }, "serplulimab__hetronifly": { "url": "https://www.ema.europa.eu/en/documents/product-information/hetronifly-epar-product-information_en.pdf", "text": "Serplulimab (HLX10) is a humanised monoclonal IgG4 antibody, which binds to the programmed cell\ndeath-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor\nis a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell\nimmune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in\nantigen presenting cells and may be expressed by tumours or other cells in the tumour\nmicroenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Serplulimab\npotentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to\nPD-L1 and PD-L2 ligands.\nThe PD-1 receptor occupation of peripheral T cells and interleukin-2 (IL-2) release ability in vitro\nwere studied in the phase 1 trial involving 29 Chinese patients with advanced solid tumour that were\ninjected with single and multiple doses (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg) of serplulimab. The\nresult showed that serplulimab could stably maintain the saturation state of receptor occupation and\nsustained functional blockage at the dosage from 0.3 mg/kg to 10 mg/kg every 2 weeks interval.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Serplulimab binds PD-1 and blocks its interaction with PD-L1 and PD-L2, potentiating T-cell and anti-tumour responses.", "quote": "Serplulimab (HLX10) is a humanised monoclonal IgG4 antibody, which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds PD-1 and blocks its interaction with PD-L1 and PD-L2, potentiating T-cell responses, including anti-tumour responses.", "quote": "Serplulimab (HLX10) is a humanised monoclonal IgG4 antibody, which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2." }, "decision": null }, "sonidegib__odomzo": { "url": "https://www.ema.europa.eu/en/documents/product-information/odomzo-epar-product-information_en.pdf", "text": "Sonidegib is an orally bioavailable inhibitor of the Hh signalling pathway. It binds to Smoothened (Smo), a\nG protein-coupled receptor-like molecule that positively regulates the Hh pathway and eventually activates\nand releases glioma-associated oncogene (GLI) transcription factors which induces the transcription of Hh\ntarget genes involved in proliferation, differentiation and survival. Aberrant Hh signalling has been linked to\nthe pathogenesis of several types of cancer, including basal cell carcinoma (BCC). Sonidegib binding to Smo\nwill inhibit Hh signalling and consequently block signal transduction.", "a": { "targets": [ "SMO" ], "modality": "small molecule", "label": "Smoothened inhibitor", "mechanism": "Sonidegib binds to Smoothened, inhibiting Hedgehog signalling and blocking downstream signal transduction involved in proliferation, differentiation, and survival.", "quote": "Sonidegib binding to Smo will inhibit Hh signalling and consequently block signal transduction." }, "b": { "targets": [ "SMO" ], "modality": "small molecule", "label": "Hedgehog pathway inhibitor (SMO)", "mechanism": "Sonidegib binds SMO, inhibiting Hedgehog signalling and blocking signal transduction.", "quote": "Sonidegib binding to Smo will inhibit Hh signalling and consequently block signal transduction." }, "decision": null }, "sorafenib__nexavar": { "url": "https://www.ema.europa.eu/en/documents/product-information/nexavar-epar-product-information_en.pdf", "text": "Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibits\ntumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a\nreduction of tumour angiogenesis. Sorafenib inhibits the activity of targets present in the tumour cell\n(CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2,\nVEGFR-3, and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas\nc-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.", "a": { "targets": [ "CRAF", "BRAF", "VEGFR2", "VEGFR3", "KIT", "PDGFRB" ], "modality": "small molecule", "label": "Multikinase inhibitor", "mechanism": "Sorafenib inhibits multiple serine/threonine and receptor tyrosine kinases, decreasing tumour cell proliferation and tumour angiogenesis.", "quote": "Sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß)." }, "b": { "targets": [ "RAF1", "BRAF", "KIT", "FLT3", "KDR", "FLT4" ], "modality": "small molecule", "label": "Multikinase inhibitor (RAF, KIT, FLT3, VEGFR)", "mechanism": "Sorafenib inhibits RAF kinases and receptor tyrosine kinases including KIT, FLT3, VEGFR-2/3 and PDGFR-β, reducing tumour-cell proliferation and tumour angiogenesis.", "quote": "Sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß)." }, "decision": { "reason": "The text names its targets plainly as \"CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3\" in the tumour cell and \"CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß\" in the vasculature, so the readings differ only in symbols and in which six to keep. Reading 2's style (CRAF, VEGFR2) matches the instructions better than Reading 1's gene names (RAF1, KDR), and RAF plus the vascular targets are the most important.", "targets": [ "CRAF", "BRAF", "VEGFR2", "VEGFR3", "PDGFRB", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (RAF, VEGFR, PDGFR)", "mechanism": "Sorafenib inhibits RAF serine/threonine kinases (CRAF, BRAF incl. V600E) and receptor tyrosine kinases (KIT, FLT3, VEGFR-2/3, PDGFR-β), reducing tumour-cell proliferation and tumour angiogenesis.", "quote": "Sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß).", "ambiguous": false } }, "sotorasib__lumykras": { "url": "https://www.ema.europa.eu/en/documents/product-information/lumykras-epar-product-information_en.pdf", "text": "Sotorasib is a selective KRAS G12C (Kirsten rat sarcoma viral oncogene homologue) inhibitor, which\ncovalently and irreversibly binds to the unique cysteine of KRAS G12C. Inactivation of KRAS G12C\nby sotorasib blocks tumour cell signalling and survival, inhibits cell growth, and promotes apoptosis\nselectively in tumours harbouring KRAS G12C, an oncogenic driver of tumourigenesis.", "a": { "targets": [ "KRAS G12C" ], "modality": "small molecule", "label": "KRAS G12C inhibitor", "mechanism": "Sotorasib covalently and irreversibly binds to KRAS G12C, blocking downstream tumour cell signalling and survival, inhibiting growth, and promoting apoptosis.", "quote": "Sotorasib is a selective KRAS G12C (Kirsten rat sarcoma viral oncogene homologue) inhibitor, which covalently and irreversibly binds to the unique cysteine of KRAS G12C." }, "b": { "targets": [ "KRAS G12C" ], "modality": "small molecule", "label": "KRAS G12C inhibitor", "mechanism": "Sotorasib covalently and irreversibly binds KRAS G12C, blocking tumour cell signalling and survival and promoting apoptosis in tumours harbouring the mutation.", "quote": "Sotorasib is a selective KRAS G12C (Kirsten rat sarcoma viral oncogene homologue) inhibitor, which covalently and irreversibly binds to the unique cysteine of KRAS G12C." }, "decision": null }, "sugemalimab__cejemly": { "url": "https://www.ema.europa.eu/en/documents/product-information/cejemly-epar-product-information_en.pdf", "text": "Sugemalimab is a fully human immunoglobulin G4 monoclonal antibody. It specifically binds to\nprogrammed cell death ligand 1 (PD-L1), thus blocking its ligation with PD-1. PD-L1, when\nexpressed on tumour cells and tumour-infiltrating immune cells, can contribute to the inhibition of an\nanti-tumour immune response. Binding of PD-L1 to the PD-1 and CD80 (B7.1) receptors found on\nT-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and\ncytokine production. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of\nimmune responses without inducing antibody dependent cell-mediated cytotoxicity (ADCC).", "a": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Sugemalimab binds to PD-L1, blocking its interactions with PD-1 and CD80 to release the inhibition of anti-tumour immune responses.", "quote": "It specifically binds to programmed cell death ligand 1 (PD-L1), thus blocking its ligation with PD-1." }, "b": { "targets": [ "PD-L1" ], "modality": "monoclonal antibody", "label": "PD-L1 inhibitor (antibody)", "mechanism": "Binds PD-L1 and blocks its interactions with PD-1 and CD80, releasing inhibition of immune responses.", "quote": "It specifically binds to programmed cell death ligand 1 (PD-L1), thus blocking its ligation with PD-1." }, "decision": null }, "sunitinib__sutent": { "url": "https://www.ema.europa.eu/en/documents/product-information/sutent-epar-product-information_en.pdf", "text": "Sunitinib inhibits multiple RTKs that are implicated in tumour growth, neoangiogenesis, and\nmetastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growth\nfactor receptors (PDGFRα and PDGFRβ), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), stem\ncell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor\n(CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). The primary metabolite\nexhibits similar potency compared to sunitinib in biochemical and cellular assays.", "a": { "targets": [ "PDGFRA", "PDGFRB", "VEGFR1", "VEGFR2", "VEGFR3", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, PDGFR, KIT)", "mechanism": "Sunitinib inhibits multiple receptor tyrosine kinases, including PDGFR, VEGFR, KIT, and FLT3, to impair tumor growth, neoangiogenesis, and metastatic progression.", "quote": "Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET)." }, "b": { "targets": [ "PDGFRA", "PDGFRB", "VEGFR1", "VEGFR2", "VEGFR3", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (PDGFR, VEGFR, KIT)", "mechanism": "Sunitinib inhibits multiple receptor tyrosine kinases implicated in tumour growth, neoangiogenesis and metastatic progression of cancer.", "quote": "Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET)." }, "decision": null }, "tabelecleucel__ebvallo": { "url": "https://www.ema.europa.eu/en/documents/product-information/ebvallo-epar-product-information_en.pdf", "text": "Ebvallo is an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates EBV-\ninfected cells in an HLA-restricted manner. Ebvallo has an equivalent mechanism of action to that\ndemonstrated by endogenous circulating T cells in the donors from which the medicinal product is\nderived. The T-cell receptor of each clonal population within Ebvallo recognises an EBV peptide in\ncomplex with a specific HLA molecule on the surface of target cells (the restricting HLA allele) and\nallows the medicinal product to exert cytotoxic activity against the EBV-infected cells.", "a": { "targets": [ "EBV", "HLA" ], "modality": "cell therapy", "label": "Allogeneic EBV-specific T-cell immunotherapy", "mechanism": "Recognises EBV peptides presented on HLA molecules on target cells via T-cell receptors, exerting cytotoxic activity to eliminate EBV-infected cells.", "quote": "The T-cell receptor of each clonal population within Ebvallo recognises an EBV peptide in complex with a specific HLA molecule on the surface of target cells (the restricting HLA allele) and allows the medicinal product to exert cytotoxic activity against the EBV-infected cells." }, "b": { "targets": [ "EBV peptide", "HLA" ], "modality": "cell therapy", "label": "EBV-specific T-cell immunotherapy", "mechanism": "T-cell receptors recognize EBV peptides presented by specific HLA molecules, enabling cytotoxic activity against EBV-infected cells.", "quote": "The T-cell receptor of each clonal population within Ebvallo recognises an EBV peptide in complex with a specific HLA molecule on the surface of target cells (the restricting HLA allele) and allows the medicinal product to exert cytotoxic activity against the EBV-infected cells." }, "decision": { "reason": "The text says the TCR \"recognises an EBV peptide in complex with a specific HLA molecule\", so the target is the EBV peptide–HLA complex, which is more precise than plain \"EBV\"; the text leaves no real doubt.", "targets": [ "EBV peptide–HLA complex" ], "modality": "cell therapy", "label": "Allogeneic EBV-specific T-cell immunotherapy", "mechanism": "Allogeneic T cells whose receptors recognise EBV peptides presented by specific HLA molecules on target cells, killing EBV-infected cells in an HLA-restricted manner.", "quote": "The T-cell receptor of each clonal population within Ebvallo recognises an EBV peptide in complex with a specific HLA molecule on the surface of target cells (the restricting HLA allele) and allows the medicinal product to exert cytotoxic activity against the EBV-infected cells.", "ambiguous": false } }, "tafasitamab__minjuvi": { "url": "https://www.ema.europa.eu/en/documents/product-information/minjuvi-epar-product-information_en.pdf", "text": "Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the\nsurface of pre-B and mature B lymphocytes.\nUpon binding to CD19, tafasitamab mediates B-cell lysis through:\n• engagement of immune effector cells like natural killer cells, γδ T cells and phagocytes\n• direct induction of cell death (apoptosis)\nThe Fc modification results in enhanced antibody-dependent cellular cytotoxicity and\nantibody-dependent cellular phagocytosis.", "a": { "targets": [ "CD19" ], "modality": "monoclonal antibody", "label": "CD19-directed monoclonal antibody", "mechanism": "Binds CD19 on B lymphocytes to mediate B-cell lysis through immune effector cell engagement (enhanced ADCC and ADCP) and direct induction of apoptosis.", "quote": "Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes." }, "b": { "targets": [ "CD19" ], "modality": "monoclonal antibody", "label": "CD19-targeting monoclonal antibody", "mechanism": "Binds CD19 on B lymphocytes and promotes their lysis through immune-effector cell engagement and apoptosis, with Fc enhancement of antibody-dependent cellular cytotoxicity and phagocytosis.", "quote": "Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes." }, "decision": null }, "tagraxofusp__elzonris": { "url": "https://www.ema.europa.eu/en/documents/product-information/elzonris-epar-product-information_en.pdf", "text": "Tagraxofusp is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and\ntruncated diphtheria toxin (DT) fusion protein that targets CD123-expressing cells. Tagraxofusp\nirreversibly inhibits protein synthesis of target cells by inactivating elongation factor 2 (EF2), resulting\nin apoptosis (cell death).", "a": { "targets": [ "CD123" ], "modality": "protein or peptide", "label": "CD123-directed cytotoxin", "mechanism": "It targets CD123-expressing cells and irreversibly inhibits protein synthesis by inactivating elongation factor 2, causing apoptosis.", "quote": "Tagraxofusp is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that targets CD123-expressing cells." }, "b": { "targets": [ "CD123" ], "modality": "protein or peptide", "label": "CD123-directed cytotoxin", "mechanism": "It targets CD123-expressing cells and irreversibly inhibits protein synthesis by inactivating elongation factor 2, resulting in apoptosis.", "quote": "Tagraxofusp is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that targets CD123-expressing cells." }, "decision": null }, "talazoparib__talzenna": { "url": "https://www.ema.europa.eu/en/documents/product-information/talzenna-epar-product-information_en.pdf", "text": "Talazoparib is an inhibitor of PARP enzymes, PARP1 (IC50=0.7 nM), and PARP2 (IC50=0.3 nM).\nPARP enzymes are involved in cellular DNA damage response signalling pathways such as DNA\nrepair, gene transcription, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancer\ncells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP\nprotein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair,\nreplication, and transcription, thereby resulting in apoptosis and/or cell death. Treatment of cancer cell\nlines that are harbouring defects in DNA repair genes with talazoparib single agent leads to increased\nlevels of γH2AX, a marker of double stranded DNA breaks, and results in decreased cell proliferation\nand increased apoptosis. Talazoparib anti-tumour activity was also observed in a patient-derived\nxenograft (PDX) BRCA mutant breast cancer model where the patient was previously treated with a\nplatinum-based regimen, as well as in an androgen receptor (AR)-positive prostate cancer xenograft\nmodel. In these PDX models talazoparib decreased tumour growth and increased γH2AX level and\napoptosis in the tumours.\nThe anti-tumour effects of combined inhibition of PARP and AR activity is based on the following\nmechanisms: AR signalling inhibition suppresses the expression of homologous recombination repair\n(HRR) genes including BRCA1, resulting in sensitivity to PARP inhibition. PARP1 activity has been\nshown to be required for maximal AR function and thus inhibiting PARP may reduce AR signalling\nand increase sensitivity to AR signalling inhibitors. Clinical resistance to AR blockade is sometimes\nassociated with co-deletion of RB1 and BRCA2, which is in turn associated with sensitivity to PARP\ninhibition.", "a": { "targets": [ "PARP1", "PARP2" ], "modality": "small molecule", "label": "PARP inhibitor", "mechanism": "Inhibits PARP1 and PARP2 catalytic activity and traps PARP on DNA lesions, preventing DNA repair and inducing apoptosis.", "quote": "Talazoparib is an inhibitor of PARP enzymes, PARP1 (IC50=0.7 nM), and PARP2 (IC50=0.3 nM)." }, "b": { "targets": [ "PARP1", "PARP2" ], "modality": "small molecule", "label": "PARP1/2 inhibitor", "mechanism": "Talazoparib inhibits PARP1 and PARP2 catalytic activity and traps PARP bound to DNA lesions, preventing DNA repair and promoting cancer cell death.", "quote": "Talazoparib is an inhibitor of PARP enzymes, PARP1 (IC50=0.7 nM), and PARP2 (IC50=0.3 nM)." }, "decision": null }, "talimogene-laherparepvec__imlygic": { "url": "https://www.ema.europa.eu/en/documents/product-information/imlygic-epar-product-information_en.pdf", "text": "Talimogene laherparepvec is an oncolytic immunotherapy that is derived from HSV-1. Talimogene\nlaherparepvec has been modified to replicate within tumours and to produce the immune stimulatory\nprotein human GM-CSF. Talimogene laherparepvec causes the death of tumour cells and the release\nof tumour-derived antigens. It is thought that together with GM-CSF, it will promote a systemic\nanti-tumour immune response and an effector T-cell response. Mice that had complete regression of\ntheir primary tumours following treatment were resistant to subsequent tumour re-challenge.\nThe modifications to talimogene laherparepvec from HSV-1 include deletion of ICP34.5 and ICP47.\nWhereas anti-viral immune responses defend normal cells following infection by talimogene\nlaherparepvec, tumours have been shown to be susceptible to injury and cell death from\nICP34.5-deficient HSV-1 viruses, including talimogene laherparepvec. Deletion of ICP47 prevents\ndown-regulation of antigen presentation molecules and increases the expression of HSV US11 gene,\nthereby enhancing viral replication in tumour cells.", "a": { "targets": [], "modality": "oncolytic virus", "label": "Oncolytic viral immunotherapy", "mechanism": "Selectively replicates within tumour cells to cause lysis and release of tumour antigens, while expressing human GM-CSF to promote a systemic anti-tumour immune response.", "quote": "Talimogene laherparepvec has been modified to replicate within tumours and to produce the immune stimulatory protein human GM-CSF." }, "b": { "targets": [], "modality": "oncolytic virus", "label": "GM-CSF-expressing oncolytic virus", "mechanism": "The modified HSV-1 replicates in tumour cells, causing cell death and antigen release, and produces GM-CSF to promote antitumour immune responses.", "quote": "Talimogene laherparepvec has been modified to replicate within tumours and to produce the immune stimulatory protein human GM-CSF." }, "decision": null }, "talquetamab__talvey": { "url": "https://www.ema.europa.eu/en/documents/product-information/talvey-epar-product-information_en.pdf", "text": "Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody\ndirected against GPRC5D and the CD3 receptor on T Cells.\nTalquetamab promotes enhanced T cell-mediated cytotoxicity through recruitment of CD3-expressing\nT cells to GPRC5D-expressing cells. This leads to the activation of T cells and induces subsequent\nlysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in the\nsecretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells with\nminimal to no expression detected on B cells and B cell precursors, talquetamab targets multiple\nmyeloma cells particularly.", "a": { "targets": [ "GPRC5D", "CD3" ], "modality": "bispecific antibody", "label": "GPRC5D × CD3 bispecific antibody", "mechanism": "Binds GPRC5D and CD3 to recruit T cells to GPRC5D-expressing cells, triggering T-cell activation and perforin- and granzyme-mediated lysis.", "quote": "Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody directed against GPRC5D and the CD3 receptor on T Cells." }, "b": { "targets": [ "GPRC5D", "CD3" ], "modality": "bispecific antibody", "label": "GPRC5D × CD3 bispecific antibody", "mechanism": "Talquetamab binds GPRC5D on target cells and CD3 on T cells, recruiting and activating T cells to lyse GPRC5D-expressing cells.", "quote": "Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody directed against GPRC5D and the CD3 receptor on T Cells." }, "decision": null }, "tarlatamab__imdylltra": { "url": "https://www.ema.europa.eu/en/documents/product-information/imdylltra-epar-product-information_en.pdf", "text": "Tarlatamab is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager that binds to DLL3\nexpressed on the surface of tumour cells and CD3 expressed on the surface of T-cells. The bispecific\nbinding of tarlatamab to T-cells and DLL3-positive tumour cells triggers T-cell activation, production\nof inflammatory cytokines, and release of cytotoxic proteins, which results in redirected lysis of\ntumour cells.", "a": { "targets": [ "DLL3", "CD3" ], "modality": "bispecific antibody", "label": "DLL3 × CD3 bispecific antibody", "mechanism": "Binds DLL3 on tumor cells and CD3 on T cells, triggering T-cell activation and release of cytotoxic proteins to lyse DLL3-positive tumor cells.", "quote": "Tarlatamab is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager that binds to DLL3 expressed on the surface of tumour cells and CD3 expressed on the surface of T-cells." }, "b": { "targets": [ "DLL3", "CD3" ], "modality": "bispecific antibody", "label": "DLL3 × CD3 bispecific T-cell engager", "mechanism": "Binds DLL3 on tumour cells and CD3 on T cells, triggering T-cell activation and redirected lysis of tumour cells.", "quote": "Tarlatamab is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager that binds to DLL3 expressed on the surface of tumour cells and CD3 expressed on the surface of T-cells." }, "decision": null }, "tasonermin__beromun": { "url": "https://www.ema.europa.eu/en/documents/product-information/beromun-epar-product-information_en.pdf", "text": "In vivo antitumour activity is probably based on direct and indirect effects:\nDirect inhibition of tumour cell proliferation: Tasonermin is cytotoxic or cytostatic in vitro for a\nvariety of tumour cell lines of different histogenesis.\nDirect effects on tumour vasculature: Tasonermin affects the morphology and reduces proliferation of\nendothelial cells and modifies expression of specific cell surface and secretory proteins (including\nadhesion molecules and proteins modulating coagulation, interleukins and haematopoietic growth\nfactors). These changes in turn lead to a procoagulant state, resulting in microvascular thrombosis.\nFurther, adherence and extravasation of leukocytes is increased, leading to infiltration of the tumour\nby lymphocytes, monocytes, and granulocytes. The reason for the differential sensitivity of the tumour\nvasculature (high) versus normal vasculature (low) are currently unknown.\nIndirect and direct immunomodulation: Tasonermin has profound effects on cellular components of\nthe immune system. Proliferation of activated B- and T-lymphocytes, development of cytotoxic\nT-cells and immunoglobulin-secreting cells is enhanced, monocytes/macrophages are activated for\nkilling of tumour cells, granulocytes are activated to display enhanced phagocytic activity, respiratory\nburst and degranulation, and adherence to endothelium. Further, in addition to its direct effects,\ntasonermin modulates immune responses by inducing production of cytokines as well as low\nmolecular weight mediators (prostaglandins, platelet activating factor). Several lines of evidence\nsuggest that these immunomodulatory activities are of relevance for the antitumour effects; e.g. the\nantitumour activities of tasonermin are much less pronounced in immunodeficient animals. Further,\nanimals that reject experimental tumours following tasonermin treatment may develop specific\nimmunity for this tumour cell type.", "a": { "targets": [], "modality": "protein or peptide", "label": "Recombinant tumor necrosis factor alfa", "mechanism": "Tasonermin directly inhibits tumour cell proliferation, disrupts tumour vasculature leading to microvascular thrombosis, and activates immune cells to promote antitumour activity.", "quote": "Tasonermin is cytotoxic or cytostatic in vitro for a variety of tumour cell lines of different histogenesis." }, "b": { "targets": [], "modality": "protein or peptide", "label": "Immunomodulatory antitumour protein", "mechanism": "Tasonermin directly inhibits tumour-cell proliferation, alters tumour vasculature to promote microvascular thrombosis, and activates immune responses.", "quote": "Tasonermin affects the morphology and reduces proliferation of endothelial cells and modifies expression of specific cell surface and secretory proteins (including adhesion molecules and proteins modulating coagulation, interleukins and haematopoietic growth factors)." }, "decision": null }, "tebentafusp__kimmtrak": { "url": "https://www.ema.europa.eu/en/documents/product-information/kimmtrak-epar-product-information_en.pdf", "text": "Tebentafusp is a bispecific fusion protein, comprised of a T cell receptor (TCR; targeting domain)\nfused to an antibody fragment targeting CD3 (cluster of differentiation 3; effector domain). The TCR\nend binds with high affinity to a gp100 peptide presented by human leukocyte antigen – A*02:01\n(HLA-A*02:01) on the cell surface of uveal melanoma tumour cells, and the effector domain binds to\nthe CD3 receptor on the polyclonal T cell.\nAn immune synapse is formed when the TCR targeting domain of tebentafusp binds to uveal\nmelanoma cells and the CD3 effector domain binds to polyclonal T cells. This immune synapse results\nin redirection and activation of polyclonal T cells regardless of their native TCR specificity.\nTebentafusp activated polyclonal T cells release inflammatory cytokines and cytolytic proteins, which\nresult in direct lysis of uveal melanoma tumour cells.", "a": { "targets": [ "gp100", "CD3" ], "modality": "bispecific antibody", "label": "gp100 × CD3 bispecific fusion protein", "mechanism": "Tebentafusp binds gp100 presented by HLA-A*02:01 on uveal melanoma cells and CD3 on T cells, redirecting and activating polyclonal T cells to directly lyse tumour cells.", "quote": "The TCR end binds with high affinity to a gp100 peptide presented by human leukocyte antigen – A*02:01 (HLA-A*02:01) on the cell surface of uveal melanoma tumour cells, and the effector domain binds to the CD3 receptor on the polyclonal T cell." }, "b": { "targets": [ "gp100 peptide/HLA-A*02:01", "CD3" ], "modality": "protein or peptide", "label": "gp100/HLA-A*02:01 × CD3 bispecific fusion protein", "mechanism": "It binds gp100 peptide presented by HLA-A*02:01 on tumour cells and CD3 on T cells, forming an immune synapse that activates T cells to lyse tumour cells.", "quote": "The TCR end binds with high affinity to a gp100 peptide presented by human leukocyte antigen – A*02:01 (HLA-A*02:01) on the cell surface of uveal melanoma tumour cells, and the effector domain binds to the CD3 receptor on the polyclonal T cell." }, "decision": { "reason": "The text calls tebentafusp \"a bispecific fusion protein, comprised of a T cell receptor... fused to an antibody fragment targeting CD3\", so it is a TCR-based fusion protein rather than a bispecific antibody, and it binds \"a gp100 peptide presented by... HLA-A*02:01\" on one arm and CD3 on the other; Reading 1 is correct.", "targets": [ "gp100 peptide/HLA-A*02:01", "CD3" ], "modality": "protein or peptide", "label": "gp100/HLA-A*02:01 × CD3 bispecific fusion protein", "mechanism": "Its TCR arm binds gp100 peptide presented by HLA-A*02:01 on uveal melanoma cells and its anti-CD3 arm binds T cells, redirecting and activating polyclonal T cells to lyse tumour cells.", "quote": "The TCR end binds with high affinity to a gp100 peptide presented by human leukocyte antigen – A*02:01 (HLA-A*02:01) on the cell surface of uveal melanoma tumour cells, and the effector domain binds to the CD3 receptor on the polyclonal T cell.", "ambiguous": false } }, "teclistamab__tecvayli": { "url": "https://www.ema.europa.eu/en/documents/product-information/tecvayli-epar-product-information_en.pdf", "text": "Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on\nthe surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of\nmalignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. With its\ndual binding sites, teclistamab is able to draw CD3+ T cells in close proximity to BCMA+ cells,\nresulting in T cell activation and subsequent lysis and death of BCMA+ cells, which is mediated by\nsecreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This\neffect occurs without regard to T cell receptor specificity or reliance on major histocompatibility\ncomplex (MHC) Class 1 molecules on the surface of antigen presenting cells.", "a": { "targets": [ "BCMA", "CD3" ], "modality": "bispecific antibody", "label": "BCMA × CD3 bispecific antibody", "mechanism": "Teclistamab binds CD3 on T cells and BCMA on myeloma cells, bringing them together to trigger T-cell activation and subsequent lysis of BCMA-positive cells.", "quote": "Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells." }, "b": { "targets": [ "BCMA", "CD3" ], "modality": "bispecific antibody", "label": "BCMA × CD3 bispecific antibody", "mechanism": "Teclistamab binds BCMA on myeloma cells and CD3 on T cells, bringing them together to activate T cells and lyse BCMA-positive cells.", "quote": "Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells." }, "decision": null }, "temsirolimus__torisel": { "url": "https://www.ema.europa.eu/en/documents/product-information/torisel-epar-product-information_en.pdf", "text": "Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds\nto an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits the\nactivity of mTOR that controls cell division. In vitro, at high concentrations (10-20 M), temsirolimus\ncan bind and inhibit mTOR in the absence of FKBP-12. Biphasic dose response of cell growth\ninhibition was observed. High concentrations resulted in complete cell growth inhibition in vitro,\nwhereas inhibition mediated by FKBP-12/temsirolimus complex alone resulted in approximately 50%\ndecrease in cell proliferation. Inhibition of mTOR activity results in a G1 growth delay at nanomolar\nconcentrations and growth arrest at micromolar concentrations in treated tumour cells resulting from\nselective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, and\nornithine decarboxylase. When mTOR activity is inhibited, its ability to phosphorylate, and thereby\ncontrol the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the\nP13 kinase/AKT pathway) that control cell division, is blocked.\nIn addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible\nfactors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to\nhypoxic microenvironments and to produce the angiogenic factor vascular endothelial growth factor\n(VEGF). The anti-tumour effect of temsirolimus, therefore, may also in part stem from its ability to\ndepress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vessel\ndevelopment.", "a": { "targets": [ "mTOR" ], "modality": "small molecule", "label": "mTOR inhibitor", "mechanism": "Binds FKBP-12 to form a complex that inhibits mTOR, disrupting downstream translation of cell cycle regulatory proteins and impairing tumor vessel development.", "quote": "Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin)." }, "b": { "targets": [ "mTOR" ], "modality": "small molecule", "label": "mTOR inhibitor", "mechanism": "Temsirolimus binds FKBP-12, and the complex inhibits mTOR, disrupting translation of cell-cycle regulatory proteins and slowing or arresting tumour-cell growth.", "quote": "Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin)." }, "decision": null }, "tepotinib__tepmetko": { "url": "https://www.ema.europa.eu/en/documents/product-information/tepmetko-epar-product-information_en.pdf", "text": "Tepotinib is a reversible Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of\nMET. Tepotinib blocked MET phosphorylation and MET-dependent downstream signalling such as\nthe phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein\nkinase/extracellular-signal regulated kinase (MAPK/ERK) pathways in a dose-dependent manner.\nTepotinib demonstrated pronounced anti-tumour activity in tumours with oncogenic activation of\nMET, such as METex14 skipping alterations.\n\n11", "a": { "targets": [ "MET" ], "modality": "small molecule", "label": "MET inhibitor", "mechanism": "A reversible ATP-competitive small molecule inhibitor that blocks MET phosphorylation and downstream PI3K/Akt and MAPK/ERK signalling.", "quote": "Tepotinib is a reversible Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET." }, "b": { "targets": [ "MET" ], "modality": "small molecule", "label": "MET inhibitor", "mechanism": "Tepotinib reversibly competes with ATP to inhibit MET, blocking MET phosphorylation and MET-dependent downstream signalling.", "quote": "Tepotinib is a reversible Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET." }, "decision": null }, "thalidomide__thalidomide-bms-previously-thalidomide-celgene-": { "url": "https://www.ema.europa.eu/en/documents/product-information/thalidomide-bms-epar-product-information_en.pdf", "text": "Thalidomide shows immunomodulatory, anti-inflammatory and potential anti-neoplastic activities.\nData from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory\nand anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis\nfactor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules\ninvolved in leukocyte migration and anti-angiogenic activity. Thalidomide is also a non-barbiturate\ncentrally active hypnotic sedative. It has no antibacterial effects.", "a": { "targets": [ "TNF-α" ], "modality": "small molecule", "label": "Immunomodulatory agent", "mechanism": "Thalidomide exerts immunomodulatory and anti-neoplastic effects potentially via suppression of excessive TNF-α production, leukocyte adhesion molecule down-modulation, and anti-angiogenic activity.", "quote": "Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity." }, "b": { "targets": [ "TNF" ], "modality": "small molecule", "label": "Immunomodulatory agent", "mechanism": "Thalidomide may suppress excessive TNF-α production, down-modulate selected adhesion molecules involved in leukocyte migration, and have anti-angiogenic activity.", "quote": "Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity." }, "decision": { "reason": "The readings differ only in symbol format (TNF-α vs TNF), and TNF-α matches the text's wording. The text hedges the mechanism (\"may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production\"), but TNF-α is the only molecular target it names, so the answer is not open.", "targets": [ "TNF-α" ], "modality": "small molecule", "label": "Immunomodulatory agent", "mechanism": "Thalidomide's immunomodulatory and anti-neoplastic effects may relate to suppression of excess TNF-α production, down-modulation of leukocyte adhesion molecules and anti-angiogenic activity.", "quote": "Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity.", "ambiguous": false } }, "thalidomide__thalidomide-lipomed": { "url": "https://www.ema.europa.eu/en/documents/product-information/thalidomide-lipomed-epar-product-information_en.pdf", "text": "Thalidomide shows immunomodulatory, anti-inflammatory and potential anti-neoplastic activities.\nData from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory\nand anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis\nfactor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules\ninvolved in leukocyte migration and anti-angiogenic activity. Thalidomide is also a non-barbiturate\ncentrally active hypnotic sedative. It has no antibacterial effects.", "a": { "targets": [ "TNF-α" ], "modality": "small molecule", "label": "Immunomodulating agent", "mechanism": "Thalidomide exhibits immunomodulatory and anti-neoplastic effects linked to suppression of excessive TNF-α production, modulation of leukocyte adhesion molecules, and anti-angiogenic activity.", "quote": "Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity." }, "b": { "targets": [ "TNF" ], "modality": "small molecule", "label": "Immunomodulatory agent", "mechanism": "It may suppress excessive TNF-α production, down-modulate selected adhesion molecules involved in leukocyte migration, and have anti-angiogenic activity.", "quote": "Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity." }, "decision": { "reason": "Both readings agree in substance; the text names only TNF-α (\"suppression of excessive tumour necrosis factor-alpha (TNF-α) production\"), and does so hedged with \"may be related to\". Cereblon is not mentioned, so the target is TNF-α and the text is not open.", "targets": [ "TNF-α" ], "modality": "small molecule", "label": "Immunomodulatory agent", "mechanism": "Thalidomide may act by suppressing excessive TNF-α production, down-modulating cell surface adhesion molecules involved in leukocyte migration, and through anti-angiogenic activity.", "quote": "Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatory and anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosis factor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion molecules involved in leukocyte migration and anti-angiogenic activity.", "ambiguous": false } }, "tisagenlecleucel__kymriah": { "url": "https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf", "text": "Tisagenlecleucel is an autologous, immunocellular cancer therapy which involves reprogramming a\npatient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and\neliminate CD19 expressing cells. The CAR is comprised of a murine single chain antibody fragment\nwhich recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and\nCD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and anti-tumour activity,\nwhile 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19-\nexpressing cells, the CAR transmits a signal promoting T-cell expansion and persistence of\ntisagenlecleucel.", "a": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "Autologous CAR T cells recognise CD19 on target cells, activating T-cell signalling to expand, persist, and eliminate CD19-expressing cells.", "quote": "The CAR is comprised of a murine single chain antibody fragment which recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and CD3 zeta." }, "b": { "targets": [ "CD19" ], "modality": "cell therapy", "label": "CD19-directed CAR T-cell therapy", "mechanism": "The engineered T cells bind CD19-expressing cells, triggering T-cell activation, expansion and anti-tumour activity.", "quote": "Tisagenlecleucel is an autologous, immunocellular cancer therapy which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19 expressing cells." }, "decision": null }, "tislelizumab__tevimbra": { "url": "https://www.ema.europa.eu/en/documents/product-information/tevimbra-epar-product-information_en.pdf", "text": "Tislelizumab is a humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1,\nbinding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1\nand PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in\nT-cells in in vitro cell-based assays.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Tislelizumab binds PD-1 and blocks PD-L1 and PD-L2 binding, inhibiting negative signaling and enhancing T-cell functional activity.", "quote": "Tislelizumab is a humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds the extracellular domain of PD-1, blocks PD-L1 and PD-L2 binding, and inhibits PD-1-mediated negative signalling.", "quote": "Tislelizumab is a humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1." }, "decision": null }, "tisotumab-vedotin__tivdak": { "url": "https://www.ema.europa.eu/en/documents/product-information/tivdak-epar-product-information_en.pdf", "text": "Tisotumab vedotin is an antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell surface\nprotein expressed at elevated levels on a variety of solid tumours relative to normal tissue. The small\nmolecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable\nlinker. Tisotumab vedotin binds to TF-expressing tumour cells, the ADC-TF complex is internalised,\nand local release of MMAE occurs via proteolytic cleavage. MMAE disrupts the microtubule network\nof actively dividing cells, leading to cell cycle arrest and apoptotic cell death.\nDirect cytotoxicity in TF-expressing cells, bystander cytotoxicity, antibody-dependent cellular\ncytotoxicity, antibody-dependent cellular phagocytosis, and immunogenic cell death has been\ndemonstrated in vitro with tisotumab and/or tisotumab vedotin.", "a": { "targets": [ "tissue factor" ], "modality": "antibody-drug conjugate", "label": "Tissue factor-directed antibody-drug conjugate", "mechanism": "Binds tissue factor on tumour cells, is internalised, and releases MMAE, which disrupts the microtubule network to cause cell cycle arrest and apoptotic cell death.", "quote": "Tisotumab vedotin is an antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell surface protein expressed at elevated levels on a variety of solid tumours relative to normal tissue." }, "b": { "targets": [ "TF (F3)" ], "modality": "antibody-drug conjugate", "label": "TF-directed antibody-drug conjugate", "mechanism": "It binds TF on tumour cells and releases MMAE after internalisation; MMAE disrupts microtubules, causing cell-cycle arrest and apoptotic cell death.", "quote": "Tisotumab vedotin is an antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell surface protein expressed at elevated levels on a variety of solid tumours relative to normal tissue." }, "decision": { "reason": "Both readings agree on the substance, since the text names a single target (\"directed to tissue factor (TF)\"), so they differ only in how the symbol is written; the standard short form \"TF\" is used here.", "targets": [ "TF" ], "modality": "antibody-drug conjugate", "label": "TF-directed antibody-drug conjugate (MMAE)", "mechanism": "Binds tissue factor (TF) on tumour cells and is internalised, then releases MMAE, which disrupts microtubules and causes cell-cycle arrest and apoptotic cell death.", "quote": "Tisotumab vedotin is an antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell surface protein expressed at elevated levels on a variety of solid tumours relative to normal tissue.", "ambiguous": false } }, "tivozanib-hydrochloride-monohydrate__fotivda": { "url": "https://www.ema.europa.eu/en/documents/product-information/fotivda-epar-product-information_en.pdf", "text": "Tivozanib potently and selectively blocks all 3 vascular endothelial growth factor receptors (VEGFR)\nand has been shown to block various VEGF-induced biochemical and biologic responses in vitro,\nincluding VEGF-ligand-induced phosphorylation of all three VEGFR 1, 2 and 3, and proliferation of\nhuman endothelial cells. The next most potently inhibited kinase is c-kit which is 8-fold less sensitive\nto inhibition by tivozanib compared to VEGFR 1, 2 and 3. VEGF is a potent mitogenic factor that\nplays a central role in angiogenesis and vascular permeability of tumour tissues. By blocking\nVEGF-induced VEGFR activation, tivozanib inhibits angiogenesis and vascular permeability in\ntumour tissues, leading to inhibition of tumour growth in vivo.", "a": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "KIT" ], "modality": "small molecule", "label": "VEGFR tyrosine kinase inhibitor", "mechanism": "Tivozanib selectively blocks VEGFR 1, 2, and 3 phosphorylation and activation, inhibiting endothelial cell proliferation, angiogenesis, vascular permeability, and tumour growth.", "quote": "Tivozanib potently and selectively blocks all 3 vascular endothelial growth factor receptors (VEGFR) and has been shown to block various VEGF-induced biochemical and biologic responses in vitro, including VEGF-ligand-induced phosphorylation of all three VEGFR 1, 2 and 3, and proliferation of human endothelial cells." }, "b": { "targets": [ "VEGFR1", "VEGFR2", "VEGFR3", "KIT" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, KIT)", "mechanism": "Tivozanib blocks VEGFR1, VEGFR2 and VEGFR3, inhibiting VEGF-driven angiogenesis and vascular permeability; it also inhibits c-kit.", "quote": "Tivozanib potently and selectively blocks all 3 vascular endothelial growth factor receptors (VEGFR) and has been shown to block various VEGF-induced biochemical and biologic responses in vitro, including VEGF-ligand-induced phosphorylation of all three VEGFR 1, 2 and 3, and proliferation of human endothelial cells." }, "decision": null }, "toremifene__fareston": { "url": "https://www.ema.europa.eu/en/documents/product-information/fareston-epar-product-information_en.pdf", "text": "Pharmacotherapeutic group: Endocrine therapy, Anti-estrogens, ATC code: L02BA02\nToremifene is a nonsteroidal triphenylethylene derivative. As other members of this class, e.g.