{"format":{"id":"small-molecule","name":"Small-molecule inhibitors","blurb":"A target and a way of hitting it: ATP-competitive, allosteric or covalent kinase inhibitors, PARP trapping, hormone receptor blockade. The grid asks which targets have been hit with which mechanism class.","route":"/modalities/small-molecule/","engine":"/pipeline/engine/small-molecule/"},"counts":{"drugs":374,"approved":201,"phase3":89,"trials":553,"companies":186,"papers":206,"ideas":87,"eras":33},"how":{"paragraphs":["Pills that block the specific enzyme a cancer relies on. Imatinib in 2001 proved a cancer could be switched off by design.","ATP-competitive or allosteric binding to the kinase domain blocks phosphotransfer."],"from":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"technologies":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/","status":"standard-of-care","tldr":"Pills that block the specific enzyme a cancer relies on. Imatinib in 2001 proved a cancer could be switched off by design."},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/","status":"approved","tldr":"Pills that block a DNA repair backup, killing cancer cells that already lost their main repair system (BRCA)."},{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/","status":"approved","tldr":"Pills that stop the cell-division engine, added to hormone therapy for the most common type of breast cancer."},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/","status":"approved","tldr":"Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021."},{"id":"bcl2-inhibitors","kind":"technology","name":"BCL-2 inhibitors","route":"/technologies/bcl2-inhibitors/","status":"approved","tldr":"Drugs that switch off BCL-2, the protein that lets cancer cells refuse to die; venetoclax transformed treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia."},{"id":"idh-inhibitors","kind":"technology","name":"IDH inhibitors","route":"/technologies/idh-inhibitors/","status":"approved","tldr":"Pills that block mutant IDH1 or IDH2 enzymes, which flood cells with a metabolite that blocks maturation; approved in leukaemia, bile duct cancer and low-grade glioma."},{"id":"menin-inhibitors","kind":"technology","name":"Menin inhibitors","route":"/technologies/menin-inhibitors/","status":"approved","tldr":"Pills that break the interaction between menin and the KMT2A protein that acute leukaemias with KMT2A rearrangements or NPM1 mutations depend on; revumenib was the first approved, in 2024."},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/","status":"standard-of-care","tldr":"Pills that block or remove oestrogen signalling, the mainstay of treatment for hormone-driven breast cancer for 50 years."},{"id":"oral-serds","kind":"technology","name":"Oral SERDs","route":"/technologies/oral-serds/","status":"approved","tldr":"Oral drugs that destroy the oestrogen receptor rather than just blocking it, working even when the receptor has mutated to escape older hormone therapies."},{"id":"pi3k-akt-mtor-inhibitors","kind":"technology","name":"PI3K, AKT and mTOR inhibitors","route":"/technologies/pi3k-akt-mtor-inhibitors/","status":"approved","tldr":"Drugs against one of the most commonly mutated growth pathways in cancer, now used with hormone therapy in breast cancer and in kidney and neuroendocrine tumours, with high blood sugar as the shared side effect."},{"id":"hedgehog-inhibitors","kind":"technology","name":"Hedgehog pathway inhibitors","route":"/technologies/hedgehog-inhibitors/","status":"approved","tldr":"Pills that block a developmental signalling pathway hijacked by basal cell skin cancer, shrinking tumours that cannot be operated on; also used in some leukaemia."},{"id":"mdm2-inhibitors","kind":"technology","name":"MDM2 inhibitors","route":"/technologies/mdm2-inhibitors/","status":"phase-3","tldr":"Drugs that stop MDM2 destroying p53, reawakening the cell's guardian protein in tumours where p53 is intact but suppressed, such as some sarcomas and leukaemias."},{"id":"her2-tyrosine-kinase-inhibitors","kind":"technology","name":"HER2 tyrosine kinase inhibitors","route":"/technologies/her2-tyrosine-kinase-inhibitors/","status":"approved","tldr":"Small pills that block HER2 from inside the cell, complementing antibody drugs; tucatinib is notable for working against brain metastases."},{"id":"atr-chk1-inhibitors","kind":"technology","name":"ATR and CHK1 inhibitors","route":"/technologies/atr-chk1-inhibitors/","status":"phase-2","tldr":"Drugs that disable the checkpoint cancer cells use to pause and repair DNA under replication stress, pushing tumours with faulty DNA repair into collapse."