\ntamoxifen and clomifene, toremifene binds to estrogen receptors and may produce estrogenic, anti-\nestrogenic or both effects, depending upon the duration of treatment, animal species, gender, target\norgan and variable selected. In general, however, nonsteroidal triphenylethylene derivatives are\npredominantly anti-estrogenic in rats and man and estrogenic in mice.\nIn post-menopausal breast cancer patients, toremifene treatment is associated with modest reductions\nin both total serum cholesterol and low density lipoprotein (LDL).\n\n7\nToremifene binds specifically to estrogen receptors, competitively with oestradiol, and inhibits\nestrogen-induced stimulation of DNA synthesis and cell replication. In some experimental cancers\nand/or using high-dose, toremifene displays anti-tumour effects which are not estrogen-dependent.\nThe anti-tumour effect of toremifene in breast cancer is mainly due to the anti-estrogenic effect,\nalthough other mechanisms (changes in oncogene expression, growth factor secretion, induction of\napoptosis and influence on cell cycle kinetics) may also be involved in the anti-tumour effect.", "a": { "targets": [ "estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor modulator", "mechanism": "Binds specifically and competitively to estrogen receptors, inhibiting estrogen-induced DNA synthesis and cell replication to exert an anti-estrogenic antitumor effect.", "quote": "Toremifene binds specifically to estrogen receptors, competitively with oestradiol, and inhibits estrogen-induced stimulation of DNA synthesis and cell replication." }, "b": { "targets": [ "Estrogen receptor" ], "modality": "small molecule", "label": "Selective estrogen receptor modulator", "mechanism": "Toremifene competitively binds estrogen receptors, blocking oestradiol-driven DNA synthesis and cell replication; its breast-cancer effect is mainly anti-estrogenic.", "quote": "Toremifene binds specifically to estrogen receptors, competitively with oestradiol, and inhibits estrogen-induced stimulation of DNA synthesis and cell replication." }, "decision": null }, "toripalimab__loqtorzi": { "url": "https://www.ema.europa.eu/en/documents/product-information/loqtorzi-epar-product-information_en.pdf", "text": "Toripalimab is a humanised IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its\ninteraction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune\nresponse, including the anti-tumour immune response. Binding of the PD-1 ligands, PD-L1 and\nPD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation, cytokine production, and\ncytotoxic activity.", "a": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Toripalimab binds to the PD-1 receptor, blocking interaction with PD-L1 and PD-L2 to release PD-1 pathway-mediated inhibition of the anti-tumour immune response.", "quote": "Toripalimab is a humanised IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response." }, "b": { "targets": [ "PD-1" ], "modality": "monoclonal antibody", "label": "PD-1 inhibitor (antibody)", "mechanism": "Binds PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response.", "quote": "Toripalimab is a humanised IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response." }, "decision": null }, "tovorafenib__ojemda": { "url": "https://www.ema.europa.eu/en/documents/product-information/ojemda-epar-product-information_en.pdf", "text": "Tovorafenib is a central nervous system (CNS) penetrant, selective small molecule Type II RAF\nkinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including\nRAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated protein\nkinase (MAPK) pathway (see section 5.3).", "a": { "targets": [ "BRAF", "CRAF" ], "modality": "small molecule", "label": "Type II RAF kinase inhibitor", "mechanism": "Tovorafenib is a Type II RAF kinase inhibitor of mutant and wild-type BRAF and CRAF, suppressing activation of the mitogen-activated protein kinase (MAPK) pathway.", "quote": "Tovorafenib is a central nervous system (CNS) penetrant, selective small molecule Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including RAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated protein kinase (MAPK) pathway (see section 5.3)." }, "b": { "targets": [ "BRAF", "RAF1" ], "modality": "small molecule", "label": "Type II RAF kinase inhibitor", "mechanism": "Inhibits mutant BRAF V600E, wild-type BRAF and wild-type CRAF, including RAF monomers and dimers and BRAF fusion, suppressing MAPK pathway activation.", "quote": "Tovorafenib is a central nervous system (CNS) penetrant, selective small molecule Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including RAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated protein kinase (MAPK) pathway (see section 5.3)." }, "decision": { "reason": "The readers disagree only on the symbol for CRAF (RAF1 vs CRAF); the text names \"wild-type CRAF kinases\" alongside \"mutant BRAF V600E, wild-type BRAF\", so the targets are clear and not ambiguous, and CRAF matches the text's own wording.", "targets": [ "BRAF", "CRAF" ], "modality": "small molecule", "label": "Type II RAF kinase inhibitor", "mechanism": "CNS-penetrant Type II RAF inhibitor of mutant BRAF V600E, wild-type BRAF and CRAF (monomers, dimers and BRAF fusions), suppressing MAPK pathway activation.", "quote": "Tovorafenib is a central nervous system (CNS) penetrant, selective small molecule Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including RAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated protein kinase (MAPK) pathway (see section 5.3).", "ambiguous": false } }, "trametinib__mekinist": { "url": "https://www.ema.europa.eu/en/documents/product-information/mekinist-epar-product-information_en.pdf", "text": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular\nsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are\ncomponents of the extracellular signal-related kinase (ERK) pathway. In melanoma and other cancers,\nthis pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits\nactivation of MEK by BRAF and inhibits MEK kinase activity. Trametinib inhibits growth of BRAF\nV600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant\nmelanoma animal models.\nCombination with dabrafenib\nDabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive\nactivation of the RAS/RAF/MEK/ERK pathway. Thus, trametinib and dabrafenib inhibit two kinases\nin this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the\npathway. The combination of trametinib with dabrafenib has shown anti-tumour activity in BRAF\nV600 mutation-positive melanoma cell lines in vitro and delays the emergence of resistance in vivo in\nBRAF V600 mutation-positive melanoma xenografts.\nDetermination of BRAF mutation status\nBefore taking trametinib or the combination with dabrafenib, patients must have BRAF V600\nmutation-positive tumour status confirmed by a validated test.\nIn melanoma clinical studies, central testing for BRAF V600 mutation using a BRAF mutation assay\nwas conducted on the most recent tumour sample available. Primary tumour or tumour from a\nmetastatic site was tested with a validated polymerase chain reaction (PCR) assay developed by\nResponse Genetics Inc. The assay was specifically designed to differentiate between the V600E and\nV600K mutations. Only patients with BRAF V600E or V600K mutation-positive tumours were\neligible for study participation.\nSubsequently, all patient samples were re-tested using the CE-marked bioMerieux (bMx) THxID\nBRAF validated assay. The bMx THxID BRAF assay is an allele-specific PCR performed on DNA\nextracted from FFPE tumour tissue. The assay was designed to detect the BRAF V600E and V600K\nmutations with high sensitivity (down to 5% V600E and V600K sequence in a background of wild-\ntype sequence using DNA extracted from FFPE tissue). Non-clinical and clinical studies with\nretrospective bi-directional Sanger sequencing analyses have shown that the test also detects the less\ncommon BRAF V600D mutation and V600E/K601E mutation with lower sensitivity. Of the\nspecimens from the non-clinical and clinical studies (n=876) that were mutation-positive by the\nTHxID BRAF assay and subsequently were sequenced using the reference method, the specificity of\nthe assay was 94%.\n\n21", "a": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Trametinib is a reversible, selective allosteric inhibitor that blocks MEK1 and MEK2 activation and kinase activity within the ERK pathway.", "quote": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity." }, "b": { "targets": [ "MEK1", "MEK2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Trametinib selectively inhibits MEK1 and MEK2 activation and kinase activity, reducing signalling through the ERK pathway.", "quote": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity." }, "decision": { "reason": "The two readings agree in substance and differ only in notation; the instructions list \"MEK1/2\" as the standard symbol, and the text says trametinib is an \"allosteric inhibitor of ... (MEK1) and MEK2 activation and kinase activity\", so the target is clear.", "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Reversible, highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity, blocking BRAF-driven signalling through the ERK pathway.", "quote": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity.", "ambiguous": false } }, "trametinib__spexotras": { "url": "https://www.ema.europa.eu/en/documents/product-information/spexotras-epar-product-information_en.pdf", "text": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular\nsignal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are\ncomponents of the extracellular signal-related kinase (ERK) pathway. In human cancers, this pathway\nis often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of\nMEK by BRAF and inhibits MEK kinase activity.\n\n17\nCombination with dabrafenib\nDabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive\nactivation of the RAS/RAF/MEK/ERK pathway.\nThus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the\ncombination provides concomitant inhibition of the pathway. The combination of trametinib with\ndabrafenib has shown anti-tumour activity in BRAF V600 mutation-positive cancer cell lines in vitro\nand delays the emergence of resistance in vivo in BRAF V600 mutation-positive xenografts.", "a": { "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Trametinib is an allosteric inhibitor of MEK1 and MEK2 activation and kinase activity, preventing downstream signaling in the ERK pathway.", "quote": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity." }, "b": { "targets": [ "MEK1", "MEK2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Trametinib allosterically inhibits MEK1 and MEK2 activation and kinase activity, reducing signalling through the ERK pathway.", "quote": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity." }, "decision": { "reason": "The text plainly names one target pair: trametinib is an \"allosteric inhibitor of ... (MEK1) and MEK2 activation and kinase activity\". The readings differ only in whether to write MEK1/2 as one item or two, and the instructions' list uses \"MEK1/2\", so the text is not ambiguous.", "targets": [ "MEK1/2" ], "modality": "small molecule", "label": "MEK1/2 inhibitor", "mechanism": "Trametinib reversibly and allosterically inhibits MEK1 and MEK2 activation by BRAF and their kinase activity, blocking ERK pathway signalling; it is used with the RAF inhibitor dabrafenib.", "quote": "Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity.", "ambiguous": false } }, "trastuzumab-deruxtecan__enhertu": { "url": "https://www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_en.pdf", "text": "Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate. The antibody is a\nhumanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by a\ntetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The function of\nthe antibody portion is to bind to HER2 expressed on the surface of certain tumour cells. After\nbinding, the trastuzumab deruxtecan complex then undergoes internalisation and intracellular linker\ncleavage by lysosomal enzymes that are upregulated in cancer cells. Upon release, the membrane-\npermeable DXd causes DNA damage and apoptotic cell death. DXd, an exatecan derivative, is\napproximately 10 times more potent than SN-38, the active metabolite of irinotecan.\nIn vitro studies indicate that the antibody portion of trastuzumab deruxtecan, which has the same\namino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibody\nmediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells that\noverexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 3-\nkinase (PI3-K) pathway in human breast cancer cells that overexpress HER2.", "a": { "targets": [ "HER2" ], "modality": "antibody-drug conjugate", "label": "HER2-directed antibody-drug conjugate", "mechanism": "Binds to HER2 on tumour cells, internalises, and releases a topoisomerase I inhibitor payload that induces DNA damage and apoptotic cell death.", "quote": "Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate." }, "b": { "targets": [ "HER2" ], "modality": "antibody-drug conjugate", "label": "HER2-directed antibody-drug conjugate", "mechanism": "The antibody binds HER2 on tumour cells and is internalised; intracellular release of the topoisomerase I inhibitor DXd causes DNA damage and apoptotic cell death.", "quote": "The function of the antibody portion is to bind to HER2 expressed on the surface of certain tumour cells." }, "decision": null }, "trastuzumab-emtansine__kadcyla": { "url": "https://www.ema.europa.eu/en/documents/product-information/kadcyla-epar-product-information_en.pdf", "text": "Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the\nhumanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a\nmaytansine derivative) via the stable thioether linker\nMCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1\ncomplex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.\n\n16\nConjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for\nHER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to\nmalignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated\ninternalisation and subsequent lysosomal degradation, resulting in release of DM1-containing\ncytotoxic catabolites (primarily lysine-MCC-DM1).\nTrastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1:\n Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain\n(ECD), as well as to Fcγ receptors and complement C1q. In addition, trastuzumab emtansine, like\ntrastuzumab, inhibits shedding of the HER2 ECD, inhibits signalling through the\nphosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated\ncytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.\n DM1, the cytotoxic component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulin\npolymerisation, both DM1 and trastuzumab emtansine cause cells to arrest in the G2/M phase of\nthe cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays\nshow that DM1 is 20-200 times more potent than taxanes and vinca alkaloids.\n The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as\ndemonstrated by detection of very low levels of free DM1 in plasma.", "a": { "targets": [ "HER2" ], "modality": "antibody-drug conjugate", "label": "HER2-directed antibody-drug conjugate", "mechanism": "Binds HER2, undergoes internalisation to release the microtubule inhibitor DM1, which inhibits tubulin polymerisation, arresting cells in G2/M phase and inducing apoptosis.", "quote": "Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate)." }, "b": { "targets": [ "HER2" ], "modality": "antibody-drug conjugate", "label": "HER2-directed antibody-drug conjugate", "mechanism": "Binds HER2 and is internalised, releasing DM1 inside tumour cells; DM1 inhibits tubulin polymerisation, causing cell-cycle arrest and apoptotic cell death.", "quote": "Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate)." }, "decision": null }, "trastuzumab__herceptin": { "url": "https://www.ema.europa.eu/en/documents/product-information/herceptin-epar-product-information_en.pdf", "text": "Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of\nHER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2\nsignalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism\nof HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit\nthe proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent\nmediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated\nADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared\nwith cancer cells that do not overexpress HER2.\nDetection of HER2 overexpression or HER2 gene amplification\nDetection of HER2 overexpression or HER2 gene amplification in breast cancer\nHerceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene\namplification as determined by an accurate and validated assay. HER2 overexpression should be\ndetected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section\n4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or\nchromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin\ntreatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive\nFISH or CISH result.\nTo ensure accurate and reproducible results, the testing must be performed in a specialised laboratory,\nwhich can ensure validation of the testing procedures.\nThe recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:\nTable 2 Recommended Scoring System to Evaluate the IHC Staining Patterns in Breast Cancer\nScore Staining pattern HER2 overexpression\nassessment\n0 No staining is observed or membrane staining is\nobserved in < 10 % of the tumour cells\nNegative\n1+ A faint/barely perceptible membrane staining is\ndetected in > 10 % of the tumour cells. The cells are\nonly stained in part of their membrane.\nNegative\n2+ A weak to moderate complete membrane staining is\ndetected in > 10 % of the tumour cells.\nEquivocal\n3+ Strong complete membrane staining is detected in\n> 10 % of the tumour cells.\nPositive\nIn general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to\nthe chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the\nHER2 gene per tumour cell if no chromosome 17 control is used.\nIn general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus\nin greater than 50 % of tumour cells.\nFor full instructions on assay performance and interpretation please refer to the package inserts of\nvalidated FISH and CISH assays. Official recommendations on HER2 testing may also apply.\nFor any other method that may be used for the assessment of HER2 protein or gene expression, the\nanalyses should only be performed by laboratories that provide adequate state-of-the-art performance\nof validated methods. Such methods must clearly be precise and accurate enough to demonstrate\noverexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and\nstrong (congruent with 3+) overexpression of HER2.\n\n18\nDetection of HER2 over expression or HER2 gene amplification in gastric cancer\nOnly an accurate and validated assay should be used to detect HER2 over expression or HER2 gene\namplification. IHC is recommended as the first testing modality and in cases where HER2 gene\namplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH\ntechnique must be applied. SISH technology is however, recommended to allow for the parallel\nevaluation of tumor histology and morphology. To ensure validation of testing procedures and the\ngeneration of accurate and reproducible results, HER2 testing must be performed in a laboratory\nstaffed by trained personnel. Full instructions on assay performance and results interpretation should\nbe taken from the product information leaflet provided with the HER2 testing assays used.\nIn the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were\ndefined as HER2 positive and thus included in the trial. Based on the clinical trial results, the\nbeneficial effects were limited to patients with the highest level of HER2 protein overexpression,\ndefined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.\nIn a method comparison study (study D008548) a high degree of concordance (>95 %) was observed\nfor SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.\nHER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of\nfixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using\neither SISH or FISH on fixed tumour blocks.\nThe recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:\nTable 3 Recommended Scoring System to Evaluate the IHC Staining Patterns in Gastric Cancer\nScore Surgical specimen - staining\npattern\nBiopsy specimen –\nstaining pattern\nHER2\noverexpression\nassessment\n0\nNo reactivity or membranous\nreactivity in < 10 % of tumour\ncells\nNo reactivity or membranous\nreactivity in any tumour cell Negative\n1+\nFaint ⁄ barely perceptible\nmembranous reactivity in ≥\n10 % of tumour cells; cells are\nreactive only in part of their\nmembrane\nTumour cell cluster with a faint ⁄\nbarely perceptible membranous\nreactivity irrespective of\npercentage of tumour cells\nstained\nNegative\n2+\nWeak to moderate complete,\nbasolateral or lateral\nmembranous reactivity in\n≥ 10 % of tumour cells\nTumour cell cluster with a weak\nto moderate complete,\nbasolateral or lateral\nmembranous reactivity\nirrespective of percentage of\ntumour cells stained\nEquivocal\n3+\nStrong complete, basolateral\nor la", "a": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2-directed monoclonal antibody", "mechanism": "Binds subdomain IV of HER2, inhibiting ligand-independent signalling, preventing extracellular domain cleavage, and mediating antibody-dependent cell-mediated cytotoxicity.", "quote": "Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain." }, "b": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2-directed monoclonal antibody", "mechanism": "Binds HER2’s extracellular domain, inhibiting ligand-independent signalling and extracellular-domain cleavage, and mediates ADCC against HER2-overexpressing cells.", "quote": "Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain." }, "decision": null }, "trastuzumab__tuznue": { "url": "https://www.ema.europa.eu/en/documents/product-information/tuznue-epar-product-information_en.pdf", "text": "Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of\nHER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2\nsignalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism\nof HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit\nthe proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent\nmediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated\nADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared\nwith cancer cells that do not overexpress HER2.\n\n17\nDetection of HER2 overexpression or HER2 gene amplification\nDetection of HER2 overexpression or HER2 gene amplification in breast cancer\nTrastuzumab should only be used in patients whose tumours have HER2 overexpression or HER2\ngene amplification as determined by an accurate and validated assay. HER2 overexpression should be\ndetected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see\nsection 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation\n(FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for\nTuznue treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a\npositive FISH or CISH result.\nTo ensure accurate and reproducible results, the testing must be performed in a specialised laboratory,\nwhich can ensure validation of the testing procedures.\nThe recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:\nTable 2 Recommended scoring system to evaluate the IHC staining patterns in breast cancer\nScore Staining pattern HER2 overexpression\nassessment\n0 No staining is observed or membrane staining is\nobserved in <10% of the tumour cells.\nNegative\n1+ A faint/barely perceptible membrane staining is\ndetected in >10% of the tumour cells. The cells are\nonly stained in part of their membrane.\nNegative\n2+ A weak to moderate complete membrane staining is\ndetected in >10% of the tumour cells.\nEquivocal\n3+ Strong complete membrane staining is detected in\n>10% of the tumour cells.\nPositive\nIn general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to\nthe chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the\nHER2 gene per tumour cell if no chromosome 17 control is used.\nIn general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus\nin greater than 50% of tumour cells.\nFor full instructions on assay performance and interpretation please refer to the package inserts of\nvalidated FISH and CISH assays. Official recommendations on HER2 testing may also apply.\nFor any other method that may be used for the assessment of HER2 protein or gene expression, the\nanalyses should only be performed by laboratories that provide adequate state-of-the-art performance\nof validated methods. Such methods must clearly be precise and accurate enough to demonstrate\noverexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and\nstrong (congruent with 3+) overexpression of HER2.\nDetection of HER2 overexpression or HER2 gene amplification in gastric cancer\nOnly an accurate and validated assay should be used to detect HER2 over expression or HER2 gene\namplification. IHC is recommended as the first testing modality and in cases where HER2 gene\namplification status is also required, either a silver-enhanced in situ hybridisation (SISH) or a FISH\ntechnique must be applied. SISH technology is however, recommended to allow for the parallel\nevaluation of tumour histology and morphology. To ensure validation of testing procedures and the\ngeneration of accurate and reproducible results, HER2 testing must be performed in a laboratory\nstaffed by trained personnel. Full instructions on assay performance and results interpretation should\nbe taken from the product information leaflet provided with the HER2 testing assays used.\n\n18\nIn the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were\ndefined as HER2 positive and thus included in the trial. Based on the clinical trial results, the\nbeneficial effects were limited to patients with the highest level of HER2 protein overexpression,\ndefined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.\nIn a method comparison study (study D008548), a high degree of concordance (>95%) was observed\nfor SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.\nHER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of\nfixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using\neither SISH or FISH on fixed tumour blocks.\nThe recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:\nTable 3 Recommended scoring system to evaluate the IHC staining patterns in gastric cancer\nScore Surgical specimen - staining\npattern\nBiopsy specimen – staining pattern HER2\noverexpression\nassessment\n0 No reactivity or membranous\nreactivity in < 10% of tumour\ncells\nNo reactivity or membranous\nreactivity in any tumour cell\nNegative\n1+ Faint/barely perceptible\nmembranous reactivity in\n≥ 10% of tumour cells; cells\nare reactive only in part of\ntheir membrane\nTumour cell cluster with a\nfaint/barely perceptible membranous\nreactivity irrespective of percentage\nof tumour cells stained\nNegative\n2+ Weak to moderate complete,\nbasolateral or lateral\nmembranous reactivity in\n≥ 10% of tumour cells\nTumour cell cluster with a weak to\nmoderate complete, basolateral or\nlateral membranous reactivity\nirrespective of percentage of tumour\ncells stained\nEquivocal\n3+ Strong complete, basolateral or\nlateral membran", "a": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2-directed monoclonal antibody", "mechanism": "Binds HER2's extracellular domain to inhibit ligand-independent signalling, prevent extracellular domain cleavage, and mediate antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing tumour cells.", "quote": "Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain." }, "b": { "targets": [ "HER2" ], "modality": "monoclonal antibody", "label": "HER2-targeted monoclonal antibody", "mechanism": "Trastuzumab binds HER2, inhibiting ligand-independent signalling and extracellular-domain cleavage; it also mediates antibody-dependent cell-mediated cytotoxicity preferentially against HER2-overexpressing cancer cells.", "quote": "Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain." }, "decision": null }, "tremelimumab__imjudo": { "url": "https://www.ema.europa.eu/en/documents/product-information/imjudo-epar-product-information_en.pdf", "text": "Cytotoxic T lymphocyte-associated antigen (CTLA-4) is primarily expressed on the surface of T\nlymphocytes. Interaction of CTLA-4 with its ligands, CD80 and CD86, limits effector T-cell\nactivation, through a number of potential mechanisms, but primarily by limiting co-stimulatory\nsignalling through CD28.\nTremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80\nand CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity\nand enhanced anti-tumour activity.\nThe combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor results in\nimproved anti-tumour responses in metastatic non-small cell lung cancer and hepatocellular\ncarcinoma.", "a": { "targets": [ "CTLA-4" ], "modality": "monoclonal antibody", "label": "CTLA-4 inhibitor (antibody)", "mechanism": "Tremelimumab is a monoclonal antibody that blocks CTLA-4 interaction with CD80 and CD86, enhancing T-cell activation and anti-tumour activity.", "quote": "Tremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity and enhanced anti-tumour activity." }, "b": { "targets": [ "CTLA-4" ], "modality": "monoclonal antibody", "label": "CTLA-4 inhibitor (antibody)", "mechanism": "Blocks CTLA-4 interaction with CD80 and CD86, enhancing T-cell activation and proliferation and increasing anti-tumour activity.", "quote": "Tremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity and enhanced anti-tumour activity." }, "decision": null }, "tucatinib__tukysa": { "url": "https://www.ema.europa.eu/en/documents/product-information/tukysa-epar-product-information_en.pdf", "text": "Tucatinib is a reversible, potent and selective tyrosine kinase inhibitor of HER2. In cellular signalling\nassays, tucatinib is > 1 000-fold more selective for HER2 compared to epidermal growth factor\nreceptor. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of\ndownstream cell signalling and cell proliferation, and induces death in HER2 driven tumour cells. In\nvivo, tucatinib inhibits the growth of HER2 driven tumours and the combination of tucatinib and\ntrastuzumab showed enhanced anti-tumour activity in vitro and in vivo compared to either medicinal\nproduct alone.", "a": { "targets": [ "HER2" ], "modality": "small molecule", "label": "HER2 tyrosine kinase inhibitor", "mechanism": "Tucatinib selectively inhibits HER2 tyrosine kinase, blocking downstream signaling and cell proliferation while inducing death in HER2-driven tumor cells.", "quote": "Tucatinib is a reversible, potent and selective tyrosine kinase inhibitor of HER2." }, "b": { "targets": [ "HER2" ], "modality": "small molecule", "label": "HER2-selective tyrosine kinase inhibitor", "mechanism": "Tucatinib inhibits HER2 phosphorylation and downstream signalling, reducing proliferation and inducing death in HER2-driven tumour cells.", "quote": "Tucatinib is a reversible, potent and selective tyrosine kinase inhibitor of HER2." }, "decision": null }, "vandetanib__caprelsa": { "url": "https://www.ema.europa.eu/en/documents/product-information/caprelsa-epar-product-information_en.pdf", "text": "Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also\nknown as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR)\nand RET tyrosine kinases. Vandetanib is also a sub-micromolar inhibitor of vascular endothelial\nreceptor-3 tyrosine kinase.\nVandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood\nvessel formation in in vitro models of angiogenesis. In addition, vandetanib inhibits epidermal growth\nfactor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells.\nVandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. Vandetanib also\ninhibits both wild type and the majority of mutated, activated forms of RET, and significantly inhibits\nthe proliferation of MTC cell lines in vitro.\n\n13\n© ESTEVE (2026) INTERNAL USE\nIn vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vessel\npermeability, tumour microvessel density, and inhibited tumour growth of a range of human xenograft\ntumour models in athymic mice. Vandetanib also inhibited the growth of MTC xenograft tumours in\nvivo.\nThe precise mechanism of action of vandetanib in locally advanced or metastatic MTC is unknown.\nClinical efficacy in adults\nClinical data from MTC\nA randomised, double-blind, placebo-controlled study (Study 58) was conducted to demonstrate safety\nand efficacy of vandetanib 300 mg versus placebo. This study included 331 patients with unresectable\nlocally advanced or metastatic MTC. Only patients with CTN ≥ 500 pg/mL (conventional units) or\n≥ 146.3 pmol/L (international standard units) were enrolled. Of the patients enrolled in the study\n10 patients on vandetanib and 4 on placebo (4% of all patients) had a World Health Organization\nperformance status (WHO PS) score of ≥ 2 and 28 (12.1%) patients on vandetanib and 10 (10.1%) on\nplacebo had cardiac impairment. Cardiac impairment was defined as patients with previous\ncardiovascular abnormality.\nThe primary objective of this study was to demonstrate an improvement in progression-free survival\n(PFS) with vandetanib compared to placebo. The secondary endpoints were evaluation of overall\nobjective response rate (ORR), disease control rate (DCR) defined as, partial response (PR) or\ncomplete response (CR) or stable disease (SD) lasting at least 24 weeks, duration of response (DOR),\ntime to worsening of pain based on Brief Pain Inventory (BPI) worst pain scale, and overall survival\n(OS). The PFS primary endpoint, ORR and DCR were based on centralized, independent blinded\nreview of the imaging data. Biochemical response with vandetanib as compared to placebo as\nmeasured by CTN and CEA was also assessed as secondary endpoints.\nPatients were treated with vandetanib or placebo until they reached objective disease progression.\nUpon objective disease progression based on the investigator’s assessment, patients were discontinued\nfrom blinded study treatment and given the option to receive open-label vandetanib. Twenty-eight of\nthe 231 patients (12.1%) on vandetanib and 3 of the 99 (3.0%) on placebo discontinued treatment\nbecause of an adverse event. Fourteen of the 28 patients (50%) who stopped vandetanib for an adverse\nevent discontinued without a dose reduction. Five out of 6 patients (83%) with moderate renal failure\nwho were treated with vandetanib had a dose reduction to 200 mg for adverse reaction; 1 patient\nrequired a further reduction to 100 mg.\nThe result of the primary analysis of PFS showed a statistically significant improvement in PFS for\npatients randomised to vandetanib compared to placebo (Hazard Ratio (HR) = 0.46; 95% Confidence\nInterval (CI) = 0.31-0.69; p=0.0001).\nThe median PFS for patients randomised to vandetanib has not been reached; however, based on\nstatistical modelling of data observed up to the 43rd percentile, the median PFS is predicted to be\n30.5 months with 95% confidence interval 25.5 to 36.5 months. The median PFS for patients\nrandomised to placebo was 19.3 months. At 12 months, the proportion of patients alive and\nprogression-free was 192 (83%) for patients randomised to vandetanib and 63 (63%) for patients\nrandomised to placebo. In the vandetanib arm, a total of 73 (32%) patients progressed: 64 (28%) by\nresponse evaluation criteria in solid tumours (RECIST) progression and 9 (4%) by death in the\nabsence of progression. The remaining 158 patients (68%) were censored in the analysis of PFS. In the\nplacebo arm, a total of 51 (51%) of patients had progressed: 46 (46%) by RECIST progression and 5\n(5%) by death in the absence of progression. The remaining 49 patients (49%) were censored in the\nanalysis of PFS.\n\n14\n© ESTEVE (2026) INTERNAL USE\nFigure 1: Kaplan Meier plot of PFS\nmonths 0 6 12 18 24 30 36\nn-vandetanib 231 196 169 140 40 1 0\nn-placebo 100 71 57 45 13 0 0\n____ vandetanib 300 mg, ------ placebo, y-axis=PFS, x-axis=time in months, n-vandetanib=number of patients at\nrisk-vandetanib, n-placebo=number of patients at risk-placebo\nHR = 0.46, 95%CI (0.31-0.69), p = 0.0001\nPFS N Median PFS HR 95% CI p-value\nVandetanib 300 mg 73/231\n(32%)\nNot reached\n(predicted\n30.5 months) 0.46 0.31, 0.69 0.0001\nPlacebo 51/100\n(51%)\n19.3 months\nSurvival status and the median final overall survival (81.6 months in the vandetanib arm and\n80.4 months in the placebo arm) were similar across both treatment arms. There was no statistically\nsignificant difference in final OS (HR 0.99, 95.002% CI 0.72, 1.38, p=0.9750). Results should be\ninterpreted with caution due to the high percentage of patients in the placebo arm switching to open-\nlabel vandetanib (79.0% [79/100] of patients).\nMost (95% of the patients) had metastatic disease. Fourteen patients treated with vandetanib, and 3\nwith placebo had unresectable locally advanced disease only. There is limited clinical experience with\nvandetanib in patients with unresectable locally advanced disease and without metastasis.\nStatistically", "a": { "targets": [ "VEGFR2", "EGFR", "RET", "VEGFR3" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR, EGFR, RET)", "mechanism": "Inhibits VEGFR-2, EGFR, and RET tyrosine kinases, thereby reducing angiogenesis, vascular permeability, and tumor cell proliferation and survival.", "quote": "Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also known as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR) and RET tyrosine kinases." }, "b": { "targets": [ "VEGFR2", "EGFR", "RET", "VEGFR3" ], "modality": "small molecule", "label": "Multikinase inhibitor (VEGFR2, EGFR, RET)", "mechanism": "Vandetanib inhibits VEGFR2, EGFR and RET tyrosine kinases, and also inhibits VEGFR3 tyrosine kinase.", "quote": "Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also known as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR) and RET tyrosine kinases." }, "decision": null }, "vemurafenib__zelboraf": { "url": "https://www.ema.europa.eu/en/documents/product-information/zelboraf-epar-product-information_en.pdf", "text": "Vemurafenib is an inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene result in\nconstitutive activation of BRAF proteins, which can cause cell proliferation without associated growth\nfactors.\nPreclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit\nBRAF kinases with activating codon 600 mutations (table 6).\nTable 6: Kinase inhibitory activity of vemurafenib against different BRAF kinases\nKinase Anticipated frequency in V600\nmutation-positive melanoma (t)\nInhibitory Concentration\n50 (nM)\nBRAFV600E 87.3% 10\nBRAFV600K 7.9% 7\nBRAFV600R 1% 9\nBRAFV600D <0.2% 7\nBRAFV600G <0.1% 8\nBRAFV600M <0.1% 7\nBRAFV600A <0.1% 14\nBRAFWT N/A 39\n(t) Estimated from 16,403 melanomas with annotated BRAF codon 600 mutations in the public COSMIC\ndatabase, release 71 (November 2014).\nThis inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays\nin available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays\nthe inhibitory concentration 50 (IC50) against V600 mutated cell lines (V600E, V600R, V600D and\nV600K mutated cell lines) ranged from 0.016 to 1.131 M whereas the IC50 against BRAF wild type\ncell lines were 12.06 and 14.32 M, respectively.\nDetermination of BRAF mutation status\nBefore taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status\nconfirmed by a validated test. In the phase II and phase III clinical trials, eligible patients were\nidentified using a real-time polymerase chain reaction assay (the cobas 4800 BRAF V600 Mutation\nTest). This test has CE marking and is used to assess the BRAF mutation status of DNA isolated from\nformalin-fixed, paraffin-embedded (FFPE) tumour tissue. It was designed to detect the predominant\nBRAF V600E mutation with high sensitivity (down to 5% V600E sequence in a background of wild\ntype sequence from FFPE-derived DNA). Non-clinical and clinical studies with retrospective\nsequencing analyses have shown that the test also detects the less common BRAF V600D mutations\nand V600K mutations with lower sensitivity. Of the specimens available from the non-clinical and\nclinical studies (n=920), that were mutation-positive by the cobas test and additionally analyzed by\nsequencing, no specimen was identified as being wild type by both Sanger and 454 sequencing.", "a": { "targets": [ "BRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Inhibits BRAF serine-threonine kinase with activating codon 600 mutations, suppressing ERK phosphorylation and cellular proliferation.", "quote": "Vemurafenib is an inhibitor of BRAF serine-threonine kinase." }, "b": { "targets": [ "BRAF" ], "modality": "small molecule", "label": "BRAF inhibitor", "mechanism": "Vemurafenib inhibits BRAF serine-threonine kinase, including BRAF kinases with activating codon 600 mutations.", "quote": "Vemurafenib is an inhibitor of BRAF serine-threonine kinase." }, "decision": null }, "venetoclax__venclyxto": { "url": "https://www.ema.europa.eu/en/documents/product-information/venclyxto-epar-product-information_en.pdf", "text": "Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein.\nOverexpression of BCL-2 has been demonstrated in CLL and AML cells where it mediates tumour\ncell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directly\nto the BH3-binding groove of BCL-2, displacing BH3 motif-containing pro-apoptotic proteins like\nBIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and\n\n22\nprogrammed cell death. In non-clinical studies, venetoclax has demonstrated cytotoxic activity in\ntumour cells that overexpress BCL-2.", "a": { "targets": [ "BCL-2" ], "modality": "small molecule", "label": "BCL-2 inhibitor", "mechanism": "Venetoclax selectively binds the BH3 groove of BCL-2, displacing pro-apoptotic proteins to induce mitochondrial outer membrane permeabilization, caspase activation, and programmed cell death.", "quote": "Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein." }, "b": { "targets": [ "BCL-2" ], "modality": "small molecule", "label": "BCL-2 inhibitor", "mechanism": "Venetoclax binds the BH3-binding groove of BCL-2, displacing pro-apoptotic proteins and initiating mitochondrial permeabilization and programmed cell death.", "quote": "Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein." }, "decision": null }, "vimseltinib__romvimza": { "url": "https://www.ema.europa.eu/en/documents/product-information/romvimza-epar-product-information_en.pdf", "text": "Vimseltinib is a selective small molecule tyrosine kinase inhibitor that targets colony stimulating\nfactor 1 receptor (CSF1R). The CSF1/CSF1R signalling axis has a critical role in the development of\nTGCT. In vitro enzyme and cell-based assays have shown that vimseltinib inhibited CSF1R\nautophosphorylation and signalling induced by CSF1 ligand binding, as well as cellular function and\nproliferation of cells expressing CSF1R. Vimseltinib also inhibited CSF1R expressing cells and\nblocked downstream signalling in preclinical models in vivo.\n\n9\nVimseltinib exerts its anti-tumour effects via depletion of CSF1R-dependent macrophages and\ninflammatory cells.\nA decline in the number of hepatic Kupffer cells due to CSF1R inhibition leads to decreased clearance\nof serum enzymes, including AST, ALT, and CPK. This results in an increase in the serum levels of\nthese enzymes.", "a": { "targets": [ "CSF1R" ], "modality": "small molecule", "label": "CSF1R kinase inhibitor", "mechanism": "Vimseltinib inhibits CSF1R autophosphorylation and downstream signalling, depleting CSF1R-dependent macrophages and inflammatory cells to exert anti-tumour effects.", "quote": "Vimseltinib is a selective small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R)." }, "b": { "targets": [ "CSF1R" ], "modality": "small molecule", "label": "Selective CSF1R inhibitor", "mechanism": "Vimseltinib inhibits CSF1R signalling and depletes CSF1R-dependent macrophages and inflammatory cells, producing anti-tumour effects.", "quote": "Vimseltinib is a selective small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R)." }, "decision": null }, "vismodegib__erivedge": { "url": "https://www.ema.europa.eu/en/documents/product-information/erivedge-epar-product-information_en.pdf", "text": "Vismodegib is an orally available small-molecule inhibitor of the Hedgehog pathway. Hedgehog\npathway signalling through the Smoothened transmembrane protein (SMO) leads to the activation and\nnuclear localisation of Glioma-Associated Oncogene (GLI) transcription factors and induction of\nHedgehog target genes. Many of these genes are involved in proliferation, survival, and\ndifferentiation. Vismodegib binds to and inhibits the SMO protein thereby blocking Hedgehog signal\ntransduction.", "a": { "targets": [ "SMO" ], "modality": "small molecule", "label": "Hedgehog pathway inhibitor", "mechanism": "Vismodegib binds to and inhibits the Smoothened transmembrane protein, blocking Hedgehog pathway signal transduction.", "quote": "Vismodegib binds to and inhibits the SMO protein thereby blocking Hedgehog signal transduction." }, "b": { "targets": [ "SMO" ], "modality": "small molecule", "label": "SMO inhibitor (Hedgehog pathway)", "mechanism": "Vismodegib binds to and inhibits SMO, blocking Hedgehog signal transduction.", "quote": "Vismodegib binds to and inhibits the SMO protein thereby blocking Hedgehog signal transduction." }, "decision": null }, "vorasidenib__voranigo": { "url": "https://www.ema.europa.eu/en/documents/product-information/voranigo-epar-product-information_en.pdf", "text": "Vorasidenib is an inhibitor that targets the mutant IDH1 and IDH2 enzymes. In patients with\nastrocytoma or oligodendroglioma, IDH1 and IDH2 mutations lead to overproduction of the\noncogenic metabolite 2-hydroxyglutarate (2-HG), resulting in impaired cellular differentiation\ncontributing to oncogenesis. Inhibition of the IDH1- and IDH2-mutated proteins by vorasidenib\ninhibits the abnormal production of 2-HG leading to differentiation of malignant cells and a reduction\nin their proliferation. Pre-clinical studies investigating the ability of vorasidenib to decrease tumour\nsize were not performed.", "a": { "targets": [ "IDH1", "IDH2" ], "modality": "small molecule", "label": "Dual mutant IDH1 and IDH2 inhibitor", "mechanism": "Inhibits mutant IDH1 and IDH2 enzymes to suppress abnormal 2-HG production, promoting malignant cell differentiation and reducing proliferation.", "quote": "Vorasidenib is an inhibitor that targets the mutant IDH1 and IDH2 enzymes." }, "b": { "targets": [ "IDH1", "IDH2" ], "modality": "small molecule", "label": "Mutant IDH1/2 inhibitor", "mechanism": "Vorasidenib inhibits mutant IDH1 and IDH2, reducing abnormal 2-HG production and promoting differentiation of malignant cells while reducing their proliferation.", "quote": "Vorasidenib is an inhibitor that targets the mutant IDH1 and IDH2 enzymes." }, "decision": null }, "zanidatamab__ziihera": { "url": "https://www.ema.europa.eu/en/documents/product-information/ziihera-epar-product-information_en.pdf", "text": "Zanidatamab is a dual HER2-targeted bispecific antibody that simultaneously binds extracellular\ndomains 2 and 4 on separate HER2 monomers (binding in trans). Binding of zanidatamab with HER2\nresults in internalization leading to a reduction of the receptor on the cell surface. Zanidatamab\ninduces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC)\nand antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumour growth\ninhibition and tumour cell death.", "a": { "targets": [ "HER2" ], "modality": "bispecific antibody", "label": "Dual HER2-targeted bispecific antibody", "mechanism": "Binds extracellular domains 2 and 4 of HER2, inducing receptor internalization, CDC, ADCC, and ADCP to inhibit tumor growth and cause tumor cell death.", "quote": "Zanidatamab is a dual HER2-targeted bispecific antibody that simultaneously binds extracellular domains 2 and 4 on separate HER2 monomers (binding in trans)." }, "b": { "targets": [ "HER2" ], "modality": "bispecific antibody", "label": "HER2-targeted bispecific antibody", "mechanism": "Binds HER2 extracellular domains 2 and 4 on separate monomers, promoting receptor internalization and inducing CDC, ADCC and ADCP, leading to tumour growth inhibition and cell death.", "quote": "Zanidatamab is a dual HER2-targeted bispecific antibody that simultaneously binds extracellular domains 2 and 4 on separate HER2 monomers (binding in trans)." }, "decision": null }, "zanubrutinib__brukinsa": { "url": "https://www.ema.europa.eu/en/documents/product-information/brukinsa-epar-product-information_en.pdf", "text": "Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib forms a covalent bond\nwith a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a\nsignalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells,\nBTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking,\nchemotaxis, and adhesion.\n\n13", "a": { "targets": [ "BTK" ], "modality": "small molecule", "label": "BTK inhibitor", "mechanism": "Zanubrutinib covalently binds and inhibits Bruton's tyrosine kinase, blocking B-cell receptor signalling pathways essential for B-cell proliferation, trafficking, and chemotaxis.", "quote": "Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK)." }, "b": { "targets": [ "BTK" ], "modality": "small molecule", "label": "BTK inhibitor", "mechanism": "Zanubrutinib covalently binds a cysteine residue in BTK’s active site, inhibiting BTK activity and B-cell signalling.", "quote": "Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK)." }, "decision": null }, "zolbetuximab__vyloy": { "url": "https://www.ema.europa.eu/en/documents/product-information/vyloy-epar-product-information_en.pdf", "text": "Zolbetuximab is a chimeric (mouse/human IgG1) monoclonal antibody directed against the tight\njunction molecule CLDN18.2. Nonclinical data suggest zolbetuximab binds selectively to cell lines\ntransfected with CLDN18.2 or those that endogenously express CLDN18.2. Zolbetuximab depletes\nCLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) and\ncomplement-dependent cytotoxicity (CDC). Cytotoxic medicinal products were shown to increase\nCLDN18.2 expression on human cancer cells and to improve zolbetuximab-induced ADCC and CDC\nactivities.", "a": { "targets": [ "CLDN18.2" ], "modality": "monoclonal antibody", "label": "CLDN18.2-directed monoclonal antibody", "mechanism": "Zolbetuximab binds CLDN18.2 and depletes CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.", "quote": "Zolbetuximab is a chimeric (mouse/human IgG1) monoclonal antibody directed against the tight junction molecule CLDN18.2." }, "b": { "targets": [ "CLDN18.2" ], "modality": "monoclonal antibody", "label": "CLDN18.2-directed monoclonal antibody", "mechanism": "Binds CLDN18.2 and depletes CLDN18.2-positive cells through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.", "quote": "Zolbetuximab is a chimeric (mouse/human IgG1) monoclonal antibody directed against the tight junction molecule CLDN18.2." }, "decision": 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"MSI", "biomarker_alteration_type": "loss", "biomarker_detail": "MSI-H or dMMR", "diagnostic_criterion": "MSI-H or dMMR", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "5a9acb3680feff71": { "b": { "tumor_type": "colorectal cancer", "organ": "colorectal", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "MSI", "biomarker_alteration_type": "loss", "biomarker_detail": "MSI-H or dMMR", "diagnostic_criterion": "MSI-H or dMMR", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "Previous fluoropyrimidine-based combination therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "4e27ca4879d97a5a": { "b": { "tumor_type": "endometrial carcinoma", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "MSI", "biomarker_alteration_type": "loss", "biomarker_detail": "MSI-H or dMMR", "diagnostic_criterion": "MSI-H or dMMR", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "Prior treatment with a platinum-containing therapy in any setting", "patient_eligibility": "Not a candidate for curative surgery or radiation", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "The text says \"prior treatment with a platinum-containing therapy in any setting\". Under rule 13, a prior regimen \"in any setting\" may have been neoadjuvant or adjuvant, so the line is any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "2L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "529394122bba790b": { "b": { "tumor_type": "gastric cancer", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "MSI", "biomarker_alteration_type": "loss", "biomarker_detail": "MSI-H or dMMR", "diagnostic_criterion": "MSI-H or dMMR", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "At least one prior therapy; disease progression on or following prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "61446e491c2efff6": { "b": { "tumor_type": "small intestine cancer", "organ": "other", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "MSI", "biomarker_alteration_type": "loss", "biomarker_detail": "MSI-H or dMMR", "diagnostic_criterion": "MSI-H or dMMR", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "At least one prior therapy; disease progression on or following prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "d48efb4d4a104f6e": { "b": { "tumor_type": "biliary cancer", "organ": "biliary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "MSI", "biomarker_alteration_type": "loss", "biomarker_detail": "MSI-H or dMMR", "diagnostic_criterion": "MSI-H or dMMR", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "At least one prior therapy; disease progression on or following prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "414f1a11b964eb1e": { "b": { "tumor_type": "oesophageal carcinoma", "organ": "esophagus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CPS ≥ 10", "diagnostic_criterion": "CPS ≥ 10", "scoring_system": "CPS", "test_method": [ "IHC" ], "combination": "+ platinum and fluoropyrimidine-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "fcc7a2a88f38b5a8": { "b": { "tumor_type": "triple-negative breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Locally advanced or early-stage; high risk of recurrence", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "92f37fddf562fc29": { "b": { "tumor_type": "triple-negative breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Neoadjuvant KEYTRUDA + chemotherapy and surgery", "patient_eligibility": "Locally advanced or early-stage; high risk of recurrence", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "b7a5f928db130ccc": { "b": { "tumor_type": "triple-negative breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CPS ≥ 10", "diagnostic_criterion": "CPS ≥ 10", "scoring_system": "CPS", "test_method": [ "IHC" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "No prior chemotherapy for metastatic disease; locally recurrent unresectable or metastatic disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "dc88470a36a80aa5": { "b": { "tumor_type": "endometrial carcinoma", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and paclitaxel", "prior_therapy": null, "patient_eligibility": "Candidates for systemic therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "6fc3430ba7cf67ad": { "b": { "tumor_type": "endometrial carcinoma", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenvatinib", "prior_therapy": "Prior treatment with a platinum-containing therapy in any setting", "patient_eligibility": "Not a candidate for curative surgery or radiation", "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "The same wording, \"platinum-containing therapy in any setting\", applies here, which gives line any under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "2L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.93, "neoplasm": 0.99 } }, "f1c13edcf2944e1a": { "b": { "tumor_type": "cervical cancer", "organ": "cervix", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chemoradiotherapy (external beam radiation therapy followed by brachytherapy)", "prior_therapy": null, "patient_eligibility": "FIGO 2014 Stage III - IVA; no prior definitive therapy", "age_group": "adult" }, "decisions": [ { "q": "q5", "ambiguous": true, "reason": "\"who have not received prior definitive therapy\" reads as treatment-naive, which supports 1L. However, rule 13 counts lines for advanced disease, and this is curative-intent chemoradiotherapy for locally advanced disease, so \"any\" is also defensible.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.93, "neoplasm": 0.99 } }, "42ef19dde725907d": { "b": { "tumor_type": "cervical cancer", "organ": "cervix", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CPS ≥ 1", "diagnostic_criterion": "CPS ≥ 1", "scoring_system": "CPS", "test_method": [ "IHC" ], "combination": "+ chemotherapy with or without bevacizumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "9dcb3b27afe28f8d": { "b": { "tumor_type": "gastric or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive; PD-L1 CPS ≥ 1", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive; PD-L1 CPS ≥ 1", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ trastuzumab, fluoropyrimidine and platinum-containing chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q6", "ambiguous": false, "reason": "The primary biomarker for this pembrolizumab row is PD-L1 \"with a CPS ≥ 1\". HER2-positive is an additional selection criterion recorded in biomarker_detail, so scoring_system stays with the primary biomarker.", "kind": "field", "field": "scoring_system", "candidates": [ { "value": "IHC-score", "from": [ "b" ] }, { "value": "CPS", "from": [ "a", "jev" ] } ], "value": "CPS", "from": [ "a", "jev" ] }, { "q": "q7", "ambiguous": false, "reason": "The row is gated on \"tumours express PD-L1 with a CPS ≥ 1\", and HER2-positive is a secondary criterion recorded in biomarker_detail.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "PD-L1", "from": [ "a" ] }, { "value": "HER2", "from": [ "b" ] } ], "value": "PD-L1", "from": [ "a" ] } ], "jev": { "supported": 0.18, "neoplasm": 0.99 } }, "6f6a34c8f942cd71": { "b": { "tumor_type": "gastric or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "HER2-negative; PD-L1 CPS ≥ 1", "diagnostic_criterion": "HER2-negative (IHC 0 or IHC 1+ or IHC 2+/ISH-negative); PD-L1 CPS ≥ 1", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ fluoropyrimidine and platinum-containing chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q8", "ambiguous": false, "reason": "The primary biomarker is PD-L1 expression at CPS ≥ 1, which is overexpression. \"HER2-negative\" is a secondary negative appended to biomarker_detail (rule 3).", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "wild-type-required", "from": [ "b" ] }, { "value": "overexpression", "from": [ "a", "jev" ] } ], "value": "overexpression", "from": [ "a", "jev" ] }, { "q": "q9", "ambiguous": false, "reason": "\"PD-L1 with a CPS ≥ 1\" gives CPS. A secondary HER2-negative does not change scoring_system (rule 5b).", "kind": "field", "field": "scoring_system", "candidates": [ { "value": "IHC-score", "from": [ "b" ] }, { "value": "CPS", "from": [ "a", "jev" ] } ], "value": "CPS", "from": [ "a", "jev" ] }, { "q": "q10", "ambiguous": false, "reason": "Under rule 3, a secondary negative such as HER2-negative keeps the primary biomarker, which here is PD-L1.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "HER2", "from": [ "b" ] }, { "value": "PD-L1", "from": [ "a" ] } ], "value": "PD-L1", "from": [ "a" ] } ], "jev": { "supported": 0.75, "neoplasm": 0.99 } }, "17359e7a2ce7353a": { "b": { "tumor_type": "biliary tract carcinoma", "organ": "biliary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ gemcitabine and cisplatin", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "6952536aedce8f93": { "b": { "tumor_type": "epithelial ovarian, fallopian tube, or primary peritoneal carcinoma", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CPS ≥ 1", "diagnostic_criterion": "CPS ≥ 1", "scoring_system": "CPS", "test_method": [ "IHC" ], "combination": "+ paclitaxel, with or without bevacizumab", "prior_therapy": "One or two prior systemic treatment regimens; platinum-resistant disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "9e1efa10a310cd23": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor; disease progression on the last therapy; refractory to lenalidomide", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Being \"refractory to lenalidomide\" means the patient received lenalidomide and progressed on it. Under rule 14 this is prior-therapy history, like \"progressed on or intolerant to imatinib\", so it belongs in prior_therapy with \"at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor\" and \"disease progression on the last therapy\".", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "At least one prior therapy including an immunomodulatory agent and a proteasome inhibitor, with disease progression on the last therapy", "from": [ "a" ] }, { "value": "At least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor; disease progression on the last therapy; refractory to lenalidomide", "from": [ "b" ] } ], "value": "At least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor; disease progression on the last therapy; refractory to lenalidomide", "from": [ "b" ] } ], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "909a508d74eaefba": { "b": { "tumor_type": "high-risk neuroblastoma", "organ": "other", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Induction chemotherapy, myeloablative therapy and stem cell transplantation", "patient_eligibility": "Aged 12 months and above; received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation; complete response after first-line therapy", "age_group": "mixed" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 1 splits monotherapy from combination with an immunotherapy partner. IL-2 is required only \"in patients who have not achieved a complete response after first line therapy\", so r1 stays \"monotherapy\" and the IL-2 branch gets its own row (q3).", "kind": "field", "field": "combination", "candidates": [ { "value": "monotherapy", "from": [ "b" ] }, { "value": "monotherapy or + interleukin-2 (IL-2)", "from": [ "a" ] } ], "value": "monotherapy", "from": [ "b" ] } ], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "fc677fc942256a8a": { "b": { "tumor_type": "high-risk neuroblastoma", "organ": "other", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ interleukin-2 (IL-2)", "prior_therapy": null, "patient_eligibility": "Aged 12 months and above; history of relapsed or refractory neuroblastoma, with or without residual disease; any actively progressing disease should be stabilised by other suitable measures prior to treatment", "age_group": "mixed" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "The row covers \"history of relapsed or refractory neuroblastoma\", and neuroblastoma is a solid tumour. Rule 10 says \"relapsed\" alone in a solid tumour maps to advanced.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "advanced", "from": [ "a" ] } ], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "f33ebf40670888c0": { "b": null, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"In patients who have not achieved a complete response after first line therapy, Qarziba should be combined with interleukin-2 (IL-2)\" is a combination branch of the first-line indication. Rule 1 requires it as a separate row from r1's monotherapy, and no existing row covers it.", "kind": "missing", "verdict": "add" } ], "jev": { "supported": 0.54, "neoplasm": 0.99 } }, "145693bf332e57e9": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After complete resection", "patient_eligibility": "Stage IIB or IIC; involvement of lymph nodes or metastatic disease", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "236a83f86ee63305": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": 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CML phase is not a split criterion under rule 1, so it stays one row at the lowest guaranteed count (rule 13), which is any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "a" ] }, { "value": "2L", "from": [ "b", "jev" ] } ], "value": "any", "from": [ "a" ] } ], "jev": { "supported": 0.53, "neoplasm": 0.99 } }, "f7979b90fa206413": { "b": { "tumor_type": "Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of BCR-ABL1 fusion", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "639183ee7fffd6ff": { "b": { "tumor_type": "Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of BCR-ABL1 fusion", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "f9d14b1c7d84ff8d": { "b": { "tumor_type": "myelodysplastic/myeloproliferative diseases (MDS/MPD)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "PDGFR", "biomarker_alteration_type": "fusion", "biomarker_detail": "PDGFR gene rearrangements", "diagnostic_criterion": "Presence of PDGFR gene rearrangement", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.18, "neoplasm": 0.98 } }, "aec31e40fe09b42f": { "b": { "tumor_type": "chronic eosinophilic leukaemia (CEL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "FIP1L1-PDGFRA", "biomarker_alteration_type": "fusion", "biomarker_detail": "FIP1L1-PDGFRα rearrangement", "diagnostic_criterion": "Presence of FIP1L1-PDGFRA rearrangement", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.24, "neoplasm": 0.84 } }, "90efd7fe7c4feb82": { "b": { "tumor_type": "gastrointestinal stromal tumour (GIST)", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "KIT", "biomarker_alteration_type": "overexpression", "biomarker_detail": "Kit (CD 117) positive", "diagnostic_criterion": "Kit (CD 117) positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable and/or metastatic", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.19, "neoplasm": 0.99 } }, "5647ba8bf433bf59": { "b": { "tumor_type": "gastrointestinal stromal tumour (GIST)", "organ": "stomach", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "KIT", "biomarker_alteration_type": "overexpression", "biomarker_detail": "Kit (CD117)-positive", "diagnostic_criterion": "Kit (CD117)-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Following resection", "patient_eligibility": "At significant risk of relapse; patients with low or very low risk of recurrence should not receive adjuvant treatment", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.22, "neoplasm": 0.99 } }, "dd473de9b5a1ede0": { "b": { "tumor_type": "dermatofibrosarcoma protuberans (DFSP)", "organ": "soft-tissue", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.44, "neoplasm": 0.98 } }, "3d51bce321f280bc": { "b": { "tumor_type": "Merkel cell carcinoma", "organ": "skin", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.56, "neoplasm": 0.99 } }, "cc0b9497a0484220": { "b": { "tumor_type": "urothelial carcinoma", "organ": "bladder", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Following platinum-based chemotherapy", "patient_eligibility": "Progression-free following platinum-based chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "550813ba34f775f5": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ axitinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.51, "neoplasm": 0.99 } }, "7b109e626cf42dc1": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR/ALK/ROS1/RET", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "No sensitising EGFR mutations; no ALK, ROS1 or RET genomic tumour aberrations", "diagnostic_criterion": "No sensitising EGFR mutations, or ALK, ROS1 or RET genomic tumour aberrations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "7e77ba44a76926d4": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "locally-advanced", "treatment_phase": "consolidation", "line_of_therapy": "any", "biomarker_name": "PD-L1/EGFR/ALK/ROS1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression on ≥ 1% of tumour cells; no sensitising EGFR mutations or ALK or ROS1 genomic tumour aberrations", "diagnostic_criterion": "PD-L1 on ≥ 1% of tumour cells; no sensitising EGFR mutations, or ALK, ROS1 genomic tumour aberrations", "scoring_system": "TPS", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "platinum-based chemoradiotherapy", "patient_eligibility": "Unresectable stage III; disease has not progressed following platinum-based chemoradiotherapy", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The positive gate is \"whose tumours express PD-L1 on ≥ 1% of tumour cells\". Under rule 3 the excluded EGFR/ALK/ROS1 aberrations are secondary negatives, so the primary biomarker is kept and the negatives stay appended in biomarker_detail, as already done.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "PD-L1", "from": [ "a" ] }, { "value": "PD-L1/EGFR/ALK/ROS1", "from": [ "b" ] } ], "value": "PD-L1", "from": [ "a" ] } ], "jev": { "supported": 0.55, "neoplasm": 0.99 } }, "54f11ef636cda02e": { "b": null, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"as monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease\" is a distinct approval scenario (monotherapy, 3L+), so the row stays.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.54, "neoplasm": 0.99 } }, "5745539b77ee539a": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ paclitaxel", "prior_therapy": "No chemotherapy for metastatic disease", "patient_eligibility": "Anthracycline not suitable", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"who have not received chemotherapy for their metastatic disease\" means no prior chemotherapy for metastatic disease; this candidate states it most clearly.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "No prior chemotherapy for metastatic disease", "from": [ "a" ] }, { "value": "No chemotherapy for metastatic disease", "from": [ "b" ] } ], "value": "No prior chemotherapy for metastatic disease", "from": [ "a" ] } ], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "029219a090c8f6a4": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ docetaxel", "prior_therapy": "No chemotherapy for metastatic disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"who have not received chemotherapy for their metastatic disease\" reads as no prior chemotherapy for metastatic disease; same wording as r2.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "No chemotherapy for metastatic disease", "from": [ "b" ] }, { "value": "No prior chemotherapy for metastatic disease", "from": [ "a" ] } ], "value": "No prior chemotherapy for metastatic disease", "from": [ "a" ] } ], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "842ee8c713d61999": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HER2/HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification; HR-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ an aromatase inhibitor", "prior_therapy": "No prior trastuzumab", "patient_eligibility": "Postmenopausal", "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "HER2 is the primary biomarker (\"HER2 positive metastatic breast cancer\"), and \"hormone-receptor positive\" is already recorded in biomarker_detail. The \"/\" join under rule 3 is for several absent alterations, so ERBB2 stays, consistent with the other rows.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "ERBB2", "from": [ "a" ] }, { "value": "HER2/HR", "from": [ "b" ] } ], "value": "ERBB2", "from": [ "a" ] } ], "jev": { "supported": 0.34, "neoplasm": 0.99 } }, "cd6350b7ebadafb8": { "b": null, "decisions": [ { "q": "q5", "ambiguous": false, "reason": "\"following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable)\" is a distinct adjuvant monotherapy scenario, so the row stays.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.21, "neoplasm": 0.99 } }, "544ec9760d002140": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ paclitaxel or docetaxel", "prior_therapy": "Adjuvant doxorubicin and cyclophosphamide", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q6", "ambiguous": false, "reason": "The label says \"following adjuvant chemotherapy with doxorubicin and cyclophosphamide\"; this candidate keeps that wording closest to verbatim.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Adjuvant doxorubicin and cyclophosphamide", "from": [ "b" ] }, { "value": "Adjuvant chemotherapy with doxorubicin and cyclophosphamide", "from": [ "a" ] } ], "value": "Adjuvant chemotherapy with doxorubicin and cyclophosphamide", "from": [ "a" ] } ], "jev": { "supported": 0.35, "neoplasm": 0.99 } }, "4fd7c03d3b74fe87": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ docetaxel and carboplatin", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.23, "neoplasm": 0.99 } }, "38bdb9b40328ab8c": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ neoadjuvant chemotherapy", "prior_therapy": null, "patient_eligibility": "Locally advanced (including inflammatory) disease or tumours > 2 cm in diameter", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.35, "neoplasm": 0.99 } }, "f0f2e74d4f564947": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Neoadjuvant chemotherapy and surgical resection", "patient_eligibility": "Locally advanced (including inflammatory) disease or tumours > 2 cm in diameter", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.04, "neoplasm": 0.99 } }, "ca1cdbf48207220c": { "b": { "tumor_type": "metastatic adenocarcinoma of the stomach or gastro-esophageal junction", "organ": "stomach", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression", "diagnostic_criterion": "IHC 2+ with confirmatory SISH or FISH, or IHC 3+", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ capecitabine or 5-fluorouracil, and cisplatin", "prior_therapy": "No prior anti-cancer treatment for metastatic disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "5c424a0c3eb3a226": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "At least two chemotherapy regimens for metastatic disease, including an anthracycline and a taxane unless patients are unsuitable; hormone receptor-positive patients must also have failed hormonal therapy unless unsuitable.", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.55, "neoplasm": 0.99 } }, "19c945147f0e0b29": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ paclitaxel", "prior_therapy": "No prior chemotherapy for metastatic disease", "patient_eligibility": "Anthracycline-ineligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "b5481fb1221d24c0": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ docetaxel", "prior_therapy": "No prior chemotherapy for metastatic disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.18, "neoplasm": 0.99 } }, "88a487dc28098ec6": { "b": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification; HR-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ aromatase inhibitor", "prior_therapy": "No prior trastuzumab", "patient_eligibility": "Postmenopausal; hormone receptor-positive", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.43, "neoplasm": 0.99 } }, "f888d58606fedd29": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Surgery and chemotherapy (neoadjuvant or adjuvant), and radiotherapy if applicable", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "The row's Herceptin is given \"following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy\", which is therapy after curative local treatment, i.e. adjuvant by the field definition. However, the word \"adjuvant\" in the text describes the chemotherapy, not Herceptin, so rule 11's explicit-naming requirement leaves it open.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": "adjuvant", "from": [ "a" ] }, { "value": null, "from": [ "b" ] } ], "value": "adjuvant", "from": [ "a" ] } ], "jev": { "supported": 0.09, "neoplasm": 0.99 } }, "b49296e16873efc6": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ paclitaxel or docetaxel", "prior_therapy": "Adjuvant doxorubicin and cyclophosphamide", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "The label says \"following adjuvant chemotherapy with doxorubicin and cyclophosphamide\". Both candidates are correct; the fuller wording follows the text most closely.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Adjuvant doxorubicin and cyclophosphamide", "from": [ "b" ] }, { "value": "Adjuvant chemotherapy with doxorubicin and cyclophosphamide", "from": [ "a" ] } ], "value": "Adjuvant chemotherapy with doxorubicin and cyclophosphamide", "from": [ "a" ] } ], "jev": { "supported": 0.32, "neoplasm": 0.99 } }, "fe3a437678fe8519": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ docetaxel and carboplatin", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.18, "neoplasm": 0.99 } }, "c8e832128978927e": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ neoadjuvant chemotherapy", "prior_therapy": null, "patient_eligibility": "Locally advanced (including inflammatory) disease or tumours > 2 cm in diameter", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.27, "neoplasm": 0.99 } }, "71a11172ee99c68f": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Neoadjuvant chemotherapy and surgical resection", "patient_eligibility": "Locally advanced (including inflammatory) disease or tumours > 2 cm in diameter", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.04, "neoplasm": 0.99 } }, "f41c6439d0349d46": { "b": { "tumor_type": "metastatic adenocarcinoma of the stomach or gastro-oesophageal junction", "organ": "stomach", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression", "diagnostic_criterion": "IHC 2+ with confirmatory SISH or FISH, or IHC 3+", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ capecitabine or 5-fluorouracil, and cisplatin", "prior_therapy": "No prior anti-cancer treatment for metastatic disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "62b5f992d13b2721": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ pertuzumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.27, "neoplasm": 0.99 } }, "c7b944eaede09e7b": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "One or more prior anti-HER2-based regimens", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.34, "neoplasm": 0.99 } }, "5803a6867784e39e": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2/HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-low or HER2-ultralow; HR-positive", "diagnostic_criterion": "HER2-low: IHC 1+ or IHC 2+/ISH-negative; HER2-ultralow: IHC 0 with membrane staining (faint, incomplete, ≤10% of tumour cells); HR-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "At least one endocrine therapy in the metastatic setting", "patient_eligibility": "Not considered suitable for endocrine therapy as the next line of treatment", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The row is gated mainly by HER2 status (\"HER2-low or HER2-ultralow\"), the drug's target. The other HER2 rows use the gene symbol ERBB2 (rule 7), and the secondary \"hormone receptor (HR)-positive\" requirement is already recorded in biomarker_detail, so it should not be joined into biomarker_name.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "ERBB2", "from": [ "a" ] }, { "value": "HER2/HR", "from": [ "b" ] } ], "value": "ERBB2", "from": [ "a" ] } ], "jev": { "supported": 0.29, "neoplasm": 0.99 } }, "3a78a08250c32983": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-low", "diagnostic_criterion": "IHC 1+ or IHC 2+/ISH-negative", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Prior chemotherapy in the metastatic setting or disease recurrence during or within 6 months of completing adjuvant chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.3, "neoplasm": 0.99 } }, "e1a227ed75d86d41": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ERBB2", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutation", "diagnostic_criterion": "presence of an activating mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Following platinum-based chemotherapy with or without immunotherapy", "patient_eligibility": "Requires systemic therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "398d60c68f820057": { "b": { "tumor_type": "gastric or gastroesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "A prior trastuzumab-based regimen", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.27, "neoplasm": 0.99 } }, "24e57684c558acff": { "b": { "tumor_type": "HER2-positive solid tumours", "organ": "tumor-agnostic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive (IHC3+)", "diagnostic_criterion": "IHC 3+", "scoring_system": "IHC-score", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Prior treatment", "patient_eligibility": "No satisfactory treatment options", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "4ed0a0a4c69f67af": { "b": { "tumor_type": "hormone-dependent prostate cancer", "organ": "prostate", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Male", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"advanced hormone-dependent prostate cancer\" gives no prior-therapy or line wording. Hormone dependence is a disease state, not a line, so under rule 13 (no line information) the line is \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b", "jev" ] } ], "value": "any", "from": [ "b", "jev" ] } ], "jev": { "supported": 0.44, "neoplasm": 0.99 } }, "f1e16b11348ca1bc": { "b": { "tumor_type": "hormone-dependent prostate cancer", "organ": "prostate", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ radiotherapy", "prior_therapy": null, "patient_eligibility": "High-risk localised and locally advanced", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"high-risk localised and locally advanced ... in combination with radiotherapy\" contains no line information, so rule 13 gives \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] }, { "q": "q3", "ambiguous": false, "reason": "Only the first bullet says \"adult male patients\". This bullet has no age qualifier and there is no section-level \"indicated in adults\", so rule 15 gives \"any\".", "kind": "field", "field": "age_group", "candidates": [ { "value": "adult", "from": [ "b" ] }, { "value": "any", "from": [ "a" ] } ], "value": "any", "from": [ "a" ] } ], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "e4d42ede9767855c": { "b": { "tumor_type": "hormone-dependent prostate cancer", "organ": "prostate", "disease_stage": "any", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy prior to radiotherapy", "prior_therapy": null, "patient_eligibility": "High-risk localised or locally advanced", "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "The text says \"in patients with high-risk localised or locally advanced...