},{"id":"kat6-inhibitors","kind":"technology","name":"KAT6 inhibitors","route":"/technologies/kat6-inhibitors/","status":"phase-3","tldr":"First-in-class drugs against the histone acetyltransferases KAT6A and KAT6B, in late trials for hormone receptor-positive breast cancer that has stopped responding to endocrine therapy."},{"id":"lsd1-inhibitors","kind":"technology","name":"LSD1 inhibitors","route":"/technologies/lsd1-inhibitors/","status":"phase-2","tldr":"Drugs against the histone demethylase LSD1, which keeps blood and neuroendocrine cancer cells from maturing; being tested in myelofibrosis, leukaemia and small cell lung cancer."},{"id":"gamma-secretase-inhibitors","kind":"technology","name":"Gamma-secretase inhibitors","route":"/technologies/gamma-secretase-inhibitors/","status":"approved","tldr":"Drugs that block the enzyme that activates Notch signalling; nirogacestat became the first approved, in 2023, for desmoid tumours, a rare but destructive growth of connective tissue."},{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/","status":"standard-of-care","tldr":"Androgen deprivation lowers testosterone or blocks its receptor, and has been the foundation of prostate cancer treatment since 1941 (Nobel Prize 1966)."},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/","status":"approved","tldr":"Drugs that change how genes are switched on and off without changing the DNA itself."},{"id":"small-molecule-api-synthesis","kind":"technology","name":"Small-molecule API synthesis","route":"/technologies/small-molecule-api-synthesis/","status":"standard-of-care","tldr":"Before a tablet or a vial exists, the active drug itself has to be made: many chemical steps in reactors, or extraction from a plant, at a handful of factories most patients never hear of. When one of those factories stops, whole cancer drugs disappear."}]},"terms":[{"id":"oncogene-addiction","kind":"term","name":"Oncogene addiction","route":"/terms/oncogene-addiction/","tldr":"When a cancer depends so completely on one mutated gene that blocking it collapses the tumour.","category":"Cancer biology"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/","tldr":"Why cancer drugs stop working: the tumour either never depended on the target or evolves around the block.","category":"Resistance"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/","tldr":"Two genes where losing either alone is fine but losing both kills the cell. Cancers that have lost one become vulnerable to drugs against the other.","category":"Cancer biology"}],"engine":{"route":"/pipeline/engine/small-molecule/","axes":["Target","Mechanism class"],"rows":114,"cols":17,"counts":{"approved":93,"development":32,"stopped":5,"unclear":0,"untried":1811},"placed":291,"total":374,"pct":78},"approved":[{"drug":{"id":"hydroxyurea","kind":"drug","name":"Hydroxyurea (hydroxycarbamide)","route":"/drugs/hydroxyurea/"},"brand":"Hydrea / Droxia / Siklos","status":"approved","modality":"Oral ribonucleotide reductase inhibitor (cytoreductive)","cancers":[{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"polycythaemia-vera","kind":"cancer","name":"Polycythaemia vera (PV)","route":"/cancers/polycythaemia-vera/"},{"id":"essential-thrombocythaemia","kind":"cancer","name":"Essential thrombocythaemia (ET)","route":"/cancers/essential-thrombocythaemia/"}],"indications":["CML, head and neck cancer with radiotherapy, melanoma, ovarian cancer (historic labelling)","Sickle cell anaemia (Droxia)"],"years":[1967,1998],"firstYear":1967,"regions":["US"],"target":{"key":"target","id":"rrm1","name":"Ribonucleotide reductase (RRM1)","href":"/targets/rrm1/"},"companies":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}]},{"drug":{"id":"tamoxifen","kind":"drug","name":"Tamoxifen","route":"/drugs/tamoxifen/"},"brand":"Nolvadex","status":"approved","modality":"Small-molecule SERM","cancers":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"}],"indications":["Advanced breast cancer","Risk reduction in high-risk women"],"years":[1977,1998],"firstYear":1977,"regions":["US"],"target":{"key":"target","id":"estrogen-receptor","name":"Estrogen receptor (ERα)","href":"/targets/estrogen-receptor/"},"companies":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"}]},{"drug":{"id":"bromocriptine","kind":"drug","name":"Bromocriptine","route":"/drugs/bromocriptine/"},"brand":"Parlodel","status":"approved","modality":"Oral ergot dopamine D2 receptor agonist","cancers":[{"id":"pituitary-tumours","kind":"cancer","name":"Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma","route":"/cancers/pituitary-tumours/"}],"indications":["Hyperprolactinaemia-associated dysfunction including prolactin-secreting adenomas; acromegaly; Parkinson's disease"],"years":[1978],"firstYear":1978,"regions":["US"],"target":{"key":"target","id":"drd2","name":"Dopamine D2 