\" with no age qualifier and no section-level adult statement, so rule 15 gives \"any\".", "kind": "field", "field": "age_group", "candidates": [ { "value": "adult", "from": [ "b" ] }, { "value": "any", "from": [ "a" ] } ], "value": "any", "from": [ "a" ] }, { "q": "q5", "ambiguous": false, "reason": "\"as neo-adjuvant treatment prior to radiotherapy\": degarelix is given alone. The radiotherapy timing is already captured by treatment_phase=neoadjuvant, and radiotherapy is not a combination partner in this phase, so the combination is \"monotherapy\".", "kind": "field", "field": "combination", "candidates": [ { "value": "monotherapy prior to radiotherapy", "from": [ "b" ] }, { "value": "monotherapy", "from": [ "a" ] } ], "value": "monotherapy", "from": [ "a" ] } ], "jev": { "supported": 0.15, "neoplasm": 0.99 } }, "1d257c4aff72bcad": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP)", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.35, "neoplasm": 0.99 } }, "b5ffa05721fc8c7d": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bendamustine and rituximab", "prior_therapy": null, "patient_eligibility": "Not a candidate for haematopoietic stem cell transplant", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.12, "neoplasm": 0.99 } }, "abf2da837e4428d6": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "In progression after at least two prior lines of systemic therapy for mCRPC (other than LHRH analogues)", "patient_eligibility": "Symptomatic bone metastases; no known visceral metastases; or ineligible for any available systemic mCRPC treatment", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "d6db0a78637da65f": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ luteinising hormone releasing hormone (LHRH) analogue", "prior_therapy": "In progression after at least two prior lines of systemic therapy for mCRPC (other than LHRH analogues)", "patient_eligibility": "Symptomatic bone metastases; no known visceral metastases; or ineligible for any available systemic mCRPC treatment", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "1db8831f14cbf987": { "b": { "tumor_type": "high-risk biochemical recurrent non-metastatic hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Men; high-risk biochemical recurrence; unsuitable for salvage-radiotherapy", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The nmHSPC sentence (\"high-risk biochemical recurrent … unsuitable for salvage-radiotherapy\") contains no line-of-therapy wording. Under rule 13, \"If no line information at all → any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "0c666c2b78eec92a": { "b": { "tumor_type": "high-risk biochemical recurrent non-metastatic hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ androgen deprivation therapy", "prior_therapy": null, "patient_eligibility": "Men; high-risk biochemical recurrence; unsuitable for salvage-radiotherapy", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "This is the same sentence as r1 and gives no line information. Salvage radiotherapy is not systemic therapy, so rule 13 gives \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "886e512a6872aa8d": { "b": { "tumor_type": "metastatic hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ androgen deprivation therapy", "prior_therapy": null, "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"in combination with androgen deprivation therapy for the treatment of adult men with metastatic hormone-sensitive prostate cancer\" states no first-line, untreated or prior-therapy wording. Rule 13 therefore gives \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "cd5eb4e5b0ee4158": { "b": { "tumor_type": "high-risk non-metastatic castration-resistant prostate cancer", "organ": "prostate", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Men; high-risk", "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "\"high-risk non-metastatic castration-resistant prostate cancer\" names a disease state, not a line. Unlike the mCRPC rule, no \"before chemotherapy\" or untreated wording is given, so rule 13 gives \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.41, "neoplasm": 0.99 } }, "6849f0c902f5def6": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after failure of androgen deprivation therapy", "patient_eligibility": "Men; asymptomatic or mildly symptomatic; chemotherapy not yet clinically indicated", "age_group": "adult" }, "decisions": [ { "q": "q5", "ambiguous": false, "reason": "Metastatic CRPC \"after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated\" is CRPC before chemotherapy. Under rule 13, castration resistance is a disease state and \"Metastatic castration-resistant prostate cancer before chemotherapy → 1L\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "62bf8beba0d168cb": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after docetaxel therapy", "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "6cd7fe6ac042ad46": { "b": { "tumor_type": "mycosis fungoides", "organ": "skin", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Mycosis fungoides is a cutaneous T-cell lymphoma. The organ definition puts every lymphoma under \"hematologic\", and \"skin\" lists only melanoma, basal cell, cutaneous squamous cell and Merkel cell carcinoma.", "kind": "field", "field": "organ", "candidates": [ { "value": "skin", "from": [ "b" ] }, { "value": "hematologic", "from": [ "a" ] } ], "value": "hematologic", "from": [ "a" ] } ], "jev": { "supported": 0.5, "neoplasm": 0.98 } }, "a92579df3a180a4e": { "b": { "tumor_type": "Sézary syndrome", "organ": "skin", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "Sézary syndrome is the leukaemic form of cutaneous T-cell lymphoma, which the definition \"hematologic: leukaemia, lymphoma…\" covers.", "kind": "field", "field": "organ", "candidates": [ { "value": "hematologic", "from": [ "a" ] }, { "value": "skin", "from": [ "b" ] } ], "value": "hematologic", "from": [ "a" ] } ], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "a161a8492f21233d": { "b": { "tumor_type": "diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ gemcitabine and oxaliplatin", "prior_therapy": null, "patient_eligibility": "ASCT-ineligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "15a565b6ecdb10d7": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "8459118b977daa0b": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "hormone receptor-positive; HER2-negative", "diagnostic_criterion": "hormone receptor-positive; HER2/neu negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ exemestane", "prior_therapy": "after recurrence or progression following a non-steroidal aromatase inhibitor", "patient_eligibility": "Postmenopausal; without symptomatic visceral disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "60261e87be7bf632": { "b": { "tumor_type": "well- or moderately-differentiated neuroendocrine tumour of pancreatic origin", "organ": "pancreas", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressive disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "aedcdeb17f6e2d48": { "b": { "tumor_type": "well-differentiated non-functional neuroendocrine tumour of gastrointestinal origin (Grade 1 or Grade 2)", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressive disease", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "\"Neuroendocrine tumours of gastrointestinal ... origin\" names no single GI site, and the stomach definition covers only gastric/GEJ adenocarcinoma and GIST, so \"other\" fits best. The rules are silent on GI NETs, so the GIST convention (\"stomach, or the named GI site\") could be read by analogy to give \"stomach\".", "kind": "field", "field": "organ", "candidates": [ { "value": "other", "from": [ "a" ] }, { "value": "stomach", "from": [ "b" ] } ], "value": "other", "from": [ "a" ] } ], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "e863799c2f9c27b3": { "b": { "tumor_type": "well-differentiated non-functional neuroendocrine tumour of lung origin (Grade 1 or Grade 2)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressive disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "437c612a88110848": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "progressed on or after treatment with VEGF-targeted therapy", "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "be914555f4c4763f": { "b": { "tumor_type": "TSC-associated renal angiomyolipoma", "organ": "kidney", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Tuberous sclerosis complex; at risk of complications; does not require immediate surgery", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.33, "neoplasm": 0.96 } }, "2214e3bba975cbde": { "b": { "tumor_type": "TSC-associated subependymal giant cell astrocytoma (SEGA)", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Tuberous sclerosis complex; requires therapeutic intervention; not amenable to surgery", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.35, "neoplasm": 0.96 } }, "1b6e9faf3371a46f": { "b": { "tumor_type": "soft tissue sarcoma of the limbs", "organ": "soft-tissue", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ melphalan via mild hyperthermic isolated limb perfusion (ILP)", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 11 sets a phase only when the label explicitly names one. \"As an adjunct to surgery for subsequent removal of the tumour\" names no phase (and describes therapy before surgery, not after it), and the row also covers \"the palliative situation\", so treatment_phase stays none.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": null, "from": [ "a", "b" ] }, { "value": "adjuvant", "from": [ "jev" ] } ], "value": null, "from": [ "a", "b" ] } ], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "79b496b9fc1fee79": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutations", "diagnostic_criterion": "Presence of EGFR-activating mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.7, "neoplasm": 0.99 } }, "5de573fabdc2e1ca": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutation", "diagnostic_criterion": "Presence of an activating EGFR-TK mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "20e8215bcaf17c74": { "b": { "tumor_type": "muscle invasive bladder cancer (MIBC)", "organ": "bladder", "disease_stage": "early", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pembrolizumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "0487920a769c0cf2": { "b": { "tumor_type": "muscle invasive bladder cancer (MIBC)", "organ": "bladder", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pembrolizumab", "prior_therapy": "neoadjuvant pembrolizumab and radical cystectomy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "19a960bce41a422a": { "b": { "tumor_type": "urothelial cancer", "organ": "bladder", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pembrolizumab", "prior_therapy": null, "patient_eligibility": "Eligible for platinum-containing chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "db199a045997be82": { "b": { "tumor_type": "urothelial cancer", "organ": "bladder", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "previously received a platinum-containing chemotherapy and a programmed death receptor-1 or programmed death-ligand 1 inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "8e406458a0524826": { "b": { "tumor_type": "de novo acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD33", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD33-positive", "diagnostic_criterion": "CD33-positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "+ daunorubicin (DNR) and cytarabine (AraC)", "prior_therapy": null, "patient_eligibility": "Aged 15 years and above; excluding acute promyelocytic leukaemia (APL)", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "8eb5f4db1067ae07": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Intermediate or poor risk", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "cd8cfa34497b639d": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Prior VEGF-targeted therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "2e5648dabc661eaa": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ nivolumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.55, "neoplasm": 0.99 } }, "820f4b143f034fad": { "b": { "tumor_type": "hepatocellular carcinoma", "organ": "liver", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Sorafenib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "33355c1e1830c040": { "b": { "tumor_type": "differentiated thyroid carcinoma", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Prior systemic therapy; disease progressed during or after treatment", "patient_eligibility": "Radioactive iodine (RAI)-refractory or not eligible to RAI", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "a3e065fc368d5c09": { "b": { "tumor_type": "well differentiated pancreatic neuroendocrine tumour", "organ": "pancreas", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior systemic therapy other than somatostatin analogues", "patient_eligibility": "Unresectable or metastatic", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.98 } }, "af6b469377d63dff": { "b": { "tumor_type": "well differentiated extra-pancreatic neuroendocrine tumour", "organ": "other", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior systemic therapy other than somatostatin analogues", "patient_eligibility": "Unresectable or metastatic", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.98 } }, "3305158a929a7155": { "b": { "tumor_type": "medullary thyroid carcinoma", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressive; unresectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.39, "neoplasm": 0.99 } }, "4c6ea24b0206674e": { "b": { "tumor_type": "NF1-associated plexiform neurofibromas", "organ": "soft-tissue", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Symptomatic, inoperable; neurofibromatosis type 1 (NF1); aged 3 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.94 } }, "993ea638a65dc56a": { "b": { "tumor_type": "NF1-associated plexiform neurofibromas", "organ": "soft-tissue", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Symptomatic, inoperable; neurofibromatosis type 1 (NF1); aged 1 year to less than 7 years or older patients with swallowing difficulties", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.64, "neoplasm": 0.94 } }, "e2b4e4d63c3b9726": { "b": { "tumor_type": "clear cell renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF-targeted therapies", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "6a84cbcbc7ce953b": { "b": { "tumor_type": "VHL disease-associated renal cell carcinoma", "organ": "kidney", "disease_stage": "early", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "von Hippel-Lindau disease; localised procedures are unsuitable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.98 } }, "1d4d00abc9592f8b": { "b": { "tumor_type": "VHL disease-associated CNS haemangioblastoma", "organ": "CNS", "disease_stage": "early", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "von Hippel-Lindau disease; localised procedures are unsuitable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.96 } }, "ed2699c04bc6a48e": { "b": { "tumor_type": "VHL disease-associated pancreatic neuroendocrine tumour", "organ": "pancreas", "disease_stage": "early", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "von Hippel-Lindau disease; localised procedures are unsuitable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.98 } }, "318821bb1f5acd29": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "ERBB2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ trastuzumab and chemotherapy", "prior_therapy": null, "patient_eligibility": "High risk of recurrence; locally advanced, inflammatory, or early stage", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.19, "neoplasm": 0.99 } }, "6ec9c1598b35a152": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "ERBB2", "biomarker_alteration_type": "overexpression", 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"test_method": [], "combination": "+ carboplatin and paclitaxel", "prior_therapy": null, "patient_eligibility": "Primary advanced or recurrent; candidates for systemic therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "16b2530c03d61fa4": { "b": { "tumor_type": "endometrial cancer", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "MMR", "biomarker_alteration_type": "loss", "biomarker_detail": "dMMR", "diagnostic_criterion": "Mismatch repair deficient (dMMR)", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Carboplatin and paclitaxel without progression", "patient_eligibility": "Primary advanced or recurrent; candidates for systemic therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.32, "neoplasm": 0.99 } }, "9d2752f7eb76127b": { "b": { "tumor_type": "endometrial cancer", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "MMR", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "pMMR", "diagnostic_criterion": "Mismatch repair proficient (pMMR)", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ olaparib", "prior_therapy": "Carboplatin and paclitaxel without progression", "patient_eligibility": "Primary advanced or recurrent; candidates for systemic therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.3, "neoplasm": 0.99 } }, "a3072e39cdaec0e6": { "b": { "tumor_type": "muscle invasive bladder cancer (MIBC)", "organ": "bladder", "disease_stage": "early", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ gemcitabine and cisplatin", "prior_therapy": null, "patient_eligibility": "Resectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.73, "neoplasm": 0.99 } }, "62ac3c1d9097fa06": { "b": { "tumor_type": "muscle invasive bladder cancer (MIBC)", "organ": "bladder", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Neoadjuvant IMFINZI + gemcitabine and cisplatin and radical cystectomy", "patient_eligibility": "Resectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "7457e46ed36b34c4": { "b": { "tumor_type": "gastric or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "early", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ FLOT chemotherapy", "prior_therapy": null, "patient_eligibility": "Resectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "4370d015ebe98adb": { "b": { "tumor_type": "gastric or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ FLOT chemotherapy", "prior_therapy": "Neoadjuvant IMFINZI + FLOT chemotherapy and surgical resection", "patient_eligibility": "Resectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.15, "neoplasm": 0.99 } }, "a0ae87da5a3478d1": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "exon 19 deletions or exon 21 L858R substitution mutations", "diagnostic_criterion": "EGFR exon 19 deletions or exon 21 L858R substitution mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ amivantamab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "8d55608741654869": { "b": { "tumor_type": "NSCLC, adenocarcinoma histology", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ docetaxel", "prior_therapy": "after first-line chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "d81912a1cbac8df0": { "b": { "tumor_type": "GIST", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After failure of imatinib treatment due to resistance or intolerance", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "2dcd56cf3c7bd802": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.38, "neoplasm": 0.99 } }, "9a9a5a83abad2f01": { "b": { "tumor_type": "well-differentiated pancreatic neuroendocrine tumours", "organ": "pancreas", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Disease progression", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.44, "neoplasm": 0.99 } }, "3db25b546636ec2c": { "b": { "tumor_type": "ER-positive, HER2-negative breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "ESR1", "biomarker_alteration_type": "mutation", "biomarker_detail": "mutation; ER-positive; HER2-negative", "diagnostic_criterion": "Presence of ESR1 mutation; ER-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "+ CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib)", "prior_therapy": "During first-line endocrine therapy + CDK4/6 inhibitor, before progression", "patient_eligibility": "Pre- or perimenopausal women and men: combine with an LHRH agonist or antagonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.92, "neoplasm": 0.99 } }, "06e99a1224fb159c": { "b": { "tumor_type": "small cell lung cancer (SCLC)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and etoposide", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "92bc456436da7769": { "b": { "tumor_type": "non-squamous non-small cell lung carcinoma (NSCLC)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR/ALK/ROS1", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "No EGFR, ALK or ROS1 positive mutations", "diagnostic_criterion": "no EGFR, ALK or ROS1 positive mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ carboplatin and pemetrexed", "prior_therapy": null, "patient_eligibility": "Locally advanced NSCLC not candidates for surgery or radiotherapy; or metastatic NSCLC", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "0530bdc8ce019c5e": { "b": { "tumor_type": "squamous non-small cell lung carcinoma", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and nab-paclitaxel", "prior_therapy": null, "patient_eligibility": "Unresectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "565765961d6986eb": { "b": { "tumor_type": "oesophageal squamous cell carcinoma (OSCC)", "organ": "esophagus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression", "diagnostic_criterion": "CPS ≥ 5", "scoring_system": "CPS", "test_method": [ "IHC" ], "combination": "+ fluoropyrimidine- and platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable; locally advanced; recurrent; or metastatic", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "8ab635b8dfb4d218": { "b": { "tumor_type": "Colorectal carcinoma", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ fluoropyrimidine-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "696108c7ae410b4f": { "b": { "tumor_type": "Metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ paclitaxel", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "f62506c29956970c": { "b": { "tumor_type": "Metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ capecitabine", "prior_therapy": "Patients who received taxane- and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded", "patient_eligibility": "Treatment with other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "The sentence \"Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded\" is an exclusion, not a therapy the patient received, and r3's patient_eligibility already holds it; rule 14 says not to split or duplicate one condition across fields, so prior_therapy stays empty. It is ambiguous because rule 13 puts drug-class naivety (\"No prior EGFR TKI\") into prior_therapy, which would also allow recording this exclusion there.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Patients who received taxane- and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded", "from": [ "b" ] }, { "value": null, "from": [ "a" ] } ], "value": null, "from": [ "a" ] } ], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "2731c320c34e78eb": { "b": { "tumor_type": "Non-small cell lung cancer, other than predominantly squamous cell histology", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.48, "neoplasm": 0.99 } }, "b101c28634ae0694": { "b": { "tumor_type": "Non-squamous non-small cell lung cancer", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutations", "diagnostic_criterion": "Presence of an activating EGFR mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ erlotinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.54, "neoplasm": 0.99 } }, "c4d02d262f3275cc": { "b": { "tumor_type": "Renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ interferon alfa-2a", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "39928b0db8d1fb9c": { "b": { "tumor_type": "Epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and paclitaxel", "prior_therapy": null, "patient_eligibility": "FIGO stages III B, III C or IV", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "e2722aed4d5e0035": { "b": { "tumor_type": "Epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and gemcitabine or carboplatin and paclitaxel", "prior_therapy": "First recurrence; no prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents", "patient_eligibility": "Platinum-sensitive", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "4ee32c4bef6fb455": { "b": { "tumor_type": "Epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ paclitaxel, topotecan or pegylated liposomal doxorubicin", "prior_therapy": "No more than two prior chemotherapy regimens; no prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents", "patient_eligibility": "Platinum-resistant", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.95, "neoplasm": 0.99 } }, "3ec8a2dc9303084e": { "b": { "tumor_type": "Carcinoma of the cervix", "organ": "cervix", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ paclitaxel and cisplatin or paclitaxel and topotecan", "prior_therapy": null, "patient_eligibility": "Unable to receive platinum therapy (for the paclitaxel and topotecan alternative)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "2c428db3c11bff5c": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "MET", "biomarker_alteration_type": "mutation", "biomarker_detail": "MET exon 14 skipping", "diagnostic_criterion": "Alterations leading to MET exon 14 (METex14) skipping", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Following prior treatment with immunotherapy and/or platinum-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"alterations leading to ... exon 14 (METex14) skipping\", and both candidates describe this same alteration correctly. \"METex14 skipping\" uses the label's own abbreviation, so it is copied verbatim.", "kind": "field", "field": "biomarker_detail", "candidates": [ { "value": "MET exon 14 skipping", "from": [ "b" ] }, { "value": "METex14 skipping", "from": [ "a" ] } ], "value": "METex14 skipping", "from": [ "a" ] } ], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "f608f0768145594a": { "b": { "tumor_type": "mantle cell lymphoma (MCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ R-CHOP alternating with R-DHAP (or R-DHAOx) without IMBRUVICA", "prior_therapy": null, "patient_eligibility": "Eligible for autologous stem cell transplantation (ASCT)", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 15a says to keep the regimen's qualifiers verbatim, including \"alternating with R-DHAP (or R-DHAOx) without IMBRUVICA, followed by IMBRUVICA monotherapy\". The label never uses the word \"maintenance\", so rule 12a does not split the row and its combination must cover the whole sequence.", "kind": "field", "field": "combination", "candidates": [ { "value": "+ R-CHOP alternating with R-DHAP (or R-DHAOx) without IMBRUVICA", "from": [ "b" ] }, { "value": "+ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (IMBRUVICA + R-CHOP) alternating with R-DHAP (or R-DHAOx) without IMBRUVICA, followed by IMBRUVICA monotherapy", "from": [ "a" ] } ], "value": "+ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (IMBRUVICA + R-CHOP) alternating with R-DHAP (or R-DHAOx) without IMBRUVICA, followed by IMBRUVICA monotherapy", "from": [ "a" ] } ], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "ebb18993531f7f57": { "b": { "tumor_type": "mantle cell lymphoma (MCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.26, "neoplasm": 0.99 } }, "27ba3ba2511afcbe": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.41, "neoplasm": 0.99 } }, "7d2519f5492e6916": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.51, "neoplasm": 0.99 } }, "a07c80c2f2b83b14": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ obinutuzumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "3189126428de0ff7": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ venetoclax", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "60030237e4c6c1a7": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "e02c170b767eb27a": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bendamustine and rituximab (BR)", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.99 } }, "113eff6ee2c0183c": { "b": { "tumor_type": "Waldenström’s macroglobulinaemia (WM)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "Row r9 is the branch \"in first line treatment for patients unsuitable for chemo-immunotherapy\", so it is 1L under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "2L", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "79aca48f38663712": { "b": { "tumor_type": "Waldenström’s macroglobulinaemia (WM)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Unsuitable for chemo-immunotherapy", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "Row r10 is the branch for patients \"who have received at least one prior therapy\", which is 2L under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "b" ] }, { "value": "2L", "from": [ "a" ] } ], "value": "2L", "from": [ "a" ] } ], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "15c44938d9fd2b9b": { "b": { "tumor_type": "Waldenström’s macroglobulinaemia (WM)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "563d551394125673": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two prior systemic therapies", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "40c17d53d5e41894": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.43, "neoplasm": 0.99 } }, "cb47f5cd3d224d77": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ obinutuzumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "8444d4102b0f100b": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ venetoclax and obinutuzumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "03577ecf3b6d95e5": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "3be5eda6d5c7f5e9": { "b": { "tumor_type": "mantle cell lymphoma (MCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bendamustine and rituximab (BR)", "prior_therapy": null, "patient_eligibility": "Not eligible for autologous stem cell transplant (ASCT)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "ef1d616f8a8c3d8f": { "b": { "tumor_type": "mantle cell lymphoma (MCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "No prior BTK inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "35bebe7b9df5361a": { "b": { "tumor_type": "polycythaemia vera", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Without symptomatic splenomegaly", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.96 } }, "b0666e577865ea2d": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.48, "neoplasm": 0.99 } }, "77743449078d172a": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "maintenance", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Induction therapy", "patient_eligibility": "Responding to induction therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.24, "neoplasm": 0.99 } }, "e5040ad4f231c6e4": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After chemotherapy; chemoresistant or in second or subsequent relapse", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "2674543bc7d1dfb0": { "b": { "tumor_type": "diffuse large B-cell lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "CD20", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD20-positive", "diagnostic_criterion": "CD20 positive", "scoring_system": "n/a", "test_method": [ "IHC", "flow-cytometry" ], "combination": "+ CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone)", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy\". Both candidates name the same regimen; the shorter one keeps the CHOP expansion faithfully and is sufficient.", "kind": "field", "field": "combination", "candidates": [ { "value": "+ CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone)", "from": [ "b" ] }, { "value": "+ CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)", "from": [ "a" ] } ], "value": "+ CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)", "from": [ "a" ] } ], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "98a6be93dd7bb202": { "b": { "tumor_type": "diffuse large B-cell lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD20", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD20-positive", "diagnostic_criterion": "CD20 positive", "scoring_system": "n/a", "test_method": [ "IHC", "flow-cytometry" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Aged 6 months to less than 18 years; previously untreated", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.51, "neoplasm": 0.99 } }, "8b155a336028485a": { "b": { "tumor_type": "Burkitt lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD20", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD20-positive", "diagnostic_criterion": "CD20 positive", "scoring_system": "n/a", "test_method": [ "IHC", "flow-cytometry" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Aged 6 months to less than 18 years; previously untreated", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "0815fb0e427eccfa": { "b": { "tumor_type": "Burkitt-like lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD20", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD20-positive", "diagnostic_criterion": "CD20 positive", "scoring_system": "n/a", "test_method": [ "IHC", "flow-cytometry" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Aged 6 months to less than 18 years; previously untreated", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "aaa1aa74bd6118c2": { "b": { "tumor_type": "chronic lymphocytic leukaemia", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Previously untreated", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.43, "neoplasm": 0.99 } }, "b009d61ea48adc67": { "b": { "tumor_type": "chronic lymphocytic leukaemia", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chemotherapy", "prior_therapy": "Relapsed or refractory CLL", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "f1594f11e83dd972": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "tumour cell PD-L1 expression", "diagnostic_criterion": "tumour cell PD-L1 expression < 1%", "scoring_system": "TPS", "test_method": [ "IHC" ], "combination": "relatlimab + nivolumab", "prior_therapy": null, "patient_eligibility": "12 years of age and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.14, "neoplasm": 0.99 } }, "a55f001ee241e96b": { "b": { "tumor_type": "hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.28, "neoplasm": 0.99 } }, "17842a869dd9c567": { "b": { "tumor_type": "acute promyelocytic leukaemia (APL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "induction", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ all-trans-retinoic acid (ATRA)", "prior_therapy": null, "patient_eligibility": "Newly diagnosed; low-to-intermediate risk; white blood cell count ≤ 10 x 103/μl", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"indicated for induction of remission, and consolidation\". Rule 1 splits rows by treatment phase, so r1 becomes the induction row and a separate consolidation row is added.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": null, "from": [ "a" ] }, { "value": "induction", "from": [ "b" ] } ], "value": "induction", "from": [ "b" ] } ], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "e061045abf357ebe": { "b": { "tumor_type": "acute promyelocytic leukaemia (APL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "induction", "line_of_therapy": "2L", "biomarker_name": "PML/RARA", "biomarker_alteration_type": "fusion", "biomarker_detail": "t(15;17) translocation and/or PML/RAR-alpha gene", "diagnostic_criterion": "presence of the t(15;17) translocation and/or the PML/RAR-alpha gene", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Previous treatment should have included a retinoid and chemotherapy", "patient_eligibility": "Relapsed/refractory", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "The same \"induction of remission, and consolidation\" wording applies to the relapsed/refractory bullet. With the phases split under rule 1, r2 is the induction row.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": null, "from": [ "a", "jev" ] }, { "value": "induction", "from": [ "b" ] } ], "value": "induction", "from": [ "b" ] } ], "jev": { "supported": 0.48, "neoplasm": 0.99 } }, "1e4a25102d1c0a21": { "b": null, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"Consolidation\" is a distinct treatment phase (rules 1 and 11), so newly diagnosed APL needs its own consolidation row at 1L (\"Newly diagnosed\").", "kind": "missing", "verdict": "add" } ], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "8f84394ea60654ce": { "b": null, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "\"Consolidation\" is a separate phase for the \"Relapsed/refractory\" APL bullet as well, so a consolidation row at 2L is needed (rule 1 phase split). Its source_sentence skips the first bullet and is not a verbatim substring (rule 9), but the scenario itself is distinct.", "kind": "missing", "verdict": "add" } ], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "e4bfde777eb39920": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "f7cb876925f8a799": { "b": { "tumor_type": "diffuse large B-cell lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "5c8504e5514d8d18": { "b": { "tumor_type": "Philadelphia chromosome-positive chronic myelogenous leukaemia (CML), chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.44, "neoplasm": 0.99 } }, "1a47c5b708cdf2f3": { "b": { "tumor_type": "Philadelphia chromosome-positive chronic myelogenous leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Prior therapy including imatinib; resistance or intolerance", "patient_eligibility": "Chronic, accelerated or blast phase", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.43, "neoplasm": 0.99 } }, "a75529ece893f55e": { "b": { "tumor_type": "Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Prior therapy; resistance or intolerance", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.42, "neoplasm": 0.99 } }, "039c8ac173d8c1f7": { "b": { "tumor_type": "Philadelphia chromosome-positive lymphoid blast CML", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Prior therapy; resistance or intolerance", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.35, "neoplasm": 0.99 } }, "5c91b22e2abc2945": { "b": { "tumor_type": "Philadelphia chromosome-positive chronic myelogenous leukaemia (CML), chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Prior therapy including imatinib; resistance or intolerance", "patient_eligibility": null, "age_group": "pediatric" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The sentence joins \"newly diagnosed Ph+ CML in chronic phase\" and \"Ph+ CML-CP resistant or intolerant to prior therapy\". Rule 1 splits an untreated branch from a pretreated one, and r6 already covers the pretreated branch, so r5 is the newly diagnosed branch and takes 1L.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "2L", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] }, { "q": "q2", "ambiguous": false, "reason": "r5 is the \"newly diagnosed\" branch, so no prior therapy applies. The resistance/intolerance wording belongs to r6.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": null, "from": [ "a" ] }, { "value": "Prior therapy including imatinib; resistance or intolerance", "from": [ "b" ] } ], "value": null, "from": [ "a" ] } ], "jev": { "supported": 0.27, "neoplasm": 0.99 } }, "988fb4b4597ac8f3": { "b": null, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"Ph+ CML-CP resistant or intolerant to prior therapy including imatinib\" is a pretreated (2L) paediatric branch. Rule 1 requires it as its own row, separate from the newly diagnosed branch.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "889494588713f5f5": { "b": { "tumor_type": "Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.43, "neoplasm": 0.99 } }, "6d385f5d0004800c": { "b": { "tumor_type": "Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "EBV", "biomarker_alteration_type": "overexpression", "biomarker_detail": "EBV-positive", "diagnostic_criterion": "EBV-positive", "scoring_system": "n/a", "test_method": [ "ISH" ], "combination": "monotherapy", "prior_therapy": "At least one prior therapy; for solid organ transplant patients, chemotherapy unless chemotherapy is inappropriate", "patient_eligibility": "Post-transplant; aged 2 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.94 } }, "db660851e3f3fbfa": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib and dexamethasone", "prior_therapy": "At least one prior treatment regimen including lenalidomide", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "c4540b1467612218": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ dexamethasone", "prior_therapy": "At least two prior treatment regimens, including both lenalidomide and bortezomib; demonstrated disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "7841ee03015d5d31": { "b": { "tumor_type": "triple-negative breast cancer (TNBC)", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HR/HER2", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "triple-negative (HR-negative and HER2-negative)", "diagnostic_criterion": "triple-negative breast cancer (TNBC)", "scoring_system": "n/a", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not a candidate for PD-1/PD-L1 inhibitor therapy", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"triple-negative breast cancer\" is defined by the absence of ER, PR and HER2. Rule 3 treats absence of several markers as the main requirement, which gives alteration_type=\"wild-type-required\" (biomarker must be ABSENT), not protein loss.", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "wild-type-required", "from": [ "b" ] }, { "value": "loss", "from": [ "a" ] } ], "value": "wild-type-required", "from": [ "b" ] }, { "q": "q2", "ambiguous": false, "reason": "Rule 3 says to name every absent biomarker joined by \"/\". Triple-negative means ER-, PR- and HER2-negative, as the row's own detail states, and rule 7 uses ER and PR for the individual receptors.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "ER/PR/HER2", "from": [ "a" ] }, { "value": "HR/HER2", "from": [ "b" ] } ], "value": "ER/PR/HER2", "from": [ "a" ] } ], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "a8a47fe63004aff3": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HR/HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Endocrine therapy and at least one line of chemotherapy in the advanced setting", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"hormone receptor (HR)-positive, HER2-negative\": HR is the primary biomarker and HER2-negative is a secondary negative. Under rule 3 the primary is kept and \"; HER2-negative\" goes into biomarker_detail only.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "HR", "from": [ "a" ] }, { "value": "HR/HER2", "from": [ "b" ] } ], "value": "HR", "from": [ "a" ] } ], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "c600cc2491005e23": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "presence of fusion by validated assay", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Adults", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "fc042d7fca7b4600": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "presence of fusion by validated assay", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "Previously treated", "patient_eligibility": "Adults", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "6866857ec539b7e9": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "ROS1", "biomarker_alteration_type": "fusion", "biomarker_detail": "ROS1-positive", "diagnostic_criterion": "presence of fusion by validated assay", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Adults", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "72c56dcdfb4c83ab": { "b": { "tumor_type": "systemic anaplastic large cell lymphoma (ALCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "presence of fusion by validated assay", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "Relapsed or refractory disease", "patient_eligibility": "Paediatric patients aged ≥1 to <18 years", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.92, "neoplasm": 0.99 } }, "5d3a1ee52b4045e1": { "b": { "tumor_type": "inflammatory myofibroblastic tumour (IMT)", "organ": "soft-tissue", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "presence of fusion by validated assay", "scoring_system": "n/a", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "Recurrent or refractory disease", "patient_eligibility": "Paediatric patients aged ≥1 to <18 years; unresectable", "age_group": "pediatric" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"recurrent or refractory ... unresectable inflammatory myofibroblastic tumour\". Under rule 10, \"Unresectable X\" maps to advanced, and the any-default for tumours without TNM staging applies only \"unless the text uses one of the stage words above\".", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "advanced", "from": [ "a" ] } ], "jev": { "supported": 0.75, "neoplasm": 0.94 } }, "4659fd70439a3ac4": { "b": { "tumor_type": "post-polycythaemia vera myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Disease-related splenomegaly or symptoms", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.52, "neoplasm": 0.98 } }, "41cbabbf65209980": { "b": { "tumor_type": "polycythaemia vera", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Hydroxyurea (resistant to or intolerant of hydroxyurea)", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.53, "neoplasm": 0.97 } }, "71c61fdd671eafb3": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "early", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ platinum-containing chemotherapy", "prior_therapy": null, "patient_eligibility": "High risk of recurrence; resectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "258c80c2cd5cba2b": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "neoadjuvant tislelizumab + platinum-containing chemotherapy and surgical resection", "patient_eligibility": "High risk of recurrence; resectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "221102006ccd2f4a": { "b": { "tumor_type": "non-squamous NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression on tumour cells; EGFR/ALK-negative", "diagnostic_criterion": "PD-L1 expression on ≥50% of tumour cells", "scoring_system": "TPS", "test_method": [ "IHC", "molecular" ], "combination": "+ pemetrexed and platinum-containing chemotherapy", "prior_therapy": null, "patient_eligibility": "For locally advanced disease: not a candidate for surgical resection or platinum-based chemoradiation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "6182240e240f5283": { "b": { "tumor_type": "squamous NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and either paclitaxel or nab-paclitaxel", "prior_therapy": null, "patient_eligibility": "For locally advanced disease: not a candidate for surgical resection or platinum-based chemoradiation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "40c8140c8481ff71": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Prior platinum-based therapy", "patient_eligibility": "Patients with EGFR-mutant or ALK-positive NSCLC must also have received targeted therapies before tislelizumab", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "cff2d64ff2fc5884": { "b": { "tumor_type": "extensive-stage SCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ etoposide and platinum chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "fb35b7465a75c6ed": { "b": { "tumor_type": "gastric or gastroesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression with TAP score ≥ 5%; HER2-negative", "diagnostic_criterion": "TAP score ≥ 5%; HER2-negative", "scoring_system": "TAP", "test_method": [ "IHC" ], "combination": "+ platinum and fluoropyrimidine-based chemotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "5bc896892aed6bb7": { "b": { "tumor_type": "oesophageal squamous cell carcinoma", "organ": "esophagus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression with TAP score ≥ 5%", "diagnostic_criterion": "TAP score ≥ 5%", "scoring_system": "TAP", "test_method": [ "IHC" ], "combination": "+ platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "969c5fd7f6e05fff": { "b": { "tumor_type": "oesophageal squamous cell carcinoma", "organ": "esophagus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Prior platinum-based chemotherapy", "patient_eligibility": "Unresectable", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "ec8c607c44cca969": { "b": { "tumor_type": "nasopharyngeal carcinoma", "organ": "head-and-neck", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ gemcitabine and cisplatin", "prior_therapy": null, "patient_eligibility": "Recurrent disease not amenable to curative surgery or radiotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.7, "neoplasm": 0.99 } }, "9a2549d9a587fcf0": { "b": { "tumor_type": "polycythaemia vera", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.52, "neoplasm": 0.96 } }, "ae9b3e1a8d709673": { "b": { "tumor_type": "essential thrombocythaemia", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.46, "neoplasm": 0.97 } }, "c5837d2263cf71f5": { "b": null, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The first sentence covers adults with \"CD19 positive relapsed or refractory\" BCP-ALL. The Ph-positive subgroup has an extra prior-therapy condition and sits in r2, so r1 is the distinct Ph-negative branch (rule 1 split, positive vs negative biomarker).", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.11, "neoplasm": 0.99 } }, "890f25bf4bf33a6a": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "CD19", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD19-positive", "diagnostic_criterion": "CD19 positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "For Philadelphia chromosome-positive disease: failed treatment with at least 2 tyrosine kinase inhibitors (TKIs) and no alternative treatment options", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "Ph+ patients \"should have failed treatment with at least 2 tyrosine kinase inhibitors\". At least two prior therapies maps to 3L+ under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "3L+", "from": [ "a" ] } ], "value": "3L+", "from": [ "a" ] }, { "q": "q3", "ambiguous": false, "reason": "The label states a concrete prior therapy: \"should have failed treatment with at least 2 tyrosine kinase inhibitors (TKIs)\".", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Failed treatment with at least 2 tyrosine kinase inhibitors (TKIs)", "from": [ "a" ] }, { "value": null, "from": [ "b" ] } ], "value": "Failed treatment with at least 2 tyrosine kinase inhibitors (TKIs)", "from": [ "a" ] } ], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "a3cba8269ea8a413": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "CD19", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD19-positive", "diagnostic_criterion": "CD19 positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Philadelphia chromosome-negative; in first or second complete remission; minimal residual disease (MRD) ≥ 0.1%", "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": true, "reason": "\"In first or second complete remission\" is a disease state (rule 14), not explicit line wording. First remission falls within first-line therapy, so the lowest count is 1L, but the rules do not settle whether a CR1/CR2 disjunction sets any line or should be left as 'any'.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.7, "neoplasm": 0.99 } }, "f4fe9d0656e7be25": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "CD19", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD19-positive", "diagnostic_criterion": "CD19 positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": "After at least two prior therapies or after prior allogeneic haematopoietic stem cell transplantation", "patient_eligibility": "Aged 1 month or older; Philadelphia chromosome-negative", "age_group": "pediatric" }, "decisions": [ { "q": "q5", "ambiguous": false, "reason": "The branches are \"refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic haematopoietic stem cell transplantation\". The ASCT-based 3L+ rule applies only to lymphomas, and relapse after allo-HSCT guarantees at least one prior line, so the lowest count is 2L (rule 13).", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "3L+", "from": [ "a" ] }, { "value": "2L", "from": [ "b" ] } ], "value": "2L", "from": [ "b" ] } ], "jev": { "supported": 0.95, "neoplasm": 0.99 } }, "e8f44fa4d720395a": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "consolidation", "line_of_therapy": "2L", "biomarker_name": "CD19", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD19-positive", "diagnostic_criterion": "CD19 positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Aged 1 month or older; Philadelphia chromosome-negative; high-risk first relapse", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.23, "neoplasm": 0.99 } }, "eb03f97621c914dc": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "consolidation", "line_of_therapy": "1L", "biomarker_name": "CD19", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD19-positive", "diagnostic_criterion": "CD19 positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Newly diagnosed; Philadelphia chromosome-negative", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "68783b049c809977": { "b": { "tumor_type": "colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Previously treated with available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents; progressed on or intolerant to trifluridine-tipiracil or regorafenib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "26ffc3392b29b358": { "b": { "tumor_type": "high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer", "organ": "ovary", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "FRα", "biomarker_alteration_type": "overexpression", "biomarker_detail": "FRα positive", "diagnostic_criterion": "FRα positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "one to three prior systemic treatment regimens", "patient_eligibility": "platinum-resistant", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"FRα positive\" is an IHC protein-expression status. Section 4.2 defines it with a quantitative composite (≥75% of tumour cells at ≥2+ intensity), the same kind of assay-specific score rule 5a gives as its CLDN18.2 example for \"other\", rather than a categorical mutation or MSI status that would take n/a.", "kind": "field", "field": "scoring_system", "candidates": [ { "value": "n/a", "from": [ "b", "jev" ] }, { "value": "other", "from": [ "a" ] } ], "value": "other", "from": [ "a" ] } ], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "501fe1902a3365f6": { "b": { "tumor_type": "GIST", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Three or more kinase inhibitors, including imatinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "08bb1ad9073a4713": { "b": { "tumor_type": "NF1-associated plexiform neurofibromas", "organ": "soft-tissue", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Symptomatic; inoperable; neurofibromatosis type 1; aged 2 years and above", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.94 } }, "a0a8e4ce6b58ac1c": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "PIK3CA", "biomarker_alteration_type": "mutation", "biomarker_detail": "PIK3CA mutation; HR-positive; HER2-negative", "diagnostic_criterion": "PIK3CA mutation; HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "molecular", "IHC", "ISH" ], "combination": "+ fulvestrant", "prior_therapy": "After disease progression following an endocrine-based regimen", "patient_eligibility": "Postmenopausal women and men", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.99 } }, "6a914720ac1ed6a5": { "b": { "tumor_type": "mantle cell lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "previously treated with a BTK inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"who have been previously treated with a Bruton’s tyrosine kinase (BTK) inhibitor\", and both candidates capture this prior therapy correctly. The first candidate keeps the label's wording verbatim, so it is copied.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Previously treated with a Bruton’s tyrosine kinase (BTK) inhibitor", "from": [ "a" ] }, { "value": "previously treated with a BTK inhibitor", "from": [ "b" ] } ], "value": "Previously treated with a Bruton’s tyrosine kinase (BTK) inhibitor", "from": [ "a" ] } ], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "88ec9b75a628dbd0": { "b": { "tumor_type": "chronic lymphocytic leukaemia", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "526bb26d139f182e": { "b": { "tumor_type": "triple-negative breast cancer (TNBC)", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression", "diagnostic_criterion": "CPS ≥ 10", "scoring_system": "CPS", "test_method": [ "IHC" ], "combination": "+ pembrolizumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "8890a2742b42e94d": { "b": { "tumor_type": "triple-negative breast cancer (TNBC)", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not a candidate for PD-1 or PD-L1 inhibitor therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "b61d47fa91e89348": { "b": { "tumor_type": "triple-negative breast cancer (TNBC)", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Two or more prior systemic therapies, including at least one for advanced disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "4691e2ce9df16ecf": { "b": { "tumor_type": "HR-positive, HER2-negative breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "IHC-score", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Endocrine-based therapy and at least two additional systemic therapies in the advanced setting", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The primary biomarker is \"hormone receptor (HR)-positive\", a categorical status with no score in the text, so scoring_system is n/a (rule 5a). Under rules 5a and 5b, the secondary \"HER2-negative\" does not change scoring_system.", "kind": "field", "field": "scoring_system", "candidates": [ { "value": "IHC-score", "from": [ "b" ] }, { "value": "n/a", "from": [ "a", "jev" ] } ], "value": "n/a", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "3abe986492330dfd": { "b": { "tumor_type": "hormone-dependent prostate cancer", "organ": "prostate", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.04, "neoplasm": 0.98 } }, "910cbcbe8dcca803": { "b": { "tumor_type": "hormone-dependent prostate cancer", "organ": "prostate", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ radiotherapy", "prior_therapy": null, "patient_eligibility": "High-risk; localised or locally advanced", "age_group": "any" }, "decisions": [], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "7fec102d46f0294e": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "cc1f1e6697094d40": { "b": { "tumor_type": "high-grade B-cell lymphoma (HGBL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "e38e31ab62f80391": { "b": { "tumor_type": "gastric or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CLDN18.2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CLDN18.2 positive", "diagnostic_criterion": "CLDN18.2 positive (see section 4.2)", "scoring_system": "other", "test_method": [ "IHC" ], "combination": "+ fluoropyrimidine- and platinum-containing chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 5a names zolbetuximab CLDN18.2 (\"moderate-to-strong membranous staining in ≥ 75% of tumour cells\") as the example of \"other\". The label's \"Claudin (CLDN) 18.2 positive\" refers to that composite readout defined in section 4.2, so it is not a categorical status.", "kind": "field", "field": "scoring_system", "candidates": [ { "value": "other", "from": [ "a", "b" ] }, { "value": "n/a", "from": [ "jev" ] } ], "value": "other", "from": [ "a", "b" ] } ], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "6772c64cec6d4d1e": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "exon 19 deletion or exon 21 (L858R) substitution mutation", "diagnostic_criterion": "EGFR exon 19 deletion or exon 21 (L858R) substitution mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "complete tumour resection", "patient_eligibility": "Stage IB-IIIA", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.99 } }, "84c9f1eceebea66c": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "locally-advanced", "treatment_phase": "consolidation", "line_of_therapy": "any", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "exon 19 deletion or exon 21 (L858R) substitution mutation", "diagnostic_criterion": "EGFR exon 19 deletion or exon 21 (L858R) substitution mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "platinum-based chemoradiation therapy", "patient_eligibility": "Unresectable; disease has not progressed during or following platinum-based chemoradiation therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "2c4089169d98021b": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutations", "diagnostic_criterion": "presence of activating EGFR mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "4aed1b98cb4921af": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "T790M mutation-positive", "diagnostic_criterion": "presence of EGFR T790M mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "1acae0b2aa6c43c1": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "exon 19 deletion or exon 21 (L858R) substitution mutation", "diagnostic_criterion": "EGFR exon 19 deletion or exon 21 (L858R) substitution mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ pemetrexed and platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "fa34fe8f53d624d2": { "b": { "tumor_type": "desmoid tumours", "organ": "soft-tissue", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressing; requires systemic treatment", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.74, "neoplasm": 0.89 } }, "f66605f9458fa143": { "b": { "tumor_type": "B-cell acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Refractory, relapse post-transplant or second or later relapse", "patient_eligibility": "Up to and including 25 years of age", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "a47afabc6dfcc42f": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "aa200e826f631321": { "b": { "tumor_type": "follicular lymphoma (FL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.44, "neoplasm": 0.99 } }, "462636a093f42c53": { "b": { "tumor_type": "Grade 2 astrocytoma", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "IDH1", "biomarker_alteration_type": "mutation", "biomarker_detail": "R132 mutation", "diagnostic_criterion": "Presence of an IDH1 R132 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Surgical intervention only", "patient_eligibility": "Aged 12 years and older; weighing at least 40 kg; not in immediate need of radiotherapy or chemotherapy", "age_group": "mixed" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy\" means no prior systemic therapy, which is equivalent to previously untreated, so the row is 1L under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] }, { "q": "q2", "ambiguous": true, "reason": "Rule 1 splits different biomarkers (\"ALK- or ROS1-positive\" → two rows), so IDH1 R132 and IDH2 R172 become separate rows. The IDH2 rows are added in q5/q6, leaving r1 as the IDH1 R132 branch. r1 still names \"IDH1/IDH2\", so a person must decide whether to treat the two genes as one pathway biomarker instead.", "kind": "field", "field": "biomarker_detail", "candidates": [ { "value": "IDH1 R132 or IDH2 R172 mutation", "from": [ "a" ] }, { "value": "R132 mutation", "from": [ "b" ] } ], "value": "IDH1 R132 or IDH2 R172 mutation", "from": [ "a" ], "suggested": "R132 mutation" } ], "jev": { "supported": 0.91, "neoplasm": 0.98 } }, "de4e2320769d8c0c": { "b": { "tumor_type": "Grade 2 oligodendroglioma", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "IDH1", "biomarker_alteration_type": "mutation", "biomarker_detail": "R132 mutation", "diagnostic_criterion": "Presence of an IDH1 R132 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Surgical intervention only", "patient_eligibility": "Aged 12 years and older; weighing at least 40 kg; not in immediate need of radiotherapy or chemotherapy", "age_group": "mixed" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"who only had surgical intervention\" guarantees no prior systemic therapy, so the row is 1L (rule 13).", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "1L", "from": [ "a" ] }, { "q": "q4", "ambiguous": true, "reason": "\"with an IDH1 R132 or IDH2 R172 mutation\" names two different genes, which rule 1 splits; the IDH2 R172 branch is covered by the added row in q6. Whether IDH1/IDH2 counts as one biomarker remains open.", "kind": "field", "field": "biomarker_detail", "candidates": [ { "value": "R132 mutation", "from": [ "b" ] }, { "value": "IDH1 R132 or IDH2 R172 mutation", "from": [ "a" ] } ], "value": "IDH1 R132 or IDH2 R172 mutation", "from": [ "a" ], "suggested": "R132 mutation" } ], "jev": { "supported": 0.91, "neoplasm": 0.98 } }, "376ca6554664c417": { "b": null, "decisions": [ { "q": "q5", "ambiguous": false, "reason": "\"IDH1 R132 or IDH2 R172 mutation\" names a different biomarker per branch, so rule 1 requires a separate IDH2 R172 row for astrocytoma.", "kind": "missing", "verdict": "add" } ], "jev": { "supported": 0.94, "neoplasm": 0.99 } }, "bbc87fe45faa0fa4": { "b": null, "decisions": [ { "q": "q6", "ambiguous": false, "reason": "Under the same rule 1 split by biomarker, oligodendroglioma needs its own IDH2 R172 row alongside the IDH1 R132 row.", "kind": "missing", "verdict": "add" } ], "jev": { "supported": 0.93, "neoplasm": 0.98 } }, "022133e7224de7a3": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ daratumumab", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "289b3a7c41f0e785": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody; demonstrated disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "39e4b63dc4cfaf4b": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "8f7fb5c904e87c74": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pomalidomide and dexamethasone", "prior_therapy": "At least one prior therapy including lenalidomide", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "02bf742ff68567c8": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide and dexamethasone or bortezomib, melphalan and prednisone", "prior_therapy": null, "patient_eligibility": "newly diagnosed; autologous stem cell transplant-ineligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.99 } }, "92829f187f44f17b": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib, thalidomide and dexamethasone", "prior_therapy": null, "patient_eligibility": "newly diagnosed; autologous stem cell transplant-eligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "12733008b33a9a3f": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide and dexamethasone or bortezomib and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "10d7e1a031eb41ef": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Prior therapy included a proteasome inhibitor and an immunomodulatory agent; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "94f4b48a34940075": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib, lenalidomide and dexamethasone", "prior_therapy": null, "patient_eligibility": "newly diagnosed", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "36671dc7cd2ec24e": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pomalidomide and dexamethasone", "prior_therapy": "One prior therapy containing a proteasome inhibitor and lenalidomide, with lenalidomide-refractory disease; or at least two prior therapies including lenalidomide and a proteasome inhibitor, with disease progression on or after the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.99 } }, "9bc20e35ffe9790b": { "b": { "tumor_type": "smouldering multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "High risk of developing multiple myeloma", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.98 } }, "3f4774f669d4402c": { "b": { "tumor_type": "systemic AL amyloidosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ cyclophosphamide, bortezomib and dexamethasone", "prior_therapy": null, "patient_eligibility": "Newly diagnosed", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.6, "neoplasm": 0.37 } }, "25c902e83791abaf": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ endocrine therapy", "prior_therapy": null, "patient_eligibility": "Node-positive; high risk of recurrence; in pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a LHRH agonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "165e590ecf84de11": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ aromatase inhibitor or fulvestrant", "prior_therapy": null, "patient_eligibility": "In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "dabe843031460237": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ aromatase inhibitor or fulvestrant", "prior_therapy": "Prior endocrine therapy", "patient_eligibility": "In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "a9a3fe80faa3ac3e": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "KRAS", "biomarker_alteration_type": "mutation", "biomarker_detail": "G12C", "diagnostic_criterion": "Presence of KRAS G12C mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After at least one prior systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "2f371941f78a3f16": { "b": { "tumor_type": "high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "completion of first-line platinum-based chemotherapy", "patient_eligibility": "In complete or partial response", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "2d1060c239ae2f5f": { "b": { "tumor_type": "high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "platinum-based chemotherapy", "patient_eligibility": "In complete or partial response", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "fc8ef328b9981832": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ aromatase inhibitor", "prior_therapy": null, "patient_eligibility": "High risk of recurrence; in pre- or perimenopausal women or men, the aromatase inhibitor should be combined with an LHRH agonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "59d7d23f2de77f37": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ aromatase inhibitor or fulvestrant", "prior_therapy": null, "patient_eligibility": "In pre- or perimenopausal women, endocrine therapy should be combined with an LHRH agonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "18b80aa6f113102c": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ aromatase inhibitor or fulvestrant", "prior_therapy": "Prior endocrine therapy", "patient_eligibility": "In pre- or perimenopausal women, endocrine therapy should be combined with an LHRH agonist", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "00dea867d50b1232": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "induction", "line_of_therapy": "1L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3-ITD positive", "diagnostic_criterion": "FLT3-ITD positive", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ standard cytarabine and anthracycline induction chemotherapy", "prior_therapy": null, "patient_eligibility": "Newly diagnosed", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 15a keeps regimen qualifiers verbatim: \"in combination with standard cytarabine and anthracycline induction\" chemotherapy, so the induction row takes \"+ standard cytarabine and anthracycline induction chemotherapy\".", "kind": "field", "field": "combination", "candidates": [ { "value": "+ cytarabine and anthracycline", "from": [ "a" ] }, { "value": "+ standard cytarabine and anthracycline induction chemotherapy", "from": [ "b" ] } ], "value": "+ standard cytarabine and anthracycline induction chemotherapy", "from": [ "b" ] } ], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "4edf6bf8c5163449": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "consolidation", "line_of_therapy": "1L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3-ITD positive", "diagnostic_criterion": "FLT3-ITD positive", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ standard cytarabine consolidation chemotherapy", "prior_therapy": "Quizartinib + standard cytarabine and anthracycline induction chemotherapy", "patient_eligibility": "Newly diagnosed", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "The label says \"standard cytarabine consolidation chemotherapy\"; rule 15a keeps qualifiers verbatim, so the consolidation row takes that wording rather than bare \"+ cytarabine\".", "kind": "field", "field": "combination", "candidates": [ { "value": "+ standard cytarabine consolidation chemotherapy", "from": [ "b" ] }, { "value": "+ cytarabine", "from": [ "a" ] } ], "value": "+ standard cytarabine consolidation chemotherapy", "from": [ "b" ] } ], "jev": { "supported": 0.03, "neoplasm": 0.99 } }, "cb9c18b595637992": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3-ITD positive", "diagnostic_criterion": "FLT3-ITD positive", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Quizartinib + standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy without progression", "patient_eligibility": "Newly diagnosed", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "Rule 12a sets the maintenance prior_therapy to \" without progression\". The full verbatim regimen (\"standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy\") is the correct reference.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "quizartinib with induction and consolidation chemotherapy without progression", "from": [ "a" ] }, { "value": "Quizartinib + standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy without progression", "from": [ "b" ] } ], "value": "Quizartinib + standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy without progression", "from": [ "b" ] } ], "jev": { "supported": 0.02, "neoplasm": 0.99 } }, "f9d36b9f796d31b5": { "b": null, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The text lists \"primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis\". These are distinct disease entities, so rule 1 gives each its own row, and r1 is the primary myelofibrosis row.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.48, "neoplasm": 0.98 } }, "0a23f6e91aaca13f": { "b": { "tumor_type": "myelofibrosis (primary, post-polycythaemia vera or post-essential thrombocythaemia)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After ruxolitinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"JAK inhibitor naïve or have been treated with ruxolitinib\": naivety to one drug class does not set a line (rule 13), so the naive branch is not 1L. With no untreated-vs-pretreated split, the row takes the lowest count, which is any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] }, { "q": "q3", "ambiguous": false, "reason": "Both alternatives belong to one condition and stay in one clause joined by \"or\" (rule 14). Narrowing to \"After ruxolitinib\" would drop the JAK-naive branch, which no other row covers.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "After ruxolitinib", "from": [ "b" ] }, { "value": "Janus Associated Kinase (JAK) inhibitor naïve or treated with ruxolitinib", "from": [ "a" ] } ], "value": "Janus Associated Kinase (JAK) inhibitor naïve or treated with ruxolitinib", "from": [ "a" ] } ], "jev": { "supported": 0.39, "neoplasm": 0.98 } }, "79a45defc2d8ed13": { "b": { "tumor_type": "myelofibrosis (primary, post-polycythaemia vera or post-essential thrombocythaemia)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "No prior JAK inhibitor", "patient_eligibility": "JAK inhibitor-naïve", "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "\"JAK inhibitor naïve or have been treated with ruxolitinib\" is not split by rule 1, so the row keeps both alternatives. \"No prior JAK inhibitor\" would drop the ruxolitinib-treated branch.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "No prior JAK inhibitor", "from": [ "b" ] }, { "value": "Janus Associated Kinase (JAK) inhibitor naïve or treated with ruxolitinib", "from": [ "a" ] } ], "value": "Janus Associated Kinase (JAK) inhibitor naïve or treated with ruxolitinib", "from": [ "a" ] } ], "jev": { "supported": 0.39, "neoplasm": 0.98 } }, "417fcb5a7bce21bc": { "b": { "tumor_type": "hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline and/or somatic BRCA 1/2 mutations", "diagnostic_criterion": "presence of BRCA 1/2 mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ prednisone or prednisolone + androgen deprivation therapy (ADT)", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The mHSPC sentence has no line wording (no \"first-line\", \"previously untreated\" or similar); ADT is a concurrent partner, not a prior line. Rule 13 says \"If no line information at all → any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.56, "neoplasm": 0.99 } }, "8c33abc055beb094": { "b": { "tumor_type": "castration-resistant prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline and/or somatic BRCA 1/2 mutations", "diagnostic_criterion": "presence of BRCA 1/2 mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ prednisone or prednisolone", "prior_therapy": null, "patient_eligibility": "Chemotherapy is not clinically indicated", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"mCRPC … in whom chemotherapy is not clinically indicated\" describes castration-resistant disease before chemotherapy. Castration resistance is a disease state, and rule 13 maps \"Metastatic castration-resistant prostate cancer before chemotherapy → 1L\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.7, "neoplasm": 0.99 } }, "6fc503fcc501a8c0": { "b": { "tumor_type": "gastroenteropancreatic neuroendocrine tumours (GEP-NETs)", "organ": "other", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "SSTR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "somatostatin receptor-positive", "diagnostic_criterion": "somatostatin receptor-positive", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressive", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.28, "neoplasm": 0.98 } }, "470a94a775b6f417": { "b": { "tumor_type": "High-grade epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline and/or somatic mutation", "diagnostic_criterion": "Presence of BRCA1/2 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Following completion of first-line platinum-based chemotherapy", "patient_eligibility": "In response (complete or partial)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "a9b21bdc7b10f95b": { "b": { "tumor_type": "High-grade epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Platinum-based chemotherapy; platinum-sensitive relapsed disease", "patient_eligibility": "In response (complete or partial) to platinum-based chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "70b94e37e108252c": { "b": { "tumor_type": "High-grade epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "HRD", "biomarker_alteration_type": "signature", "biomarker_detail": "HRD-positive", "diagnostic_criterion": "BRCA1/2 mutation and/or genomic instability", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ bevacizumab", "prior_therapy": "Following completion of first-line platinum-based chemotherapy in combination with bevacizumab", "patient_eligibility": "In response (complete or partial)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.99 } }, "3475dc4d18a18a9f": { "b": { "tumor_type": "Breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline mutation; HER2-negative", "diagnostic_criterion": "Presence of germline BRCA1/2 mutation; HER2-negative", "scoring_system": "n/a", "test_method": [ "molecular", "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Previously treated with neoadjuvant or adjuvant chemotherapy", "patient_eligibility": "High risk early breast cancer", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.93, "neoplasm": 0.99 } }, "a0cb8f1001415748": { "b": { "tumor_type": "Breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline mutation; HER2-negative", "diagnostic_criterion": "Presence of germline BRCA1/2 mutation; HER2-negative", "scoring_system": "n/a", "test_method": [ "molecular", "IHC", "ISH" ], "combination": "+ endocrine therapy", "prior_therapy": "Previously treated with neoadjuvant or adjuvant chemotherapy", "patient_eligibility": "High risk early breast cancer", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "07605f151c5cc084": { "b": { "tumor_type": "Breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline mutation; HER2-negative", "diagnostic_criterion": "Presence of germline BRCA1/2 mutation; HER2-negative", "scoring_system": "n/a", "test_method": [ "molecular", "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Previously treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting unless not suitable; for HR-positive disease, progressed on or after prior endocrine therapy unless unsuitable for endocrine therapy", "patient_eligibility": "For HR-positive breast cancer: progressed on or after prior endocrine therapy, or considered unsuitable for endocrine therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.99 } }, "74a03de26b6caf86": { "b": { "tumor_type": "Pancreatic adenocarcinoma", "organ": "pancreas", "disease_stage": "metastatic", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline mutation", "diagnostic_criterion": "Presence of germline BRCA1/2 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "No progression after a minimum of 16 weeks of platinum treatment within a first-line chemotherapy regimen", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "1a715aa0548bf219": { "b": { "tumor_type": "Castration-resistant prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRCA1/BRCA2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline and/or somatic mutation", "diagnostic_criterion": "Presence of BRCA1/2 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Progressed following prior therapy that included a new hormonal agent", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.99 } }, "86571c7fd95bc980": { "b": { "tumor_type": "Castration-resistant prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ abiraterone and prednisone or prednisolone", "prior_therapy": null, "patient_eligibility": "Chemotherapy is not clinically indicated", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "The label says \"mCRPC in whom chemotherapy is not clinically indicated\". Rule 13 maps mCRPC before chemotherapy to 1L, since castration resistance is a disease state and not a prior line. The text never states that no prior systemic therapy was given for mCRPC, so \"any\" (no line information) remains arguable.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.14, "neoplasm": 0.99 } }, "4ac561bb1d2f226f": { "b": { "tumor_type": "Endometrial cancer", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "MMR", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "pMMR", "diagnostic_criterion": "pMMR", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ durvalumab", "prior_therapy": "First-line treatment with durvalumab in combination with carboplatin and paclitaxel; disease has not progressed", "patient_eligibility": "Primary advanced or recurrent disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "53d4336706482a9a": { "b": { "tumor_type": "Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (Ph+ CML-CP)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "Presence of the Philadelphia chromosome", "scoring_system": "n/a", "test_method": [ "cytogenetics", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.32, "neoplasm": 0.99 } }, "85bbeb21feca3a65": { "b": { "tumor_type": "Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (Ph+ CML-CP)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "mutation", "biomarker_detail": "T315I mutation; Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "Presence of the T315I mutation", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics", "ISH" ], "combination": "monotherapy", "prior_therapy": "Resistant to or intolerant to ponatinib", "patient_eligibility": "Ponatinib-ineligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.33, "neoplasm": 0.99 } }, "ea70adf8f3c748fe": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "First-line chemoimmunotherapy; relapsed within 12 months of completion or refractory", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 10 says haematological malignancies → any unless a stage word is used; \"relapsed within 12 months ... or refractory\" is a line descriptor, not a stage, and \"Relapsed\" alone → advanced applies only to solid tumours.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "5de932ec4e9ce13a": { "b": { "tumor_type": "high grade B-cell lymphoma (HGBCL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "First-line chemoimmunotherapy; relapsed within 12 months of completion or refractory", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "No stage words for HGBCL; rule 10 sets haematological malignancies without stage wording to any, and the relapse wording sets only the line.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "2e846c07e1afe126": { "b": { "tumor_type": "primary mediastinal large B-cell lymphoma (PMBCL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "First-line chemoimmunotherapy; relapsed within 12 months of completion or refractory", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "No stage words for PMBCL; rule 10 sets haematological malignancies without stage wording to any, and the relapse wording sets only the line.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "any", "from": [ "a", "jev" ] }, { "value": "advanced", "from": [ "b" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.57, "neoplasm": 1 } }, "be17d81fd9c53a6d": { "b": { "tumor_type": "follicular lymphoma grade 3B (FL3B)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "First-line chemoimmunotherapy; relapsed within 12 months of completion or refractory", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "No stage words for FL3B; rule 10 sets haematological malignancies without stage wording to any, and the relapse wording sets only the line.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "1b2e154c45f9977d": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q5", "ambiguous": false, "reason": "\"relapsed or refractory DLBCL\" carries no stage word; the rule that relapsed means advanced is limited to solid tumours, so haematological disease → any (rule 10).", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.56, "neoplasm": 0.99 } }, "cabef418a1fb7586": { "b": { "tumor_type": "primary mediastinal large B-cell lymphoma (PMBCL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q6", "ambiguous": false, "reason": "\"relapsed or refractory ... PMBCL\" carries no stage word; the rule that relapsed means advanced is limited to solid tumours, so haematological disease → any (rule 10).", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.55, "neoplasm": 0.99 } }, "687806c657684061": { "b": { "tumor_type": "follicular lymphoma grade 3B (FL3B)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q7", "ambiguous": false, "reason": "\"relapsed or refractory ... FL3B\" carries no stage word; the rule that relapsed means advanced is limited to solid tumours, so haematological disease → any (rule 10).", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.51, "neoplasm": 0.99 } }, "a830d9e64f19dc44": { "b": { "tumor_type": "follicular lymphoma (FL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q8", "ambiguous": false, "reason": "\"relapsed or refractory follicular lymphoma\" carries no stage word; the rule that relapsed means advanced is limited to solid tumours, so haematological disease → any (rule 10).", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "any", "from": [ "a", "jev" ] }, { "value": "advanced", "from": [ "b" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.54, "neoplasm": 0.99 } }, "05cea983401ba352": { "b": { "tumor_type": "mantle cell lymphoma (MCL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two lines of systemic therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q9", "ambiguous": false, "reason": "\"relapsed or refractory mantle cell lymphoma\" carries no stage word; the rule that relapsed means advanced is limited to solid tumours, so haematological disease → any (rule 10).", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "4a11eedfc7fc215e": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "89208b8e778eb1b9": { "b": { "tumor_type": "follicular lymphoma (FL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide and rituximab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.46, "neoplasm": 0.99 } }, "12db1df2f8e4d95e": { "b": { "tumor_type": "follicular lymphoma (FL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after two or more lines of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "074864336419e6d9": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "ec0c4a25b1a74cbd": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib and dexamethasone", "prior_therapy": "Received at least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "5cfbae7aaabfbbb7": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ dexamethasone", "prior_therapy": "Received at least four prior therapies; disease refractory to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody; demonstrated disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "6fc9fdb192970048": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ daratumumab and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "bf799d0d58be4fcf": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "4b469c1b49f74e5b": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ dexamethasone alone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.46, "neoplasm": 0.99 } }, "7f7c35bd62c716ba": { "b": { "tumor_type": "RET-mutant medullary thyroid cancer (MTC)", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "RET", "biomarker_alteration_type": "mutation", "biomarker_detail": "mutant", "diagnostic_criterion": "presence of RET mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Aggressive and symptomatic; unresectable", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.33, "neoplasm": 0.99 } }, "1e55d584bbd5a839": { "b": { "tumor_type": "nasopharyngeal carcinoma", "organ": "head-and-neck", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ cisplatin and gemcitabine", "prior_therapy": null, "patient_eligibility": "Recurrent disease not amenable to surgery or radiotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.64, "neoplasm": 0.99 } }, "5ba2dada800818c1": { "b": { "tumor_type": "esophageal squamous cell carcinoma", "organ": "esophagus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ cisplatin and paclitaxel", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.6, "neoplasm": 0.99 } }, "e83d1e8518755976": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ESR1", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutation; ER-positive; HER2-negative", "diagnostic_criterion": "presence of activating ESR1 mutation", "scoring_system": "n/a", "test_method": [ "molecular", "IHC" ], "combination": "monotherapy", "prior_therapy": "Progression following at least one line of endocrine therapy including a CDK 4/6 inhibitor", "patient_eligibility": "Postmenopausal women; men", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.98 } }, "bd235794ccb5ed87": { "b": { "tumor_type": "NTRK fusion-positive solid tumours", "organ": "tumor-agnostic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "NTRK1/NTRK2/NTRK3", "biomarker_alteration_type": "fusion", "biomarker_detail": "NTRK gene fusion", "diagnostic_criterion": "Presence of NTRK gene fusion", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Locally advanced, metastatic or where surgical resection is likely to result in severe morbidity; no satisfactory treatment options", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.48, "neoplasm": 0.98 } }, "6c169a7db7bd3037": { "b": { "tumor_type": "chronic myeloid leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After dasatinib or nilotinib", "patient_eligibility": "Chronic, accelerated, or blast phase; resistant to dasatinib or nilotinib, or intolerant to dasatinib or nilotinib and subsequent treatment with imatinib is not clinically appropriate", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate\". Under rule 14, alternatives within one condition stay one clause in prior_therapy, so the full wording is kept.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "After dasatinib or nilotinib", "from": [ "b" ] }, { "value": "Resistant to dasatinib or nilotinib, or intolerant to dasatinib or nilotinib and subsequent treatment with imatinib is not clinically appropriate", "from": [ "a" ] } ], "value": "Resistant to dasatinib or nilotinib, or intolerant to dasatinib or nilotinib and subsequent treatment with imatinib is not clinically appropriate", "from": [ "a" ] } ], "jev": { "supported": 0.55, "neoplasm": 0.99 } }, "4f30b049ad271c69": { "b": { "tumor_type": "chronic myeloid leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "T315I", "biomarker_alteration_type": "mutation", "biomarker_detail": "T315I", "diagnostic_criterion": "Presence of T315I mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Chronic, accelerated, or blast phase", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"who have the T315I mutation\": T315I is the variant, already in biomarker_detail. biomarker_name takes the uppercase gene symbol (rule 7), which is ABL1.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "ABL1", "from": [ "a" ] }, { "value": "T315I", "from": [ "b" ] } ], "value": "ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.36, "neoplasm": 0.99 } }, "85a28be2c34bc64b": { "b": { "tumor_type": "Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After dasatinib", "patient_eligibility": "Resistant to dasatinib, or intolerant to dasatinib and subsequent treatment with imatinib is not clinically appropriate", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"Philadelphia chromosome positive\" names the BCR::ABL1 translocation, a gene fusion, so the alteration type is fusion.", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "fusion", "from": [ "a", "jev" ] } ], "value": "fusion", "from": [ "a", "jev" ] }, { "q": "q4", "ambiguous": false, "reason": "\"Philadelphia chromosome positive acute lymphoblastic leukaemia\" names the Ph chromosome, i.e. the BCR::ABL1 fusion, as the biomarker. This matches the row's detail and diagnostic_criterion.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "BCR::ABL1", "from": [ "a" ] }, { "value": "none", "from": [ "b" ] } ], "value": "BCR::ABL1", "from": [ "a" ] }, { "q": "q5", "ambiguous": false, "reason": "\"resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate\": per rule 14 the whole condition stays as one clause in prior_therapy.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Resistant to dasatinib, or intolerant to dasatinib and subsequent treatment with imatinib is not clinically appropriate", "from": [ "a" ] }, { "value": "After dasatinib", "from": [ "b" ] } ], "value": "Resistant to dasatinib, or intolerant to dasatinib and subsequent treatment with imatinib is not clinically appropriate", "from": [ "a" ] } ], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "c8305d46225bd232": { "b": { "tumor_type": "Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "T315I", "biomarker_alteration_type": "mutation", "biomarker_detail": "T315I", "diagnostic_criterion": "Presence of T315I mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q6", "ambiguous": false, "reason": "For \"T315I mutation\" the gene symbol is ABL1 (rule 7); the variant T315I belongs in biomarker_detail.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "T315I", "from": [ "b" ] }, { "value": "ABL1", "from": [ "a" ] } ], "value": "ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.44, "neoplasm": 0.99 } }, "e0d51767e86158a4": { "b": { "tumor_type": "Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ reduced-intensity chemotherapy", "prior_therapy": null, "patient_eligibility": "Newly diagnosed", "age_group": "adult" }, "decisions": [ { "q": "q7", "ambiguous": false, "reason": "\"newly diagnosed Ph+ ALL\": Ph+ is the BCR::ABL1 fusion, so the alteration type is fusion.", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "fusion", "from": [ "a", "jev" ] }, { "value": "none", "from": [ "b" ] } ], "value": "fusion", "from": [ "a", "jev" ] }, { "q": "q8", "ambiguous": false, "reason": "\"Ph+ ALL\" names the Philadelphia chromosome (BCR::ABL1) as the gating biomarker.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "BCR::ABL1", "from": [ "a" ] } ], "value": "BCR::ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "f1e94968e936da2c": { "b": { "tumor_type": "chronic myeloid leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After dasatinib or nilotinib", "patient_eligibility": "Pediatric patients aged 6 years or older; chronic phase; resistant to dasatinib or nilotinib, or intolerant to dasatinib or nilotinib and subsequent treatment with imatinib is not clinically appropriate", "age_group": "pediatric" }, "decisions": [ { "q": "q9", "ambiguous": false, "reason": "\"resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate\": per rule 14 the condition is kept whole in one clause.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Resistant to dasatinib or nilotinib, or intolerant to dasatinib or nilotinib and subsequent treatment with imatinib is not clinically appropriate", "from": [ "a" ] }, { "value": "After dasatinib or nilotinib", "from": [ "b" ] } ], "value": "Resistant to dasatinib or nilotinib, or intolerant to dasatinib or nilotinib and subsequent treatment with imatinib is not clinically appropriate", "from": [ "a" ] } ], "jev": { "supported": 0.53, "neoplasm": 0.99 } }, "c21a19d2149ff2ad": { "b": { "tumor_type": "chronic myeloid leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "T315I", "biomarker_alteration_type": "mutation", "biomarker_detail": "T315I", "diagnostic_criterion": "Presence of T315I mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Pediatric patients aged 6 years or older; chronic phase", "age_group": "pediatric" }, "decisions": [ { "q": "q10", "ambiguous": false, "reason": "For \"T315I mutation\" biomarker_name is the gene symbol ABL1 (rule 7), with T315I in biomarker_detail.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "T315I", "from": [ "b" ] }, { "value": "ABL1", "from": [ "a" ] } ], "value": "ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.51, "neoplasm": 0.99 } }, "b064708c05e07a4d": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "KRAS", "biomarker_alteration_type": "mutation", "biomarker_detail": "G12C", "diagnostic_criterion": "presence of KRAS G12C mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "after at least one prior line of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "86ffa9f5f295e558": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600", "diagnostic_criterion": "presence of a BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ binimetinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "941187f62f3e75de": { "b": { "tumor_type": "colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "presence of a BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ cetuximab", "prior_therapy": "after prior systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "35727b5d3f5ecd7f": { "b": { "tumor_type": "colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "presence of a BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ cetuximab and FOLFOX", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "b3629c06056dc3db": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "presence of a BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ binimetinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "d21c03a1a3f7d504": { "b": { "tumor_type": "urothelial carcinoma", "organ": "bladder", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After prior platinum-containing chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "68036066812bdbce": { "b": { "tumor_type": "urothelial carcinoma", "organ": "bladder", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression", "diagnostic_criterion": "PD-L1 expression ≥ 5%", "scoring_system": "IC", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "cisplatin-ineligible", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The cisplatin-ineligible branch (\"who are considered cisplatin ineligible\") gives no line wording. Under rule 14 ineligibility is a patient status, not a prior line, so rule 13's \"no line information\" applies and the value is any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.04, "neoplasm": 0.99 } }, "3479f7085e6d9b6b": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression; EGFR-mutant or ALK-positive NSCLC excluded", "diagnostic_criterion": "TC ≥ 50%", "scoring_system": "TC", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": "Following complete resection and platinum-based chemotherapy", "patient_eligibility": "High risk of recurrence", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": true, "reason": "The sentence itself says only \"following complete resection\", which rule 10 maps to any for adjuvant rows. However, the label heads this indication \"Early-stage non-small cell lung cancer\", which names exactly one category (early); the rules do not say whether a section heading counts.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "early", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "early", "from": [ "a" ] } ], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "14750b1e6421ad00": { "b": { "tumor_type": "metastatic non-squamous NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR/ALK", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "EGFR-mutant or ALK-positive NSCLC excluded", "diagnostic_criterion": "No EGFR mutation or ALK positivity", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ bevacizumab, paclitaxel and carboplatin", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.53, "neoplasm": 0.99 } }, "d280eebb2b4370de": { "b": { "tumor_type": "metastatic non-squamous NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "EGFR-mutant", "diagnostic_criterion": "Presence of an EGFR mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ bevacizumab, paclitaxel and carboplatin", "prior_therapy": "After failure of appropriate targeted therapies", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "db071bc005355a0f": { "b": { "tumor_type": "metastatic non-squamous NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "Presence of an ALK alteration", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ bevacizumab, paclitaxel and carboplatin", "prior_therapy": "After failure of appropriate targeted therapies", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "72f88d296eb9e9c6": { "b": { "tumor_type": "metastatic non-squamous NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR/ALK", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "EGFR-mutant or ALK-positive NSCLC excluded", "diagnostic_criterion": "No EGFR mutation or ALK positivity", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ nab-paclitaxel and carboplatin", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "1bcfec6cc0b2a362": { "b": { "tumor_type": "metastatic NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression; EGFR-mutant or ALK-positive NSCLC excluded", "diagnostic_criterion": "TC ≥ 50% or IC ≥ 10%", "scoring_system": "TC", "test_method": [ "IHC", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "d838fab10faf8569": { "b": { "tumor_type": "advanced NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Ineligible for platinum-based therapy", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "The text says \"indicated for the first-line treatment\", so rule 13 gives 1L; platinum ineligibility is eligibility, not line information.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.65, "neoplasm": 0.99 } }, "18e010451586c6b5": { "b": null, "decisions": [ { "q": "q4", "ambiguous": false, "reason": "\"locally advanced or metastatic NSCLC after prior chemotherapy\" is a distinct 2L monotherapy scenario. r10 covers all patients, with the EGFR/ALK targeted-therapy requirement kept in prior_therapy.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "fd945770ac441599": { "b": { "tumor_type": "extensive-stage small cell lung cancer (ES-SCLC)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and etoposide", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "050505d035e18e46": { "b": { "tumor_type": "triple-negative breast cancer (TNBC)", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PD-L1 expression", "diagnostic_criterion": "PD-L1 expression ≥ 1%", "scoring_system": "IC", "test_method": [ "IHC" ], "combination": "+ nab-paclitaxel", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.1, "neoplasm": 0.99 } }, "e3aa34c660128236": { "b": { "tumor_type": "hepatocellular carcinoma (HCC)", "organ": "liver", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bevacizumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.92, "neoplasm": 0.99 } }, "d90a43cdf00c6fec": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "PSMA", "biomarker_alteration_type": "overexpression", "biomarker_detail": "PSMA-positive", "diagnostic_criterion": "PSMA-positive", "scoring_system": "n/a", "test_method": [], "combination": "+ androgen deprivation therapy (ADT), with or without androgen receptor (AR) pathway inhibition", "prior_therapy": "after treatment with AR pathway inhibition and taxane-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The patients \"have been treated with AR pathway inhibition and taxane-based chemotherapy\", which are two distinct prior systemic therapies. Under rule 13, prior regimens whose setting the label leaves open count as lines, and at least two prior lines gives 3L+; castration resistance itself is a disease state, not a line.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "3L+", "from": [ "a" ] } ], "value": "3L+", "from": [ "a" ] } ], "jev": { "supported": 0.95, "neoplasm": 0.99 } }, "68c83ac42b92a329": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "Exon 19 deletions or Exon 21 L858R substitution mutations", "diagnostic_criterion": "Presence of EGFR Exon 19 deletion or Exon 21 L858R substitution mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ lazertinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "e61a829de4c4dbc7": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "Exon 19 deletions or Exon 21 L858R substitution mutations", "diagnostic_criterion": "Presence of EGFR Exon 19 deletion or Exon 21 L858R substitution mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ carboplatin and pemetrexed", "prior_therapy": "After failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI)", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI)\". Both candidates state this prior therapy correctly, so the choice is only one of wording; the near-verbatim candidate is kept.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "After failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI)", "from": [ "b" ] }, { "value": "After failure of prior therapy including an EGFR TKI", "from": [ "a" ] } ], "value": "After failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI)", "from": [ "b" ] } ], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "64dec14e5b5ef210": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "Activating Exon 20 insertion mutations", "diagnostic_criterion": "Presence of activating EGFR Exon 20 insertion mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ carboplatin and pemetrexed", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "8c2806b1492bd614": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "Activating Exon 20 insertion mutations", "diagnostic_criterion": "Presence of activating EGFR Exon 20 insertion mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After failure of platinum-based therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "ce7d425b59e42efe": { "b": { "tumor_type": "metastatic colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "RAS", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "RAS wild-type; EGFR-expressing", "diagnostic_criterion": "RAS wild-type; EGFR-expressing", "scoring_system": "n/a", "test_method": [ "molecular", "IHC" ], "combination": "+ irinotecan-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "51e7f11d5698f8d1": { "b": { "tumor_type": "metastatic colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "RAS", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "RAS wild-type; EGFR-expressing", "diagnostic_criterion": "RAS wild-type; EGFR-expressing", "scoring_system": "n/a", "test_method": [ "molecular", "IHC" ], "combination": "+ FOLFOX", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.73, "neoplasm": 0.99 } }, "928b49935b9f7100": { "b": { "tumor_type": "metastatic colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "RAS", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "RAS wild-type; EGFR-expressing", "diagnostic_criterion": "RAS wild-type; EGFR-expressing", "scoring_system": "n/a", "test_method": [ "molecular", "IHC" ], "combination": "monotherapy", "prior_therapy": "Failed oxaliplatin- and irinotecan-based therapy", "patient_eligibility": "Intolerant to irinotecan", "age_group": "any" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "\"who have failed oxaliplatin- and irinotecan-based therapy\" most naturally means two failed regimens whose setting the label leaves open, which count as lines under rule 13, giving 3L+. The singular \"therapy\" could also be read as one combined oxaliplatin/irinotecan regimen, which would give only 2L, so a person has to decide.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "3L+", "from": [ "a" ] }, { "value": "2L", "from": [ "b" ] } ], "value": "3L+", "from": [ "a" ] } ], "jev": { "supported": 0.95, "neoplasm": 0.99 } }, "d210baada03a3136": { "b": { "tumor_type": "metastatic colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "Presence of BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ encorafenib and FOLFOX", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "adfeca21a8311bc1": { "b": { "tumor_type": "metastatic colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "Presence of BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ encorafenib", "prior_therapy": "Received prior systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "8b83822b0fe9c186": { "b": { "tumor_type": "squamous cell carcinoma of the head and neck", "organ": "head-and-neck", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ radiation therapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "ed01ec0a82d5349c": { "b": { "tumor_type": "squamous cell carcinoma of the head and neck", "organ": "head-and-neck", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.6, "neoplasm": 0.99 } }, "11410af04cc80b98": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ acalabrutinib with or without obinutuzumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "bf61126e18c63126": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ obinutuzumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "bb10ca524db6b679": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ ibrutinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "cfdcf8b8bc8aeb7e": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "26904f2f306786bd": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "TP53", "biomarker_alteration_type": "mutation", "biomarker_detail": "mutation", "diagnostic_criterion": "presence of TP53 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Unsuitable for or have failed a B-cell receptor pathway inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "1da9ba60b5e5ef81": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "17p/TP53", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "absence of 17p deletion or TP53 mutation", "diagnostic_criterion": "absence of 17p deletion or TP53 mutation", "scoring_system": "n/a", "test_method": [ "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "Failed both chemoimmunotherapy and a B-cell 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Under rule 3, when the absence of several alterations is the main requirement, all of them are named in biomarker_name joined by \"/\".", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "17p/TP53", "from": [ "b" ] }, { "value": "TP53", "from": [ "a" ] } ], "value": "17p/TP53", "from": [ "b" ] } ], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "fadb9dae84fa7dcc": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ hypomethylating agent", "prior_therapy": null, "patient_eligibility": "Ineligible for intensive chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "c54497ed6d5290a4": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pomalidomide and dexamethasone", "prior_therapy": "At least two prior therapies including lenalidomide and a proteasome inhibitor; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "cd98063822320897": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carfilzomib and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "1027014941ab6434": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib, lenalidomide, and dexamethasone", "prior_therapy": null, "patient_eligibility": "Transplant-ineligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "47a765468a13f6e7": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "induction", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib, lenalidomide, and dexamethasone", "prior_therapy": null, "patient_eligibility": "Transplant-eligible", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "edb243f48af17712": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "RET", "biomarker_alteration_type": "fusion", "biomarker_detail": "fusion-positive", "diagnostic_criterion": "presence of RET fusion by validated assay", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "No prior RET inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "5e8c86061c9c8fea": { "b": { "tumor_type": "RET fusion-positive thyroid cancer", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "RET", "biomarker_alteration_type": "fusion", "biomarker_detail": "fusion-positive", "diagnostic_criterion": "presence of RET fusion by validated assay", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Radioactive iodine-refractory (if radioactive iodine is appropriate); aged 2 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "89469527f89e91e1": { "b": { "tumor_type": "medullary thyroid cancer (MTC)", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "RET", "biomarker_alteration_type": "mutation", "biomarker_detail": "mutant", "diagnostic_criterion": "presence of RET mutation by validated assay", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Aged 2 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.54, "neoplasm": 0.99 } }, "8bba369c24d538e3": { "b": { "tumor_type": "RET fusion-positive solid tumours", "organ": "tumor-agnostic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "RET", "biomarker_alteration_type": "fusion", "biomarker_detail": "fusion-positive", "diagnostic_criterion": "presence of RET fusion by validated assay", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Aged 2 years and older; treatment options not targeting RET provide limited clinical benefit or have been exhausted", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "b3bae27c8511772c": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "presence of ALK rearrangement/fusion", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "No prior ALK inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "7f06b382aa69f58c": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "presence of ALK rearrangement/fusion", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "After alectinib or ceritinib as the first ALK TKI therapy; 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The label's \"whose disease has progressed after: alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy; or crizotinib and at least one other ALK TKI\" is reproduced in full, including the progression wording, by the second candidate.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "After alectinib or ceritinib as the first ALK TKI therapy; or after crizotinib and at least one other ALK TKI", "from": [ "b" ] }, { "value": "Disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI", "from": [ "a" ] } ], "value": "Disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI", "from": [ "a" ] } ], "jev": { "supported": 0.83, "neoplasm": 0.98 } }, "e3cde08110b40132": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Adults and adolescents 12 years of age and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "4f8f8b2593d2044d": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ nivolumab", "prior_therapy": null, "patient_eligibility": "Adults and adolescents 12 years of age and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "69d26e9e4641962c": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ nivolumab", "prior_therapy": null, "patient_eligibility": "Intermediate/poor-risk", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "759c4a5f59f3fddd": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR/ALK", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "No sensitising EGFR mutation or ALK translocation", "diagnostic_criterion": "no sensitising EGFR mutation or ALK translocation", "scoring_system": "n/a", "test_method": [ "molecular", "ISH" ], "combination": "+ nivolumab and 2 cycles of platinum-based 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"tumor_type": "oesophageal squamous cell carcinoma", "organ": "esophagus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "Tumour cell PD-L1 expression", "diagnostic_criterion": "tumour cell PD-L1 expression ≥ 1%", "scoring_system": "TPS", "test_method": [ "IHC" ], "combination": "+ nivolumab", "prior_therapy": null, "patient_eligibility": "Unresectable, advanced, recurrent or metastatic disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "7d1c7a2d9fbaa1f7": { "b": { "tumor_type": "hepatocellular carcinoma", "organ": "liver", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ nivolumab", "prior_therapy": null, "patient_eligibility": "Unresectable or advanced disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "6062873be6c42e5a": { "b": { "tumor_type": "urothelial carcinoma", "organ": "bladder", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "FGFR3", "biomarker_alteration_type": "mutation", "biomarker_detail": "susceptible genetic alterations", "diagnostic_criterion": "presence of susceptible FGFR3 genetic alterations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "At least one line of therapy containing a PD-1 or PD-L1 inhibitor in the unresectable or metastatic treatment setting", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "da38d4ba57509211": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ aromatase inhibitor", "prior_therapy": null, "patient_eligibility": "In pre- or perimenopausal women, endocrine therapy should be combined with an LHRH agonist.", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "e69630cf2997dcb4": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ fulvestrant", "prior_therapy": "prior endocrine therapy", "patient_eligibility": "Women; in pre- or perimenopausal women, endocrine therapy should be combined with an LHRH agonist.", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "5756c9f572e0c776": { "b": { "tumor_type": "extensive-stage small cell lung cancer (ES-SCLC)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Following disease progression on or after first-line treatment with platinum-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "66c4906abaa3aa18": { "b": { "tumor_type": "non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumours", "organ": "bladder", "disease_stage": "early", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "BCG-unresponsive", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.43, "neoplasm": 0.98 } }, "4177efc499c07635": { "b": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "After neoadjuvant taxane-based and HER2-targeted therapy", "patient_eligibility": "Residual invasive disease in the breast and/or lymph nodes", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.27, "neoplasm": 0.99 } }, "02cc7176d1221323": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Previously received trastuzumab and a taxane, separately or in combination; prior therapy for locally advanced or metastatic disease, or disease recurrence during or within six months of completing adjuvant therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.26, "neoplasm": 0.99 } }, "a53706e6cefd3c68": { "b": { "tumor_type": "biliary tract cancer", "organ": "biliary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+", "scoring_system": "IHC-score", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "At least one prior line of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "1285bef661380092": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Following autologous stem cell transplantation", "patient_eligibility": "Newly diagnosed", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "2ea90f3a401fe1c4": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ dexamethasone or bortezomib and dexamethasone or melphalan and prednisone", "prior_therapy": null, "patient_eligibility": "Transplant-ineligible; previously untreated", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "be40f318d1624455": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "64cc9ee8196b3937": { "b": { "tumor_type": "myelodysplastic syndromes", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "del(5q)", "biomarker_alteration_type": "loss", "biomarker_detail": "isolated deletion 5q", "diagnostic_criterion": "Isolated deletion 5q cytogenetic abnormality", "scoring_system": "n/a", "test_method": [ "cytogenetics" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Transfusion-dependent anaemia; other therapeutic options insufficient or inadequate; low- or intermediate-1-risk myelodysplastic syndromes", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.73, "neoplasm": 0.98 } }, "ce3635d83956180d": { "b": { "tumor_type": "mantle cell lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Relapsed or refractory", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The text says only \"relapsed or refractory mantle cell lymphoma\". Under rule 10, \"relapsed\" sets advanced only in a solid tumour, and this lymphoma gives no Ann Arbor stage or \"advanced stage\" wording, so the stage is any.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "any", "from": [ "a", "jev" ] }, { "value": "advanced", "from": [ "b" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "d324653731cf37b2": { "b": { "tumor_type": "follicular lymphoma, Grade 1–3a", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab (anti-CD20 antibody)", "prior_therapy": "Previously treated", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "20be1d3a3ac34d81": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "ER", "biomarker_alteration_type": "overexpression", "biomarker_detail": "estrogen receptor positive", "diagnostic_criterion": "estrogen receptor positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "No prior endocrine therapy", "patient_eligibility": "Postmenopausal women", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.99 } }, "4991b3f8b319e68b": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ER", "biomarker_alteration_type": "overexpression", "biomarker_detail": "estrogen receptor positive", "diagnostic_criterion": "estrogen receptor positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Disease relapse on or after adjuvant antiestrogen therapy, or disease progression on antiestrogen therapy", "patient_eligibility": "Postmenopausal women", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.95, "neoplasm": 0.99 } }, "6e6afcfcfa72665b": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HR-positive; HER2-negative", "diagnostic_criterion": "HR-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ palbociclib; in pre- or perimenopausal women, + LHRH agonist", "prior_therapy": "Received prior endocrine therapy", "patient_eligibility": "Women; pre- or perimenopausal women should receive an LHRH agonist with palbociclib", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "00977b078c5f498c": { "b": { "tumor_type": "non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumours", "organ": "bladder", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ BCG", "prior_therapy": null, "patient_eligibility": "BCG-unresponsive", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "\"non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ\" describes disease confined to the mucosa/lamina propria (Tis/Ta/T1). Under rule 10's ESMO convention this is localised, i.e. early. However, rule 10 lists no explicit stage word for NMIBC, and its fallback (\"no stage → any\") could also be argued.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "early", "from": [ "a" ] } ], "value": "early", "from": [ "a" ] } ], "jev": { "supported": 0.44, "neoplasm": 0.98 } }, "94676965c630292e": { "b": { "tumor_type": "high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "following completion of first-line platinum-based chemotherapy", "patient_eligibility": "In complete or partial response", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "92d7492bb2e0ffde": { "b": { "tumor_type": "platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer", "organ": "ovary", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "platinum-based chemotherapy", "patient_eligibility": "In complete or partial response to platinum-based chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "67f3eccb9fbac90c": { "b": { "tumor_type": "post polycythaemia vera myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "No prior JAK inhibitor", "patient_eligibility": "Moderate to severe anaemia; disease-related splenomegaly or symptoms; JAK inhibitor-naïve", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"JAK inhibitor naïve or have been treated with ruxolitinib\". Under rule 1 both prior-therapy routes stay in one row at line \"any\", so prior_therapy must cover both branches. \"No prior JAK inhibitor\" would narrow the row to one branch.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "No prior JAK inhibitor", "from": [ "b" ] }, { "value": "Janus Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib", "from": [ "a" ] } ], "value": "Janus Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib", "from": [ "a" ] } ], "jev": { "supported": 0.39, "neoplasm": 0.98 } }, "e5c3447228a83d04": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "first-line chemoimmunotherapy", "patient_eligibility": "Relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.42, "neoplasm": 0.99 } }, "57ca4248e04a91db": { "b": { "tumor_type": "high-grade B-cell lymphoma (HGBL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "first-line chemoimmunotherapy", "patient_eligibility": "Relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "5fc513464e4e1a21": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "two or more lines of systemic therapy", "patient_eligibility": "Relapsed or refractory (r/r)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.39, "neoplasm": 0.99 } }, "b52f32b4897d4f3f": { "b": { "tumor_type": "primary mediastinal large B-cell lymphoma (PMBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "two or more lines of systemic therapy", "patient_eligibility": "Relapsed or refractory (r/r)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.53, "neoplasm": 0.99 } }, "eedbe18349370c6e": { "b": { "tumor_type": "follicular lymphoma (FL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "three or more lines of systemic therapy", "patient_eligibility": "Relapsed or refractory (r/r)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.53, "neoplasm": 0.99 } }, "d42c65e85a6cfc6c": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "ALK-positive", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "complete tumour resection", "patient_eligibility": "High risk of recurrence", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.99 } }, "228f7a6481052e0c": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "ALK-positive", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.73, "neoplasm": 0.99 } }, "e8c56f903dd5a751": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "ALK-positive", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "crizotinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "a649097104ff9d48": { "b": { "tumor_type": "cervical cancer", "organ": "cervix", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After systemic therapy, with disease progression on or after treatment", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "ad412094b3fc2eb8": { "b": { "tumor_type": "extensive-stage small cell lung cancer (ES-SCLC)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ atezolizumab", "prior_therapy": "first-line induction therapy with atezolizumab, carboplatin and etoposide", "patient_eligibility": "Disease has not progressed after first-line induction therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.75, "neoplasm": 0.99 } }, "2a2538659d47ea1a": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "Presence of a BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable or metastatic melanoma; adults and adolescents aged 12 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "3c07bcc1da93c164": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "Presence of a BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ dabrafenib", "prior_therapy": null, "patient_eligibility": "Unresectable or metastatic melanoma; adults and adolescents aged 12 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.57, "neoplasm": 0.99 } }, "592fc910345ff454": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "locally-advanced", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "Presence of a BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ dabrafenib", "prior_therapy": null, "patient_eligibility": "Stage III melanoma; following complete resection; adults and adolescents aged 12 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "16a2ed1efa0c81c8": { "b": { "tumor_type": "non-small cell lung cancer (NSCLC)", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "Presence of a BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ dabrafenib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.6, "neoplasm": 0.99 } }, "60abda0d5819f3e4": { "b": { "tumor_type": "differentiated thyroid cancer", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "Presence of a BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ dabrafenib", "prior_therapy": "Progressed during or after prior systemic therapy", "patient_eligibility": "Refractory to or not eligible for radioactive iodine (RAI)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "7bff74550c696b1a": { "b": { "tumor_type": "low-grade glioma", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ dabrafenib", "prior_therapy": null, "patient_eligibility": "Aged 1 year and older; requires systemic therapy", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.98 } }, "a7260396525685f4": { "b": { "tumor_type": "high-grade glioma", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ dabrafenib", "prior_therapy": "At least one prior radiation and/or chemotherapy treatment", "patient_eligibility": "Aged 1 year and older", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.98, "neoplasm": 0.99 } }, "bebfa56a09b8a9ff": { "b": { "tumor_type": "mantle cell lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After two or more lines of systemic therapy, including a BTK inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.48, "neoplasm": 0.99 } }, "f797978f83e2bd85": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "26 years of age and above", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.32, "neoplasm": 0.99 } }, "4af78ed1a463ec4d": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "84215500abc20b1b": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ trametinib", "prior_therapy": null, "patient_eligibility": "Unresectable", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.64, "neoplasm": 0.99 } }, "f576c88855c4d721": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "locally-advanced", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ trametinib", "prior_therapy": "Complete resection", "patient_eligibility": "Stage III; following complete resection", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.97, "neoplasm": 0.99 } }, "e39aff22f2478cf0": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600 mutation", "diagnostic_criterion": "BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ trametinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "253a82648c6482cf": { "b": { "tumor_type": "differentiated thyroid cancer", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ trametinib", "prior_therapy": "Progressed during or after prior systemic therapy", "patient_eligibility": "Refractory to or not eligible for radioactive iodine (RAI)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.93, "neoplasm": 0.99 } }, "2fd5b8d49a1e4c8f": { "b": { "tumor_type": "low-grade glioma", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "presence of BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ trametinib", "prior_therapy": null, "patient_eligibility": "Require systemic therapy; aged 1 year and older", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.98 } }, "d941077c42c56cca": { "b": { "tumor_type": "high-grade glioma", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "presence of BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ trametinib", "prior_therapy": "At least one prior radiation and/or chemotherapy treatment", "patient_eligibility": "Aged 1 year and older", "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.98, "neoplasm": 0.99 } }, "d603c2c5126abe1a": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "CD22", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD22-positive", "diagnostic_criterion": "CD22-positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": "Relapsed or refractory disease; for Ph+ disease, failed treatment with at least 1 TKI", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 10 sets leukaemias to \"any\" unless the text uses a stage word. \"Relapsed or refractory\" maps to advanced only in a solid tumour, so this ALL row stays any.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "b" ] }, { "value": "any", "from": [ "a", "jev" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "f8d8dca9bd94dc73": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (ALL)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "CD22", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD22-positive", "diagnostic_criterion": "CD22-positive", "scoring_system": "n/a", "test_method": [ "flow-cytometry" ], "combination": "monotherapy", "prior_therapy": "First relapse after allo-HSCT; first relapse in VHR disease; second or greater relapse; or refractory disease. Ph+ disease requires exhaustion of relevant BCR-ABL targeting treatment options.", "patient_eligibility": "Aged 1 year and older; Very High Risk (VHR) disease for the first-relapse branch", "age_group": "pediatric" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "Under rule 10, leukaemias without stage wording are \"any\". \"In first relapse\" and \"refractory disease\" in paediatric ALL are line descriptors, not stage words, since the relapsed-equals-advanced mapping applies only to solid tumours.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "any", "from": [ "a", "jev" ] }, { "value": "advanced", "from": [ "b" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.95, "neoplasm": 0.99 } }, "a9c1e9e52a4a8a88": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating EGFR mutation(s)", "diagnostic_criterion": "presence of activating EGFR mutation(s)", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "No prior EGFR TKI", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.9, "neoplasm": 0.99 } }, "3f6efe10149958fc": { "b": { "tumor_type": "squamous NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after platinum-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "236e27469c17ba5b": { "b": { "tumor_type": "paediatric low-grade glioma (LGG)", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRAF", "biomarker_alteration_type": "fusion", "biomarker_detail": "fusion or rearrangement", "diagnostic_criterion": "presence of BRAF fusion or rearrangement", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Progressed after one or more prior systemic therapies", "patient_eligibility": "Aged 6 months and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.98 } }, "e2e1117501ca02a0": { "b": { "tumor_type": "paediatric low-grade glioma (LGG)", "organ": "CNS", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600", "diagnostic_criterion": "presence of BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Progressed after one or more prior systemic therapies", "patient_eligibility": "Aged 6 months and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.96, "neoplasm": 0.98 } }, "bcce27fd7845c4ad": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "PIK3CA", "biomarker_alteration_type": "mutation", "biomarker_detail": "PIK3CA-mutated; ER-positive; HER2-negative", "diagnostic_criterion": "PIK3CA mutation; ER-positive; HER2-negative", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "+ palbociclib and fulvestrant", "prior_therapy": "Adjuvant endocrine treatment; recurrence on or within 12 months of completing treatment", "patient_eligibility": "If previously treated with a CDK4/6 inhibitor in the (neo)adjuvant setting, at least 12 months between termination of CDK4/6 inhibitor treatment and detection of recurrence; in pre/perimenopausal women and men, endocrine therapy should be combined with an LHRH agonist", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The row treats \"locally advanced or metastatic breast cancer, following recurrence on or within 12 months of completing adjuvant endocrine treatment\". Here adjuvant therapy is the prior therapy, not the phase in which Itovebi is given, so under rule 11 the phase is null (none).", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": null, "from": [ "a", "b" ] }, { "value": "adjuvant", "from": [ "jev" ] } ], "value": null, "from": [ "a", "b" ] } ], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "1028b2df1b990efa": { "b": { "tumor_type": "EpCAM-positive carcinomas", "organ": "other", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "EpCAM", "biomarker_alteration_type": "overexpression", "biomarker_detail": "EpCAM-positive", "diagnostic_criterion": "EpCAM-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not eligible for further systemic anticancer therapy", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "The label names \"EpCAM-positive carcinomas\" with no organ, but it does not say \"solid tumours regardless of histology\", which rule 4 requires for tumor-agnostic. Whether a cross-organ \"carcinomas\" counts as the \"or equivalent\" wording is left open.", "kind": "field", "field": "organ", "candidates": [ { "value": "other", "from": [ "b" ] }, { "value": "tumor-agnostic", "from": [ "a" ] } ], "value": "tumor-agnostic", "from": [ "a" ], "suggested": "other" }, { "q": "q2", "ambiguous": false, "reason": "No stage word is used. \"Malignant ascites\" implies peritoneal spread, but rule 10 says \"If the text gives no stage, use 'any' — do NOT guess.\"", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "advanced", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] }, { "q": "q3", "ambiguous": true, "reason": "\"Not eligible for further systemic anticancer therapy\" implies earlier treatment but is worded as an eligibility status and never names a prior line. Whether \"further\" guarantees one prior line (2L) or sets no line (any) is open under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "a" ] }, { "value": "any", "from": [ "b", "jev" ] } ], "value": "2L", "from": [ "a" ], "suggested": "any" }, { "q": "q4", "ambiguous": false, "reason": "\"EpCAM-positive\" is a categorical status with no numeric score or threshold, so rule 5a gives n/a.", "kind": "field", "field": "scoring_system", "candidates": [ { "value": "n/a", "from": [ "b", "jev" ] }, { "value": "other", "from": [ "a" ] } ], "value": "n/a", "from": [ "b", "jev" ] }, { "q": "q5", "ambiguous": false, "reason": "The tumour entity is \"EpCAM-positive carcinomas\". Malignant ascites is already recorded in patient_eligibility, so \"carcinoma\" is correct.", "kind": "field", "field": "tumor_type", "candidates": [ { "value": "carcinoma", "from": [ "a", "b" ] } ], "value": "carcinoma", "from": [ "a", "b" ] } ], "jev": { "supported": 0.24, "neoplasm": 0.97 } }, "9c5ef84aabf310c2": { "b": { "tumor_type": "ER-positive, HER2-negative breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "PIK3CA/AKT1/PTEN", "biomarker_alteration_type": "mutation", "biomarker_detail": "One or more alterations; ER-positive; HER2-negative", "diagnostic_criterion": "One or more PIK3CA/AKT1/PTEN alterations", "scoring_system": "n/a", "test_method": [ "molecular", "IHC", "ISH" ], "combination": "+ fulvestrant", "prior_therapy": "Following recurrence or progression on or after an endocrine-based regimen", "patient_eligibility": "Pre- or perimenopausal women: combine with LHRH agonist; men: consider LHRH agonist according to current clinical practice standards", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "5f31e146bf4afdfb": { "b": { "tumor_type": "non-metastatic castration-resistant prostate cancer (nmCRPC)", "organ": "prostate", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Men; high risk of developing metastatic disease", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says only \"treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease\". Under rule 13, castration resistance is a disease state, not a prior line, and no wording such as \"first-line\" or \"before chemotherapy\" fixes the line, so it is \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.35, "neoplasm": 0.99 } }, "f2bce8ad6f8b2e58": { "b": { "tumor_type": "hormone-sensitive prostate cancer (mHSPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ androgen deprivation therapy (ADT)", "prior_therapy": null, "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy\" gives no line wording such as \"first-line\" or \"previously untreated\". Rule 13 says \"If no line information at all → any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "b42cfed85ec114f7": { "b": { "tumor_type": "hepatocellular carcinoma", "organ": "liver", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.41, "neoplasm": 0.99 } }, "bc17a16e222c0596": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Failed prior interferon-alpha or interleukin-2 based therapy, or considered unsuitable for such therapy", "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "ed85b39076036bc2": { "b": { "tumor_type": "differentiated thyroid carcinoma (papillary/follicular/Hürthle cell)", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Progressive; refractory to radioactive iodine", "age_group": "any" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says only \"refractory to radioactive iodine\", which under rule 13 is a disease state, not a prior line. It never states \"no prior systemic therapy\", so no line information remains and the row defaults to \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.33, "neoplasm": 0.99 } }, "56f8396570aa0c25": { "b": { "tumor_type": "renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pembrolizumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "3333eba65e2ab982": { "b": { "tumor_type": "renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ everolimus", "prior_therapy": "Following one prior VEGF-targeted therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.75, "neoplasm": 0.99 } }, "d0267aed7f8a0441": { "b": { "tumor_type": "Differentiated thyroid carcinoma (papillary/follicular/Hürthle cell)", "organ": "thyroid", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The DTC text says only \"refractory to radioactive iodine (RAI)\" and gives no prior systemic therapy. Under rule 13, RAI refractoriness is a disease state, not a line, so with no line information the value is any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "46b412e31847c265": { "b": { "tumor_type": "Hepatocellular carcinoma", "organ": "liver", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.45, "neoplasm": 0.99 } }, "568cedaca955b0df": { "b": { "tumor_type": "Endometrial carcinoma", "organ": "uterus", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pembrolizumab", "prior_therapy": "After prior treatment with a platinum-containing therapy in any setting", "patient_eligibility": "Not candidates for curative surgery or radiation", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"prior treatment with a platinum-containing therapy in any setting\" may have been neoadjuvant or adjuvant. Rule 13 says a prior regimen \"in any setting\" → any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "any", "from": [ "a" ] } ], "value": "any", "from": [ "a" ] } ], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "3fa00bf15dc19734": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least 1 prior therapy", "patient_eligibility": "Already undergone or unsuitable for haematopoietic stem cell transplantation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "4bddae37e01d7ed2": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pegylated liposomal doxorubicin or dexamethasone", "prior_therapy": "At least 1 prior therapy", "patient_eligibility": "Already undergone or unsuitable for haematopoietic stem cell transplantation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "6f2d91e57eb60deb": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ melphalan and prednisone", "prior_therapy": null, "patient_eligibility": "Not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.73, "neoplasm": 0.99 } }, "ffb155e2189f3191": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "induction", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ dexamethasone or dexamethasone and thalidomide", "prior_therapy": null, "patient_eligibility": "Eligible for high-dose chemotherapy with haematopoietic stem cell transplantation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "e6380c0d6629dace": { "b": { "tumor_type": "mantle cell lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab, cyclophosphamide, doxorubicin and prednisone", "prior_therapy": null, "patient_eligibility": "Unsuitable for haematopoietic stem cell transplantation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "065cea8d797fb7da": { "b": { "tumor_type": "metastatic colorectal cancer (CRC)", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Previously treated with, or not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "440bf9476bfb506a": { "b": { "tumor_type": "gastrointestinal stromal tumour (GIST)", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Progressed on or intolerant to prior treatment with imatinib and sunitinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.98 } }, "efa849e1653054d6": { "b": { "tumor_type": "hepatocellular carcinoma (HCC)", "organ": "liver", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Previously treated with sorafenib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "ff5ed26e23cff96e": { "b": { "tumor_type": "squamous cell carcinoma of the anal canal (SCAC)", "organ": "other", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ carboplatin and paclitaxel", "prior_therapy": null, "patient_eligibility": "Inoperable locally recurrent disease", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The row is \"squamous cell carcinoma of the anal canal\". The organ definition for colorectal covers only \"colon, rectal, colorectal cancer\", and anal canal SCC is a distinct entity that no listed organ covers, so it falls under \"other\".", "kind": "field", "field": "organ", "candidates": [ { "value": "other", "from": [ "b" ] }, { "value": "colorectal", "from": [ "a" ] } ], "value": "other", "from": [ "b" ] } ], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "39f8aedcd5888bb4": { "b": { "tumor_type": "Merkel cell carcinoma (MCC)", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not amenable to curative surgery or radiation therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "e9bb5ce179722648": { "b": { "tumor_type": "Hodgkin lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD30", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD30-positive", "diagnostic_criterion": "CD30-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ doxorubicin, vinblastine and dacarbazine (AVD)", "prior_therapy": null, "patient_eligibility": "Stage III or IV", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "2cb412eb791b9c6c": { "b": { "tumor_type": "Hodgkin lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD30", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD30-positive", "diagnostic_criterion": "CD30-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "+ etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (BrECADD)", "prior_therapy": null, "patient_eligibility": "Stage IIB with risk factors, Stage III or Stage IV", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 1 } }, "f1f04714666003bf": { "b": { "tumor_type": "Hodgkin lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "consolidation", "line_of_therapy": "2L", "biomarker_name": "CD30", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD30-positive", "diagnostic_criterion": "CD30-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Following autologous stem cell transplant (ASCT)", "patient_eligibility": "Increased risk of relapse or progression", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": true, "reason": "The label says only \"at increased risk of relapse or progression following autologous stem cell transplant\" and never uses the word consolidation, while rule 11 says to set a phase only when the text names it. However, rule 11 itself gives \"brentuximab post-ASCT in Hodgkin lymphoma\" as its consolidation example, so the rules conflict and a person has to decide.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": "consolidation", "from": [ "a", "b" ] }, { "value": null, "from": [ "jev" ] } ], "value": "consolidation", "from": [ "a", "b" ] } ], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "6be3dc07f0089939": { "b": { "tumor_type": "Hodgkin lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "CD30", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD30-positive", "diagnostic_criterion": "CD30-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "Following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"Relapsed or refractory CD30+ Hodgkin lymphoma\" gives no Ann Arbor stage, and \"relapsed\" maps to advanced only in solid tumours. Rule 10 sets haematological malignancies to any unless stage words are used.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "any", "from": [ "a", "jev" ] }, { "value": "advanced", "from": [ "b" ] } ], "value": "any", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "2836f3a9c74b230a": { "b": { "tumor_type": "systemic anaplastic large cell lymphoma (sALCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ cyclophosphamide, doxorubicin and prednisone (CHP)", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.19, "neoplasm": 0.99 } }, "9d5d91cc1958ecc0": { "b": { "tumor_type": "systemic anaplastic large cell lymphoma (sALCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Relapsed or refractory disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.26, "neoplasm": 0.99 } }, "e99157477b3642a9": { "b": { "tumor_type": "cutaneous T-cell lymphoma (CTCL)", "organ": "skin", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "CD30", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD30-positive", "diagnostic_criterion": "CD30-positive", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": "After at least 1 prior systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"cutaneous T-cell lymphoma\" is a lymphoma, which falls under organ=hematologic. The skin category covers melanoma and skin carcinomas, not lymphomas.", "kind": "field", "field": "organ", "candidates": [ { "value": "skin", "from": [ "b" ] }, { "value": "hematologic", "from": [ "a" ] } ], "value": "hematologic", "from": [ "a" ] } ], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "d159d6ff4b4f5648": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chlorambucil", "prior_therapy": null, "patient_eligibility": "Comorbidities making them unsuitable for full-dose fludarabine based therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.63, "neoplasm": 0.99 } }, "28dec7b0ddd98e03": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Previously untreated", "age_group": "any" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 12a: \"in combination with chemotherapy followed by Gazyvaro maintenance\" splits into a first-phase row and a maintenance row. The text does not say \"induction\", so Row A (r2) takes treatment_phase none; r3 is the maintenance row.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": null, "from": [ "a", "b" ] }, { "value": "maintenance", "from": [ "jev" ] } ], "value": null, "from": [ "a", "b" ] } ], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "22f001464288f55f": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Gazyvaro + chemotherapy without progression", "patient_eligibility": "Previously untreated; achieving a response", "age_group": "any" }, "decisions": [], "jev": { "supported": 0.06, "neoplasm": 0.99 } }, "8d124eaa84782621": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bendamustine", "prior_therapy": "After rituximab or a rituximab-containing regimen; did not respond or progressed during or up to 6 months after treatment", "patient_eligibility": null, "age_group": "any" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "Rule 12a applies to \"in combination with bendamustine followed by Gazyvaro maintenance\" as well. The first-phase row r4 has no phase word and so takes none; maintenance is covered by r5.", "kind": "field", "field": "treatment_phase", "candidates": [ { "value": null, "from": [ "a", "b" ] }, { "value": "maintenance", "from": [ "jev" ] } ], "value": null, "from": [ "a", "b" ] } ], "jev": { "supported": 0.82, "neoplasm": 0.99 } }, "1e60e635127e1199": { "b": { "tumor_type": "follicular lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "maintenance", "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After rituximab or a rituximab-containing regimen; Gazyvaro + bendamustine without progression", "patient_eligibility": "Did not respond or progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen", "age_group": "any" }, "decisions": [], "jev": { "supported": 0.03, "neoplasm": 0.99 } }, "4bea7fa93a70a7e1": { "b": { "tumor_type": "cholangiocarcinoma", "organ": "biliary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "FGFR2", "biomarker_alteration_type": "fusion", "biomarker_detail": "fusion or rearrangement", "diagnostic_criterion": "presence of FGFR2 fusion or rearrangement", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After at least one prior line of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "a277d788858f1698": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "IDH1", "biomarker_alteration_type": "mutation", "biomarker_detail": "R132", "diagnostic_criterion": "presence of an IDH1 R132 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ azacitidine", "prior_therapy": null, "patient_eligibility": "Not eligible to receive standard induction chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "748a3dfc91e07785": { "b": { "tumor_type": "cholangiocarcinoma", "organ": "biliary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "IDH1", "biomarker_alteration_type": "mutation", "biomarker_detail": "R132", "diagnostic_criterion": "presence of an IDH1 R132 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "At least one prior line of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "d940ff77a859802c": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ESR1", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating ESR1 mutation; ER-positive; HER2-negative", "diagnostic_criterion": "presence of an activating ESR1 mutation", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "After disease progression following prior treatment with an endocrine based regimen", "patient_eligibility": "Not pre- or perimenopausal women or men (these patients should receive an LHRH agonist combination)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "eff2831f6a456c80": { "b": { "tumor_type": "hepatocellular carcinoma (HCC)", "organ": "liver", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ durvalumab", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "18d405e2d4d7eb85": { "b": { "tumor_type": "non-small cell lung cancer (NSCLC)", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR/ALK", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "No sensitising EGFR mutations or ALK-positive mutations", "diagnostic_criterion": "Absence of sensitising EGFR mutations and ALK-positive mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ durvalumab and platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "1325110e16c9c648": { "b": { "tumor_type": "tenosynovial giant cell tumor", "organ": "soft-tissue", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Symptomatic; clinically relevant physical function deterioration; surgical options exhausted or surgery would induce unacceptable morbidity or disability", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.4, "neoplasm": 0.87 } }, "4f3e2dd327080cdc": { "b": { "tumor_type": "chronic myelogenous leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label names \"Philadelphia chromosome positive (Ph+)\", which is the BCR::ABL1 fusion. This matches the other Ph+ rows.", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "fusion", "from": [ "a", "jev" ] } ], "value": "fusion", "from": [ "a", "jev" ] }, { "q": "q2", "ambiguous": false, "reason": "\"Philadelphia chromosome positive (Ph+)\" refers to the BCR::ABL1 rearrangement, so the biomarker name is the fusion, consistent with r3 and r5–r7.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "BCR::ABL1", "from": [ "a" ] }, { "value": "none", "from": [ "b" ] } ], "value": "BCR::ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.41, "neoplasm": 0.99 } }, "218ca8b70974cba4": { "b": { "tumor_type": "chronic myelogenous leukaemia (CML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Resistance or intolerance to prior therapy including imatinib", "patient_eligibility": "Chronic, accelerated or blast phase", "age_group": "adult" }, "decisions": [ { "q": "q3", "ambiguous": true, "reason": "This bullet says only \"chronic, accelerated or blast phase CML\" without restating Ph+. CML is defined by BCR::ABL1, and the row already carries Ph+, so fusion fits; whether an unstated defining biomarker should be recorded is left open under rule 2.", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "fusion", "from": [ "a", "jev" ] }, { "value": "none", "from": [ "b" ] } ], "value": "fusion", "from": [ "a", "jev" ] }, { "q": "q4", "ambiguous": true, "reason": "As for q3: CML implies BCR::ABL1 and the row's detail is Ph+, but the bullet does not name Ph+ explicitly.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "BCR::ABL1", "from": [ "a" ] } ], "value": "BCR::ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "653341d59e00a6ab": { "b": { "tumor_type": "Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "monotherapy", "prior_therapy": "Resistance or intolerance to prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "2af0283923a3a348": { "b": { "tumor_type": "lymphoid blast CML", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Resistance or intolerance to prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q5", "ambiguous": false, "reason": "In \"Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML\", the Ph+ qualifier applies to a disease defined by BCR::ABL1, so the alteration type is fusion.", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "fusion", "from": [ "a", "jev" ] } ], "value": "fusion", "from": [ "a", "jev" ] }, { "q": "q6", "ambiguous": false, "reason": "Ph+ lymphoid blast CML corresponds to the BCR::ABL1 fusion.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "BCR::ABL1", "from": [ "a" ] } ], "value": "BCR::ABL1", "from": [ "a" ] } ], "jev": { "supported": 0.27, "neoplasm": 0.99 } }, "fb3fc53cf51b6304": { "b": { "tumor_type": "Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML) in chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "monotherapy", "prior_therapy": "Resistance or intolerance to prior therapy including imatinib", "patient_eligibility": null, "age_group": "pediatric" }, "decisions": [ { "q": "q7", "ambiguous": false, "reason": "The paediatric sentence pairs \"newly diagnosed Ph+ CML-CP\" with a \"resistant or intolerant\" branch. Row r6 covers the pretreated branch, so r5 is the untreated branch: 1L under rules 1 and 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "1L", "from": [ "a" ] }, { "q": "q8", "ambiguous": false, "reason": "r5 is the \"newly diagnosed\" branch, so no prior therapy applies; the resistance branch is carried by r6.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "Resistance or intolerance to prior therapy including imatinib", "from": [ "b" ] }, { "value": null, "from": [ "a" ] } ], "value": null, "from": [ "a" ] } ], "jev": { "supported": 0.21, "neoplasm": 0.99 } }, "2a05933564da8e75": { "b": null, "decisions": [ { "q": "q9", "ambiguous": false, "reason": "\"Ph+ CML-CP resistant or intolerant to prior therapy including imatinib\" is a pretreated branch that rule 1 requires to be split from the newly diagnosed branch.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.38, "neoplasm": 0.99 } }, "efafe1b95e2b0420": { "b": { "tumor_type": "Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "015f6471f379a779": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "Presence of ALK fusion", "scoring_system": "n/a", "test_method": [ "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.56, "neoplasm": 0.99 } }, "4cf33271c37c0b80": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "Presence of ALK fusion", "scoring_system": "n/a", "test_method": [ "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "Previously treated with crizotinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "589fb3c704983c7e": { "b": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide", "prior_therapy": null, "patient_eligibility": "Not eligible for autologous stem cell transplant (ASCT)", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.59, "neoplasm": 0.99 } }, "9eed9048fb569fca": { "b": { "tumor_type": "follicular lymphoma (FL), Grade 1-3a", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide + rituximab", "prior_therapy": "After at least one line of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "d3c25ee056d2a6b4": { "b": { "tumor_type": "basal cell carcinoma", "organ": "skin", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Symptomatic", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Row r1 covers the branch \"symptomatic metastatic basal cell carcinoma\", which is a separate list item with no \"advanced\" umbrella wording. Under rule 10 (\"Metastatic X\" → metastatic), this row is metastatic; the locally advanced branch is already covered by r2.", "kind": "field", "field": "disease_stage", "candidates": [ { "value": "metastatic", "from": [ "a", "b" ] }, { "value": "advanced", "from": [ "jev" ] } ], "value": "metastatic", "from": [ "a", "b" ] } ], "jev": { "supported": 0.32, "neoplasm": 0.99 } }, "c0cd29d222a02136": { "b": { "tumor_type": "basal cell carcinoma", "organ": "skin", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Inappropriate for surgery or radiotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.33, "neoplasm": 0.99 } }, "6d24b7fb7c08214a": { "b": { "tumor_type": "cutaneous squamous cell carcinoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not a candidate for curative surgery or curative radiation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.99 } }, "2522ad9e7006e2d8": { "b": { "tumor_type": "cutaneous squamous cell carcinoma", "organ": "skin", "disease_stage": "any", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after surgery and radiation", "patient_eligibility": "High risk of recurrence", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.87, "neoplasm": 0.99 } }, "304088f20dd4ba5d": { "b": { "tumor_type": "basal cell carcinoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Progressed on or intolerant to a hedgehog pathway inhibitor (HHI)", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "1524dbdade55f851": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "≥ 50% tumour cells; no EGFR, ALK or ROS1 aberrations", "diagnostic_criterion": "PD-L1 expression in ≥ 50% tumour cells", "scoring_system": "TPS", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "For locally advanced NSCLC: not a candidate for definitive chemoradiation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "49cf1181bf364b49": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "PD-L1", "biomarker_alteration_type": "overexpression", "biomarker_detail": "≥ 1% of tumour cells; no EGFR, ALK or ROS1 aberrations", "diagnostic_criterion": "PD-L1 expression in ≥ 1% of tumour cells", "scoring_system": "TPS", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "+ platinum-based chemotherapy", "prior_therapy": null, "patient_eligibility": "For locally advanced NSCLC: not a candidate for definitive chemoradiation", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.54, "neoplasm": 0.99 } }, "bd31449d2fe57c30": { "b": { "tumor_type": "cervical cancer", "organ": "cervix", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after platinum-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.8, "neoplasm": 0.99 } }, "b9957787f92efd8e": { "b": { "tumor_type": "basal cell carcinoma", "organ": "skin", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not amenable to curative surgery or radiation therapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.5, "neoplasm": 0.99 } }, "d6d30d214f344983": { "b": { "tumor_type": "metastatic hormone-sensitive prostate cancer (mHSPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ prednisone or prednisolone + androgen deprivation therapy (ADT)", "prior_therapy": null, "patient_eligibility": "Men; high risk", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.67, "neoplasm": 0.99 } }, "c3f24efb752a5834": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ prednisone or prednisolone", "prior_therapy": "after failure of androgen deprivation therapy", "patient_eligibility": "Men; asymptomatic or mildly symptomatic; chemotherapy not yet clinically indicated", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "0f5e2fbba3c2700e": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ prednisone or prednisolone", "prior_therapy": "after progression on or after a docetaxel-based chemotherapy regimen", "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "932271ef2d28aed3": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "75b1f6c53166b3f5": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3 mutation", "diagnostic_criterion": "presence of a FLT3 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.84, "neoplasm": 0.99 } }, "ff3c7e3badb506cc": { "b": { "tumor_type": "gastric cancer or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ paclitaxel", "prior_therapy": "After prior platinum and fluoropyrimidine chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.86, "neoplasm": 0.99 } }, "a0e8114f48c82ea2": { "b": { "tumor_type": "gastric cancer or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "After prior platinum or fluoropyrimidine chemotherapy", "patient_eligibility": "Treatment in combination with paclitaxel is not appropriate", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.94, "neoplasm": 0.99 } }, "ab5db4cfc5383db5": { "b": { "tumor_type": "metastatic colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil)", "prior_therapy": "Progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.88, "neoplasm": 0.99 } }, "6fef2f02d5dc047f": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutation", "diagnostic_criterion": "Presence of activating EGFR mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ erlotinib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.68, "neoplasm": 0.99 } }, "64c0ae460e577b60": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ docetaxel", "prior_therapy": "After platinum-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "e96f6fe24ad4b96b": { "b": { "tumor_type": "hepatocellular carcinoma", "organ": "liver", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "AFP", "biomarker_alteration_type": "overexpression", "biomarker_detail": "serum alpha fetoprotein (AFP)", "diagnostic_criterion": "serum alpha fetoprotein (AFP) of ≥ 400 ng/ml", "scoring_system": "other", "test_method": [], "combination": "monotherapy", "prior_therapy": "Previously treated with sorafenib", "patient_eligibility": "Advanced or unresectable hepatocellular carcinoma", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.75, "neoplasm": 0.99 } }, "1286734ed88d3367": { "b": { "tumor_type": "metastatic hormone-sensitive prostate cancer (mHSPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ prednisone or prednisolone + androgen deprivation therapy (ADT)", "prior_therapy": null, "patient_eligibility": "High risk; men", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "c11594da84ccbbff": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ prednisone or prednisolone", "prior_therapy": "After failure of androgen deprivation therapy", "patient_eligibility": "Men; asymptomatic or mildly symptomatic; chemotherapy not yet clinically indicated", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "0f22cedd4ab60249": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ prednisone or prednisolone", "prior_therapy": "After a docetaxel-based chemotherapy regimen", "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.64, "neoplasm": 0.99 } }, "4ea6c98af2562dbc": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "induction", "line_of_therapy": "1L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3 mutation-positive", "diagnostic_criterion": "presence of FLT3 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ standard daunorubicin and cytarabine induction", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "c903fad7b5f1e402": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "consolidation", "line_of_therapy": "1L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3 mutation-positive", "diagnostic_criterion": "presence of FLT3 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ high-dose cytarabine consolidation chemotherapy", "prior_therapy": "standard daunorubicin and cytarabine induction", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The consolidation phase is \"high-dose cytarabine consolidation chemotherapy\". The phase is already in treatment_phase, and r1 writes its partner without the phase word (\"+ standard daunorubicin and cytarabine\"), so the matching form is \"+ high-dose cytarabine\".", "kind": "field", "field": "combination", "candidates": [ { "value": "+ high-dose cytarabine consolidation chemotherapy", "from": [ "b" ] }, { "value": "+ high-dose cytarabine", "from": [ "a" ] } ], "value": "+ high-dose cytarabine", "from": [ "a" ] }, { "q": "q2", "ambiguous": false, "reason": "Consolidation follows \"standard daunorubicin and cytarabine induction ... chemotherapy\", so prior_therapy names the induction regimen. This wording matches the style of r3's prior_therapy.", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": "standard daunorubicin and cytarabine induction chemotherapy", "from": [ "a" ] }, { "value": "standard daunorubicin and cytarabine induction", "from": [ "b" ] } ], "value": "standard daunorubicin and cytarabine induction chemotherapy", "from": [ "a" ] } ], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "35f2af4d7f890ce9": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "FLT3", "biomarker_alteration_type": "mutation", "biomarker_detail": "FLT3 mutation-positive", "diagnostic_criterion": "presence of FLT3 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy", "patient_eligibility": "Complete response", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.16, "neoplasm": 0.99 } }, "b98e209a378038ce": { "b": { "tumor_type": "aggressive systemic mastocytosis (ASM)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.98 } }, "4e259b687d0c7e34": { "b": { "tumor_type": "systemic mastocytosis with associated haematological neoplasm (SM-AHN)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.98 } }, "0d9783be9103a8c9": { "b": { "tumor_type": "mast cell leukaemia (MCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.64, "neoplasm": 0.99 } }, "7f24d4b8601040cf": { "b": { "tumor_type": "chronic myeloid leukaemia (CML), chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Aged 6 years and older", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "d56012e7506928c9": { "b": { "tumor_type": "chronic myeloid leukaemia (CML), chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Previously treated with one or more tyrosine kinase inhibitors (TKIs)", "patient_eligibility": "Aged 6 years and older; imatinib, nilotinib and dasatinib are not considered appropriate treatment options", "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "d70a6d433b625011": { "b": { "tumor_type": "chronic myeloid leukaemia (CML), accelerated or blast phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Previously treated with one or more tyrosine kinase inhibitors (TKIs)", "patient_eligibility": "Imatinib, nilotinib and dasatinib are not considered appropriate treatment options", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "ddc90dbc1b64380b": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ capecitabine", "prior_therapy": "Progression following prior therapy, which must have included anthracyclines and taxanes and trastuzumab in the metastatic setting", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.25, "neoplasm": 0.99 } }, "d4b66df7ea5db85e": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression; HR-negative", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ trastuzumab", "prior_therapy": "Prior trastuzumab therapy in combination with chemotherapy; disease progressed on this therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.17, "neoplasm": 0.99 } }, "41b8767f36dd3d82": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression; HR-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ an aromatase inhibitor", "prior_therapy": null, "patient_eligibility": "Postmenopausal women; not currently intended for chemotherapy", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The r3 indication (\"for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy\") contains no first-line or untreated wording. Under rule 14 the registration-study statement is a note, not a condition, so rule 13 (\"If no line information at all → any\") gives any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.18, "neoplasm": 0.99 } }, "f24ed680af98afcc": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Unresectable; no bone, brain, lung or other visceral disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.41, "neoplasm": 0.99 } }, "a7e2260785f975d9": { "b": { "tumor_type": "Philadelphia chromosome positive chronic myelogenous leukaemia (CML), chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive", "diagnostic_criterion": "presence of Philadelphia chromosome", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "mixed" }, "decisions": [], "jev": { "supported": 0.3, "neoplasm": 0.99 } }, "e1d74840bcde3b42": { "b": { "tumor_type": "Philadelphia chromosome positive CML, chronic phase or accelerated phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive", "diagnostic_criterion": "presence of Philadelphia chromosome", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Resistance or intolerance to prior therapy including imatinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "b2a77c2049de9c7a": { "b": { "tumor_type": "Philadelphia chromosome positive CML, chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive", "diagnostic_criterion": "presence of Philadelphia chromosome", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": "Resistance or intolerance to prior therapy including imatinib", "patient_eligibility": null, "age_group": "pediatric" }, "decisions": [], "jev": { "supported": 0.35, "neoplasm": 0.99 } }, "0db4b830dc33daed": { "b": { "tumor_type": "uveal melanoma", "organ": "eye", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HLA-A*02:01", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HLA-A*02:01-positive", "diagnostic_criterion": "HLA-A*02:01-positive", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "03b81bf383f4b3b1": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least two prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "830f3ac69204e150": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "d71f8a5ec4bd35da": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ trastuzumab and capecitabine", "prior_therapy": "At least 2 prior anti-HER2 treatment regimens", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.19, "neoplasm": 0.99 } }, "0c801035af783d94": { "b": { "tumor_type": "myelofibrosis (primary, post-polycythaemia vera or post-essential thrombocythaemia)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Disease-related splenomegaly or symptoms", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.55, "neoplasm": 0.98 } }, "3556b810a367aaae": { "b": { "tumor_type": "polycythaemia vera", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Resistant to or intolerant of hydroxyurea", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"resistant to or intolerant of hydroxyurea\" guarantees a prior systemic therapy (hydroxyurea) under both branches, comparable to \"refractory\" or \"progressed on or intolerant to\", so rule 13 gives 2L.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "2L", "from": [ "a" ] } ], "value": "2L", "from": [ "a" ] }, { "q": "q2", "ambiguous": false, "reason": "Both branches imply hydroxyurea was actually given, and rule 14 keeps \"resistant to or intolerant of\" together as one prior_therapy clause, like \"Progressed on or intolerant to imatinib and sunitinib\".", "kind": "field", "field": "prior_therapy", "candidates": [ { "value": null, "from": [ "b" ] }, { "value": "Resistant to or intolerant of hydroxyurea", "from": [ "a" ] } ], "value": "Resistant to or intolerant of hydroxyurea", "from": [ "a" ] } ], "jev": { "supported": 0.61, "neoplasm": 0.97 } }, "b3e73130514382e6": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600", "diagnostic_criterion": "presence of BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ encorafenib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.69, "neoplasm": 0.99 } }, "dbaf73993c170cbc": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600E", "diagnostic_criterion": "presence of BRAF V600E mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ encorafenib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "7b22f24f689c81ff": { "b": { "tumor_type": "cholangiocarcinoma", "organ": "biliary", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "FGFR2", "biomarker_alteration_type": "fusion", "biomarker_detail": "fusion or rearrangement", "diagnostic_criterion": "presence of FGFR2 fusion or rearrangement", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After at least one prior line of systemic therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.91, "neoplasm": 0.99 } }, "e294c1ea3d4f0e4b": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "any", "treatment_phase": "neoadjuvant", "line_of_therapy": "any", "biomarker_name": "ERBB2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "locally advanced, inflammatory, or early stage; high risk of recurrence", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.17, "neoplasm": 0.99 } }, "739b21ce6c81a57c": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "ERBB2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "high risk of recurrence", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.17, "neoplasm": 0.99 } }, "545af94fefd811ea": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "ERBB2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "+ docetaxel", "prior_therapy": "No previous anti-HER2 therapy or chemotherapy for metastatic disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.31, "neoplasm": 0.99 } }, "73da364d90c5f9bc": { "b": { "tumor_type": "renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.13, "neoplasm": 0.99 } }, "1c0d07295f560494": { "b": { "tumor_type": "renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "cytokine therapy for advanced disease", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.41, "neoplasm": 0.99 } }, "78aeff681444d1b7": { "b": { "tumor_type": "advanced soft-tissue sarcoma (STS), selective subtypes", "organ": "soft-tissue", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "prior chemotherapy for metastatic disease or progressed within 12 months after (neo) adjuvant therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.49, "neoplasm": 0.99 } }, "92902b3109da09ca": { "b": { "tumor_type": "blastic plasmacytoid dendritic cell neoplasm (BPDCN)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.48, "neoplasm": 0.99 } }, "f0d0cae2b9caf8c6": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ bortezomib and dexamethasone", "prior_therapy": "At least two prior regimens including bortezomib and an immunomodulatory agent", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.78, "neoplasm": 0.99 } }, "46b4a1ad05361f24": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ lenalidomide and dexamethasone", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "2f01eb3b87a39429": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ pomalidomide and dexamethasone", "prior_therapy": "At least two prior therapies including lenalidomide and a proteasome inhibitor; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "398016140df22350": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ melphalan and prednisone", "prior_therapy": null, "patient_eligibility": "Aged ≥65 years or ineligible for high-dose chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "10c517cb7cd27b24": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ melphalan and prednisone", "prior_therapy": null, "patient_eligibility": "Aged ≥65 years or ineligible for high dose chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "4f6676a52500fb09": { "b": { "tumor_type": "renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after failure of prior treatment with sunitinib or a cytokine", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "f811150478450986": { "b": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRCA1/2", "biomarker_alteration_type": "mutation", "biomarker_detail": "germline BRCA1/2 mutations; HER2-negative", "diagnostic_criterion": "Presence of germline BRCA1/2 mutation; HER2-negative", "scoring_system": "n/a", "test_method": [ "molecular", "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting, unless not suitable; for HR-positive disease, prior endocrine-based therapy or considered unsuitable for endocrine-based therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.79, "neoplasm": 0.99 } }, "2cd6b21016de71c7": { "b": { "tumor_type": "metastatic castration-resistant prostate cancer (mCRPC)", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ enzalutamide", "prior_therapy": null, "patient_eligibility": "Chemotherapy is not clinically indicated", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Rule 13 treats castration resistance as a disease state and maps \"metastatic castration-resistant prostate cancer before chemotherapy\" to 1L. The label's \"mCRPC in whom chemotherapy is not clinically indicated\" names no prior systemic therapy for mCRPC, so this is the pre-chemotherapy setting.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.76, "neoplasm": 0.99 } }, "ab24209cab8ae3ce": { "b": { "tumor_type": "non-metastatic castration-resistant prostate cancer (nmCRPC)", "organ": "prostate", "disease_stage": "locally-advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Men; high risk of developing metastatic disease", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.42, "neoplasm": 0.99 } }, "0959217a6f5f64a0": { "b": { "tumor_type": "hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ androgen deprivation therapy", "prior_therapy": null, "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says only \"metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy\". It has no first-line or previously-untreated wording, and under rule 13 hormone sensitivity is a disease state, not a line, so \"no line information at all → any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "any", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "3c4ddb0a22eed848": { "b": { "tumor_type": "hormone-sensitive prostate cancer", "organ": "prostate", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ docetaxel and androgen deprivation therapy", "prior_therapy": null, "patient_eligibility": "Men", "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "\"mHSPC in combination with docetaxel and androgen deprivation therapy\" gives no line wording such as \"first-line\" or \"previously untreated\". Rule 13 counts only stated prior systemic therapy, so the value is any.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "1L", "from": [ "a" ] }, { "value": "any", "from": [ "b" ] } ], "value": "any", "from": [ "b" ] } ], "jev": { "supported": 0.52, "neoplasm": 0.99 } }, "41f1fa6b9d948b8f": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "MET", "biomarker_alteration_type": "mutation", "biomarker_detail": "MET exon 14 skipping", "diagnostic_criterion": "Presence of alterations leading to MET exon 14 skipping", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Following prior treatment with immunotherapy and/or platinum-based chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"alterations leading to ... exon 14 (METex14) skipping\". Both candidates name the same qualitative descriptor, so either is correct and there is one clear answer. \"METex14 skipping\" follows the label's own abbreviation verbatim.", "kind": "field", "field": "biomarker_detail", "candidates": [ { "value": "MET exon 14 skipping", "from": [ "b" ] }, { "value": "METex14 skipping", "from": [ "a" ] } ], "value": "METex14 skipping", "from": [ "a" ] } ], "jev": { "supported": 0.74, "neoplasm": 0.99 } }, "d8466144c1a019ea": { "b": { "tumor_type": "B-cell precursor acute lymphoblastic leukaemia (B-ALL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "26 years of age and above", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.47, "neoplasm": 0.99 } }, "d5340ccaa994e73e": { "b": { "tumor_type": "cutaneous T-cell lymphoma (CTCL)", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Refractory to at least one systemic treatment", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "\"cutaneous T-cell lymphoma\" is a lymphoma, and the field definition maps lymphoma to organ=\"hematologic\". The skin list covers only melanoma, BCC, cSCC and Merkel cell, and treating \"skin manifestations\" does not change the tumour entity.", "kind": "field", "field": "organ", "candidates": [ { "value": "hematologic", "from": [ "a" ] }, { "value": "skin", "from": [ "b" ] } ], "value": "hematologic", "from": [ "a" ] } ], "jev": { "supported": 0.56, "neoplasm": 0.99 } }, "aa99541fab65550d": { "b": { "tumor_type": "multiple myeloma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "At least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody; disease progression on the last therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "65e50aa9aa3b8d3d": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600", "diagnostic_criterion": "BRAF V600 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ vemurafenib", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.58, "neoplasm": 0.99 } }, "3ddda2514e27e1a5": { "b": { "tumor_type": "melanoma", "organ": "skin", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BRAF", "biomarker_alteration_type": "mutation", "biomarker_detail": "V600", "diagnostic_criterion": "BRAF V600 mutation-positive", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "d027c30198372926": { "b": { "tumor_type": "hormone receptor-positive HER2-positive breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "overexpression or gene amplification; HR-positive", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive; hormone receptor-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Completed adjuvant trastuzumab-based therapy less than one year ago", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.12, "neoplasm": 0.99 } }, "22d2c4d95beca8a9": { "b": { "tumor_type": "myelodysplastic syndromes (MDS)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "del(5q)", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "without an isolated deletion 5q cytogenetic (non-del 5q) abnormality", "diagnostic_criterion": "without an isolated deletion 5q cytogenetic abnormality", "scoring_system": "n/a", "test_method": [ "cytogenetics" ], "combination": "monotherapy", "prior_therapy": "Unsatisfactory response to or ineligible for erythropoietin-based therapy", "patient_eligibility": "Transfusion-dependent anaemia; very low, low or intermediate risk", "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label requires the patient to be \"without an isolated deletion 5q cytogenetic (non-del 5q) abnormality\", and under rule 3 the biomarker that must be absent is named. \"del(5q)\" names that alteration itself, whereas \"5q\" names only the chromosome arm.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "5q", "from": [ "a" ] }, { "value": "del(5q)", "from": [ "b" ] } ], "value": "del(5q)", "from": [ "b" ] } ], "jev": { "supported": 0.15, "neoplasm": 0.98 } }, "dc9f6bf482158608": { "b": { "tumor_type": "metastatic colorectal cancer (mCRC)", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "RAS", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "RAS wild-type", "diagnostic_criterion": "RAS wild-type", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ FOLFOX or FOLFIRI", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.62, "neoplasm": 0.99 } }, "3e522aff66e61413": { "b": { "tumor_type": "metastatic colorectal cancer (mCRC)", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "RAS", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "RAS wild-type", "diagnostic_criterion": "RAS wild-type", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ FOLFIRI", "prior_therapy": "First-line fluoropyrimidine-based chemotherapy (excluding irinotecan)", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "b5861932f04c3635": { "b": { "tumor_type": "metastatic colorectal cancer (mCRC)", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "RAS", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "RAS wild-type", "diagnostic_criterion": "RAS wild-type", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens\". The plural \"regimens\" guarantees at least two prior lines, which is 3L+ under rule 13 (\"after multiple prior therapies\").", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "3L+", "from": [ "a", "jev" ] }, { "value": "2L", "from": [ "b" ] } ], "value": "3L+", "from": [ "a", "jev" ] } ], "jev": { "supported": 0.7, "neoplasm": 0.99 } }, "cdf354de2cd208e4": { "b": { "tumor_type": "acute myeloid leukaemia (AML)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ low-dose cytarabine", "prior_therapy": null, "patient_eligibility": "Not a candidate for standard induction chemotherapy", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.77, "neoplasm": 0.99 } }, "52ba0388ceebac3f": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "Presence of an ALK rearrangement or fusion by a validated assay", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "No prior ALK inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.81, "neoplasm": 0.99 } }, "cedc2eaf670aa5a2": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "Presence of an ALK rearrangement or fusion by a validated assay", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "monotherapy", "prior_therapy": "After crizotinib", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.83, "neoplasm": 0.99 } }, "a2e74aff883c4e66": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutations", "diagnostic_criterion": "Presence of EGFR activating mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.46, "neoplasm": 0.99 } }, "47af145de0759ca6": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": "maintenance", "line_of_therapy": "1L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating mutations", "diagnostic_criterion": "Presence of EGFR activating mutations", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "after first-line chemotherapy", "patient_eligibility": "Stable disease", "age_group": "any" }, "decisions": [], "jev": { "supported": 0.71, "neoplasm": 0.99 } }, "fa0878c0e0614235": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "after failure of at least one prior chemotherapy regimen", "patient_eligibility": null, "age_group": "any" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Row r4 covers the branch \"In patients with tumours without EGFR activating mutations\". That leaves r3 as the EGFR-mutation-positive branch of \"after failure of at least one prior chemotherapy regimen\", consistent with its detail and criterion. Under rule 1, positive and negative branches are split, so r3 takes \"mutation\".", "kind": "field", "field": "biomarker_alteration_type", "candidates": [ { "value": "mutation", "from": [ "a" ] }, { "value": "none", "from": [ "b" ] } ], "value": "mutation", "from": [ "a" ] }, { "q": "q2", "ambiguous": false, "reason": "r3 is the EGFR activating-mutation branch and its diagnostic_criterion is \"presence of EGFR activating mutations\", so the biomarker is EGFR.", "kind": "field", "field": "biomarker_name", "candidates": [ { "value": "none", "from": [ "b" ] }, { "value": "EGFR", "from": [ "a" ] } ], "value": "EGFR", "from": [ "a" ] } ], "jev": { "supported": 0.22, "neoplasm": 0.99 } }, "73e7ed522f25a3e6": { "b": null, "decisions": [ { "q": "q3", "ambiguous": false, "reason": "\"In patients with tumours without EGFR activating mutations, Tarceva is indicated when other treatment options are not considered suitable\" is a distinct negative-biomarker scenario with its own restriction. Rule 1 requires splitting positive vs negative branches, so r4 stays.", "kind": "extra", "verdict": "keep" } ], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "f9bb83f382873965": { "b": { "tumor_type": "pancreatic cancer", "organ": "pancreas", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ gemcitabine", "prior_therapy": null, "patient_eligibility": null, "age_group": "any" }, "decisions": [], "jev": { "supported": 0.72, "neoplasm": 0.99 } }, "58e42c0e63e54054": { "b": { "tumor_type": "renal cell carcinoma", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "At least three of six prognostic risk factors", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.38, "neoplasm": 0.99 } }, "bd550de1cca19097": { "b": { "tumor_type": "mantle cell lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.37, "neoplasm": 0.99 } }, "5dc36ff2118c96b8": { "b": { "tumor_type": "NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "ROS1", "biomarker_alteration_type": "fusion", "biomarker_detail": "ROS1-positive", "diagnostic_criterion": "ROS1-positive", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.66, "neoplasm": 0.99 } }, "639b8fc01411e263": { "b": { "tumor_type": "advanced solid tumours", "organ": "tumor-agnostic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "NTRK1/NTRK2/NTRK3", "biomarker_alteration_type": "fusion", "biomarker_detail": "NTRK gene fusion", "diagnostic_criterion": "presence of an NTRK gene fusion", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "Received a prior NTRK inhibitor, or has not received a prior NTRK inhibitor and treatment options not targeting NTRK provide limited clinical benefit or have been exhausted", "patient_eligibility": null, "age_group": "mixed" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "Only one branch guarantees a prior line (\"who have received a prior NTRK inhibitor\"). The other allows patients who \"have not received a prior NTRK inhibitor and treatment options not targeting NTRK provide limited clinical benefit\", which guarantees no prior systemic therapy. Rule 13 counts the minimum the wording guarantees, and this branch is not explicitly untreated, so the row takes \"any\".", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "any", "from": [ "a" ] } ], "value": "any", "from": [ "a" ] } ], "jev": { "supported": 0.88, "neoplasm": 0.98 } }, "0a3cda19726c88e3": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ rituximab", "prior_therapy": "At least one prior therapy", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.61, "neoplasm": 0.99 } }, "9f8827080169723f": { "b": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "TP53", "biomarker_alteration_type": "mutation", "biomarker_detail": "TP53 mutation", "diagnostic_criterion": "presence of TP53 mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "+ rituximab", "prior_therapy": null, "patient_eligibility": "Not eligible for any other therapies", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.32, "neoplasm": 0.99 } }, "c08bbb0cbcac7653": { "b": { "tumor_type": "follicular lymphoma (FL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Refractory to two prior lines of treatment", "patient_eligibility": null, "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.89, "neoplasm": 0.99 } }, "7bafc012b1fb5aa9": { "b": { "tumor_type": "colorectal cancer", "organ": "colorectal", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ FOLFIRI chemotherapy", "prior_therapy": "after an oxaliplatin-containing regimen", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "The label says \"in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy\". Rule 15a asks for the regimen verbatim, so the candidate that spells out its components is the more faithful one; both candidates name the same regimen.", "kind": "field", "field": "combination", "candidates": [ { "value": "+ irinotecan/5-fluorouracil/folinic acid (FOLFIRI)", "from": [ "a" ] }, { "value": "+ FOLFIRI chemotherapy", "from": [ "b" ] } ], "value": "+ irinotecan/5-fluorouracil/folinic acid (FOLFIRI)", "from": [ "a" ] } ], "jev": { "supported": 0.85, "neoplasm": 0.99 } }, "35bb9664b3a5c7f0": { "b": { "tumor_type": "hormone-dependent breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "HR", "biomarker_alteration_type": "overexpression", "biomarker_detail": "hormone-dependent; estrogen receptor-negative tumours not recommended", "diagnostic_criterion": "hormone-dependent", "scoring_system": "n/a", "test_method": [ "IHC" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Postmenopausal", "age_group": "adult" }, "decisions": [], "jev": { "supported": 0.39, "neoplasm": 0.99 } }, "2cc07ac29058cb21": { "b": { "tumor_type": "advanced renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "One prior treatment with cytokine therapy for advanced RCC; no prior VEGFR or mTOR pathway inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q1", "ambiguous": false, "reason": "r1 covers \"the first line treatment of adult patients with advanced renal cell carcinoma\", which is 1L under rule 13.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "b" ] }, { "value": "1L", "from": [ "a" ] } ], "value": "1L", "from": [ "a" ] } ], "jev": { "supported": 0.11, "neoplasm": 0.99 } }, "45e829478cd6ea07": { "b": { "tumor_type": "advanced renal cell carcinoma (RCC)", "organ": "kidney", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decisions": [ { "q": "q2", "ambiguous": false, "reason": "r2 covers patients with \"disease progression after one prior treatment with cytokine therapy for advanced RCC\". That guarantees one prior systemic line for advanced disease, so it is 2L under rule 13; the VEGFR/mTOR naivety does not change the count.", "kind": "field", "field": "line_of_therapy", "candidates": [ { "value": "2L", "from": [ "a" ] }, { "value": "1L", "from": [ "b" ] } ], "value": "2L", "from": [ "a" ] } ], "jev": { "supported": 0.42, "neoplasm": 0.99 } } }, "removed": [ { "product": "Keytruda", "inn": "pembrolizumab", "row": { "tumor_type": "classical Hodgkin lymphoma", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Failed autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT is not a treatment option", "patient_eligibility": "Aged 12 years and older", "age_group": "mixed" }, "decision": { "q": "q11", "ambiguous": false, "reason": "The adolescent cHL sentence (\"adults and adolescents aged 12 years and older\", same prior therapy and line) falls within r11's \"adult and paediatric patients aged 3 years and older\". Another row therefore already covers it.", "kind": "extra", "verdict": "remove" } } ], "skipped": [ { "product": "Glivec", "inn": "imatinib", "row": { "tumor_type": "chronic myeloid leukaemia (CML)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "BCR-ABL1", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of BCR-ABL1 fusion", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Accelerated phase or blast crisis", "age_group": "mixed" }, "decision": { "q": "q2", "ambiguous": false, "reason": "Accelerated phase or blast crisis is the same tumour entity (CML) with the same biomarker, regimen and age group, and no branch is untreated. Rule 1 therefore does not split it, and r2 already covers it. The candidate's \"advanced\" stage is also not stated in the text.", "kind": "missing", "verdict": "skip" } }, { "product": "Glivec", "inn": "imatinib", "row": { "tumor_type": "hypereosinophilic syndrome (HES)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "FIP1L1-PDGFRA", "biomarker_alteration_type": "fusion", "biomarker_detail": "FIP1L1-PDGFRα rearrangement", "diagnostic_criterion": "Presence of FIP1L1-PDGFRA rearrangement", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q3", "ambiguous": true, "reason": "\"hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL)\" names two disease entities, and rule 1 splits different tumour entities into one row each. A separate HES row is therefore warranted, with r6 then narrowed to CEL. Whether HES and CEL count as distinct entities or one spectrum is left open.", "kind": "missing", "verdict": "skip", "suggested": "add" } }, { "product": "Glivec", "inn": "imatinib", "row": { "tumor_type": "dermatofibrosarcoma protuberans (DFSP)", "organ": "soft-tissue", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Not eligible for surgery", "age_group": "adult" }, "decision": { "q": "q4", "ambiguous": false, "reason": "r9 already covers the DFSP sentence. The candidate's 2L line has no support: \"recurrent and/or metastatic DFSP who are not eligible for surgery\" names no prior systemic therapy.", "kind": "missing", "verdict": "skip" } }, { "product": "Tuznue", "inn": "trastuzumab", "row": { "tumor_type": "metastatic breast cancer", "organ": "breast", "disease_stage": "metastatic", "treatment_phase": null, "line_of_therapy": "3L+", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "At least two chemotherapy regimens for metastatic disease, including at least an anthracycline and a taxane unless unsuitable; hormone receptor-positive patients must also have failed hormonal therapy unless unsuitable", "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q7", "ambiguous": false, "reason": "This duplicates r1, the monotherapy row \"after at least two chemotherapy regimens for their metastatic disease\", which is already in the table.", "kind": "missing", "verdict": "skip" } }, { "product": "Tuznue", "inn": "trastuzumab", "row": { "tumor_type": "early breast cancer", "organ": "breast", "disease_stage": "early", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "HER2", "biomarker_alteration_type": "overexpression", "biomarker_detail": "HER2 overexpression or gene amplification", "diagnostic_criterion": "IHC 3+ or IHC 2+/ISH-positive", "scoring_system": "IHC-score", "test_method": [ "IHC", "ISH" ], "combination": "monotherapy", "prior_therapy": "Surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable)", "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q8", "ambiguous": false, "reason": "This duplicates r5, the post-surgery/chemotherapy/radiotherapy monotherapy scenario, which is already covered.", "kind": "missing", "verdict": "skip" } }, { "product": "Imfinzi", "inn": "durvalumab", "row": { "tumor_type": "gastric or gastro-oesophageal junction adenocarcinoma", "organ": "stomach", "disease_stage": "early", "treatment_phase": "adjuvant", "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Neoadjuvant IMFINZI + FLOT chemotherapy, surgical resection, and adjuvant IMFINZI + FLOT chemotherapy", "patient_eligibility": "Resectable", "age_group": "adult" }, "decision": { "q": "q1", "ambiguous": false, "reason": "The label says \"as neoadjuvant and adjuvant treatment, followed by adjuvant IMFINZI monotherapy\". Both adjuvant parts are one sequential regimen in a single phase, not alternatives. Rules 12/12a split only by phase, and r16 already covers the whole adjuvant phase as \"+ FLOT chemotherapy, followed by monotherapy\".", "kind": "missing", "verdict": "skip" } }, { "product": "Imbruvica", "inn": "ibrutinib", "row": { "tumor_type": "mantle cell lymphoma (MCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "IMBRUVICA + R-CHOP alternating with R-DHAP (or R-DHAOx) without IMBRUVICA", "patient_eligibility": "Eligible for autologous stem cell transplantation (ASCT)", "age_group": "adult" }, "decision": { "q": "q4", "ambiguous": true, "reason": "The label says \"followed by IMBRUVICA monotherapy\" without naming maintenance (rules 11 and 12a), and the sequence is one regimen, not an alternative. Row r1's full verbatim combination already covers it, so the extra row is skipped. The rules leave open whether an unnamed continuation phase counts as maintenance for a 12a split.", "kind": "missing", "verdict": "skip", "suggested": "skip" } }, { "product": "Calquence", "inn": "acalabrutinib", "row": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "+ venetoclax", "prior_therapy": null, "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q1", "ambiguous": false, "reason": "Rule 1 keeps \"with or without\" a partner in one row: its example is \"with or without bevacizumab\". Both branches here are combinations with venetoclax, and r3 (\"+ venetoclax with or without obinutuzumab\") already covers \"in combination with venetoclax with or without obinutuzumab\", so a separate \"+ venetoclax\" row would duplicate it.", "kind": "missing", "verdict": "skip" } }, { "product": "MabThera", "inn": "rituximab", "row": { "tumor_type": "Burkitt leukaemia (mature B-cell acute leukaemia)", "organ": "hematologic", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "CD20", "biomarker_alteration_type": "overexpression", "biomarker_detail": "CD20-positive", "diagnostic_criterion": "CD20 positive", "scoring_system": "n/a", "test_method": [ "IHC", "flow-cytometry" ], "combination": "+ chemotherapy", "prior_therapy": null, "patient_eligibility": "Aged 6 months to less than 18 years; previously untreated", "age_group": "pediatric" }, "decision": { "q": "q2", "ambiguous": false, "reason": "The label writes \"Burkitt lymphoma (BL)/Burkitt leukaemia (mature B-cell acute leukaemia) (BAL)\" as one slash-joined entity, the leukaemic presentation of the same disease. Rule 1's own example (\"DLBCL, Burkitt lymphoma or Burkitt-like lymphoma\" → one row per entity) gives three entities, and r6 already covers Burkitt lymphoma/leukaemia.", "kind": "missing", "verdict": "skip" } }, { "product": "Sprycel", "inn": "dasatinib (anhydrous)", "row": { "tumor_type": "Philadelphia chromosome-positive chronic myelogenous leukaemia (CML), chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome-positive (Ph+)", "diagnostic_criterion": "presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "cytogenetics", "molecular" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "pediatric" }, "decision": { "q": "q4", "ambiguous": false, "reason": "The paediatric \"newly diagnosed Ph+ CML in chronic phase\" scenario is already covered by r5 (1L, pediatric). Adding this row would duplicate it.", "kind": "missing", "verdict": "skip" } }, { "product": "Ruxolitinib Viatris", "inn": "ruxolitinib hemifumarate", "row": { "tumor_type": "primary myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Disease-related splenomegaly or symptoms", "age_group": "adult" }, "decision": { "q": "q1", "ambiguous": false, "reason": "The label groups \"primary myelofibrosis ..., post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis\" under one heading, \"Myelofibrosis (MF)\", and all three share every field value. Under rule 1 they are forms of one entity listed with \"or\", so r1 already covers this branch and a separate row would duplicate it.", "kind": "missing", "verdict": "skip" } }, { "product": "Ruxolitinib Viatris", "inn": "ruxolitinib hemifumarate", "row": { "tumor_type": "post-essential thrombocythaemia myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": "Disease-related splenomegaly or symptoms", "age_group": "adult" }, "decision": { "q": "q2", "ambiguous": false, "reason": "Post essential thrombocythaemia myelofibrosis is one of the myelofibrosis forms in r1's combined row, and no field differs between the branches. Rule 1 therefore keeps one row, and a split row would duplicate r1.", "kind": "missing", "verdict": "skip" } }, { "product": "Tecentriq", "inn": "atezolizumab", "row": { "tumor_type": "locally advanced or metastatic NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "EGFR/ALK", "biomarker_alteration_type": "wild-type-required", "biomarker_detail": "EGFR-mutant or ALK-positive NSCLC excluded", "diagnostic_criterion": "No EGFR mutation or ALK positivity", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After prior chemotherapy", "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q5", "ambiguous": false, "reason": "Unlike the first-line case, the indication does not exclude EGFR/ALK-positive patients; they are included after targeted therapy. An EGFR/ALK wild-type-required row misstates this, and r10 already covers the scenario.", "kind": "missing", "verdict": "skip" } }, { "product": "Tecentriq", "inn": "atezolizumab", "row": { "tumor_type": "locally advanced or metastatic NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "EGFR", "biomarker_alteration_type": "mutation", "biomarker_detail": "EGFR-mutant", "diagnostic_criterion": "Presence of an EGFR mutation", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After prior chemotherapy and targeted therapies", "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q6", "ambiguous": false, "reason": "\"Patients with EGFR-mutant or ALK-positive NSCLC should also have received targeted therapies\" stays at the same 2L line. That condition is already recorded in r10's prior_therapy, so no separate row is needed.", "kind": "missing", "verdict": "skip" } }, { "product": "Tecentriq", "inn": "atezolizumab", "row": { "tumor_type": "locally advanced or metastatic NSCLC", "organ": "lung", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ALK", "biomarker_alteration_type": "fusion", "biomarker_detail": "ALK-positive", "diagnostic_criterion": "Presence of an ALK alteration", "scoring_system": "n/a", "test_method": [ "molecular" ], "combination": "monotherapy", "prior_therapy": "After prior chemotherapy and targeted therapies", "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q7", "ambiguous": false, "reason": "The ALK-positive subgroup is covered by r10 at the same line, with \"should also have received targeted therapies\" in prior_therapy; no separate row is needed.", "kind": "missing", "verdict": "skip" } }, { "product": "Venclyxto", "inn": "venetoclax", "row": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "17p", "biomarker_alteration_type": "loss", "biomarker_detail": "deletion", "diagnostic_criterion": "presence of 17p deletion", "scoring_system": "n/a", "test_method": [ "ISH" ], "combination": "monotherapy", "prior_therapy": "Unsuitable for or have failed a B-cell receptor pathway inhibitor", "patient_eligibility": null, "age_group": "adult" }, "decision": { "q": "q2", "ambiguous": true, "reason": "r5 already covers \"in the presence of 17p deletion or TP53 mutation\" with both legs in biomarker_detail and diagnostic_criterion. Both describe TP53 disruption, so keeping one row like r6 fits. Rule 1 could also treat them as different biomarkers needing separate rows, which leaves the split open.", "kind": "missing", "verdict": "skip", "suggested": "skip" } }, { "product": "Omjjara", "inn": "momelotinib", "row": { "tumor_type": "primary myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "No prior JAK inhibitor", "patient_eligibility": "Moderate to severe anaemia; disease-related splenomegaly or symptoms; JAK inhibitor-naïve", "age_group": "adult" }, "decision": { "q": "q2", "ambiguous": false, "reason": "\"JAK inhibitor naïve\" is naivety to one drug class, not an untreated (1L) branch (rule 13), so there is no 1L-vs-pretreated split. The three myelofibrosis forms are one disease (myelofibrosis), so r1 already covers this scenario.", "kind": "missing", "verdict": "skip" } }, { "product": "Omjjara", "inn": "momelotinib", "row": { "tumor_type": "primary myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Treated with ruxolitinib", "patient_eligibility": "Moderate to severe anaemia; disease-related splenomegaly or symptoms", "age_group": "adult" }, "decision": { "q": "q3", "ambiguous": false, "reason": "The ruxolitinib-treated branch is an alternative prior-therapy route to the same population. Rule 13 keeps one row at the lowest line (\"any\"), and r1 covers it.", "kind": "missing", "verdict": "skip" } }, { "product": "Omjjara", "inn": "momelotinib", "row": { "tumor_type": "post polycythaemia vera myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Treated with ruxolitinib", "patient_eligibility": "Moderate to severe anaemia; disease-related splenomegaly or symptoms", "age_group": "adult" }, "decision": { "q": "q4", "ambiguous": false, "reason": "There is no line split, because JAK-naive is class naivety and not 1L. Post-PV myelofibrosis is one of the myelofibrosis forms already held in r1.", "kind": "missing", "verdict": "skip" } }, { "product": "Omjjara", "inn": "momelotinib", "row": { "tumor_type": "post essential thrombocythaemia myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "any", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "No prior JAK inhibitor", "patient_eligibility": "Moderate to severe anaemia; disease-related splenomegaly or symptoms; JAK inhibitor-naïve", "age_group": "adult" }, "decision": { "q": "q5", "ambiguous": false, "reason": "The JAK-naive branch does not justify a separate row (rule 13: class naivety → any). Post-ET myelofibrosis is already covered by r1.", "kind": "missing", "verdict": "skip" } }, { "product": "Omjjara", "inn": "momelotinib", "row": { "tumor_type": "post essential thrombocythaemia myelofibrosis", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "Treated with ruxolitinib", "patient_eligibility": "Moderate to severe anaemia; disease-related splenomegaly or symptoms", "age_group": "adult" }, "decision": { "q": "q6", "ambiguous": false, "reason": "The ruxolitinib-treated branch is a prior-therapy alternative within one row at the lowest line. Post-ET myelofibrosis is covered by r1.", "kind": "missing", "verdict": "skip" } }, { "product": "Inluriyo", "inn": "imlunestrant", "row": { "tumor_type": "breast cancer", "organ": "breast", "disease_stage": "advanced", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "ESR1", "biomarker_alteration_type": "mutation", "biomarker_detail": "activating ESR1 mutation; ER-positive; HER2-negative", "diagnostic_criterion": "presence of an activating ESR1 mutation", "scoring_system": "n/a", "test_method": [ "IHC", "ISH", "molecular" ], "combination": "+ LHRH agonist", "prior_therapy": "After disease progression following prior treatment with an endocrine based regimen", "patient_eligibility": "Pre- or perimenopausal women or men", "age_group": "adult" }, "decision": { "q": "q1", "ambiguous": false, "reason": "Rule 14 says \"how a subgroup receives it, from the same paragraph\" (\"In pre- or perimenopausal women, or men, Inluriyo should be combined with a LHRH agonist\") is appended to patient_eligibility of the existing row, not split off. An LHRH agonist is an endocrine partner, not a targeted or immunotherapy partner (rule 1), so r1 already covers this scenario.", "kind": "missing", "verdict": "skip" } }, { "product": "Dasatinib Accord Healthcare", "inn": "dasatinib", "row": { "tumor_type": "Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML) in chronic phase", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "BCR-ABL", "biomarker_alteration_type": "fusion", "biomarker_detail": "Philadelphia chromosome positive (Ph+)", "diagnostic_criterion": "Presence of Philadelphia chromosome (Ph+)", "scoring_system": "n/a", "test_method": [ "molecular", "cytogenetics" ], "combination": "monotherapy", "prior_therapy": null, "patient_eligibility": null, "age_group": "pediatric" }, "decision": { "q": "q10", "ambiguous": false, "reason": "The paediatric \"newly diagnosed Ph+ CML in chronic phase\" scenario is already covered by r5 at 1L.", "kind": "missing", "verdict": "skip" } }, { "product": "Minjuvi", "inn": "tafasitamab", "row": { "tumor_type": "diffuse large B-cell lymphoma (DLBCL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "2L", "biomarker_name": "none", "biomarker_alteration_type": "none", "biomarker_detail": "n/a", "diagnostic_criterion": "n/a", "scoring_system": "n/a", "test_method": [], "combination": "monotherapy", "prior_therapy": "MINJUVI + lenalidomide", "patient_eligibility": "Not eligible for autologous stem cell transplant (ASCT)", "age_group": "adult" }, "decision": { "q": "q1", "ambiguous": true, "reason": "The label describes one sequential regimen, \"in combination with lenalidomide followed by MINJUVI monotherapy\", not alternative monotherapy and combination options, and r1's combination already covers the whole sequence. The word \"maintenance\" is absent, so rules 11 and 12a do not explicitly require a separate maintenance-phase row. Whether rule 12a's phase split should extend to an unnamed continuation phase is left open.", "kind": "missing", "verdict": "skip", "suggested": "skip" } }, { "product": "Zydelig", "inn": "idelalisib", "row": { "tumor_type": "chronic lymphocytic leukaemia (CLL)", "organ": "hematologic", "disease_stage": "any", "treatment_phase": null, "line_of_therapy": "1L", "biomarker_name": "17p deletion", "biomarker_alteration_type": "loss", "biomarker_detail": "17p deletion", "diagnostic_criterion": "presence of 17p deletion", "scoring_system": "n/a", "test_method": [ "ISH", "cytogenetics" ], "combination": "+ rituximab", "prior_therapy": null, "patient_eligibility": "Not eligible for any other therapies", "age_group": "adult" }, "decision": { "q": "q1", "ambiguous": true, "reason": "\"in the presence of 17p deletion or TP53 mutation\" names two alterations of different kinds: a chromosomal deletion (loss, cytogenetics/FISH) and a gene mutation (mutation, molecular). Rule 1 splits different biomarkers into separate rows, so a 17p deletion row is a distinct scenario, and r2 would then keep the TP53 mutation branch. The rules leave it open whether both are one TP53-aberration biomarker with alternative results.", "kind": "missing", "verdict": "skip", "suggested": "add" } } ] }