receptor","href":"/targets/drd2/"},"companies":[{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}]},{"drug":{"id":"aminoglutethimide","kind":"drug","name":"Aminoglutethimide","route":"/drugs/aminoglutethimide/"},"brand":"Cytadren","status":"historic","modality":"Oral steroidogenesis inhibitor","cancers":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"indications":["Cushing's syndrome (used off label as medical adrenalectomy in breast and prostate cancer)"],"years":[1980],"firstYear":1980,"regions":["US"],"target":{"key":"target","id":"aromatase+cyp11a1","name":"Aromatase x CYP11A1","href":"/targets/aromatase/"},"companies":[]},{"drug":{"id":"isotretinoin","kind":"drug","name":"Isotretinoin","route":"/drugs/isotretinoin/"},"brand":"Accutane","status":"approved","modality":"Oral retinoid (differentiating agent)","cancers":[{"id":"neuroblastoma","kind":"cancer","name":"Neuroblastoma (paediatric)","route":"/cancers/neuroblastoma/"},{"id":"neuroblastoma-high-risk","kind":"cancer","name":"High-risk neuroblastoma","route":"/cancers/neuroblastoma-high-risk/"},{"id":"medulloblastoma-group-3-4","kind":"cancer","name":"Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)","route":"/cancers/medulloblastoma-group-3-4/"}],"indications":["Severe recalcitrant nodular acne (use in high-risk neuroblastoma is off-label but standard)"],"years":[1982],"firstYear":1982,"regions":["US"],"target":{"key":"target","id":"rara+rxr","name":"Retinoic acid receptor alpha x Retinoid X receptor","href":"/targets/rara/"},"companies":[]},{"drug":{"id":"dronabinol","kind":"drug","name":"Dronabinol","route":"/drugs/dronabinol/"},"brand":"Marinol / Syndros","status":"established","modality":"Oral small-molecule synthetic cannabinoid","cancers":[],"indications":["Nausea and vomiting from cancer chemotherapy in patients who have failed conventional antiemetics"],"years":[1985],"firstYear":1985,"regions":["US"],"target":{"key":"target","id":"cnr1","name":"Cannabinoid receptor 1","href":"/targets/cnr1/"},"companies":[{"id":"abbvie","kind":"company","name":"AbbVie (incl. ImmunoGen, Capstan)","route":"/companies/abbvie/"},{"id":"insys-therapeutics","kind":"company","name":"Insys Therapeutics","route":"/companies/insys-therapeutics/"}]},{"drug":{"id":"nabilone","kind":"drug","name":"Nabilone","route":"/drugs/nabilone/"},"brand":"Cesamet","status":"established","modality":"Oral small-molecule synthetic cannabinoid","cancers":[],"indications":["Nausea and vomiting from cancer chemotherapy in patients who have failed conventional antiemetics"],"years":[1985],"firstYear":1985,"regions":["US"],"target":{"key":"target","id":"cnr1","name":"Cannabinoid receptor 1","href":"/targets/cnr1/"},"companies":[{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"}]},{"drug":{"id":"octreotide-lanreotide","kind":"drug","name":"Somatostatin analogues (octreotide, lanreotide)","route":"/drugs/octreotide-lanreotide/"},"brand":"Sandostatin LAR, Somatuline Depot","status":"approved","modality":"Peptide hormone analogue (SSTR2 agonist)","cancers":[{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"small-intestinal-net","kind":"cancer","name":"Small intestinal neuroendocrine tumours","route":"/cancers/small-intestinal-net/"},{"id":"pancreatic-net","kind":"cancer","name":"Pancreatic neuroendocrine tumours","route":"/cancers/pancreatic-net/"},{"id":"lung-net","kind":"cancer","name":"Lung neuroendocrine tumours (typical and atypical carcinoid)","route":"/cancers/lung-net/"},{"id":"thymoma","kind":"cancer","name":"Thymoma (WHO types A, AB, B1, B2 and B3)","route":"/cancers/thymoma/"}],"indications":["Carcinoid syndrome symptoms (octreotide)","Unresectable GEP-NETs to improve PFS (lanreotide)"],"years":[1988,2014],"firstYear":1988,"regions":["US"],"target":{"key":"target","id":"sstr2","name":"Somatostatin receptor 2","href":"/targets/sstr2/"},"companies":[{"id":"ipsen","kind":"company","name":"Ipsen","route":"/companies/ipsen/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}]},{"drug":{"id":"flutamide","kind":"drug","name":"Flutamide","route":"/drugs/flutamide/"},"brand":"Eulexin (historic)","status":"approved","modality":"Non-steroidal antiandrogen (first generation)","cancers":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"indications":["Locally advanced (B2 to C) and metastatic (D2) prostate cancer in combination with an LHRH agonist"],"years":[1989],"firstYear":1989,"regions":["US"],"target":{"key":"target","id":"androgen-receptor","name":"Androgen receptor","href":"/targets/androgen-receptor/"},"companies":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}]},{"drug":{"id":"pentostatin","kind":"drug","name":"Pentostatin","route":"/drugs/pentostatin/"},"brand":"Nipent","status":"approved","modality":"Purine analogue, adenosine deaminase inhibitor","cancers":[{"id":"hairy-cell-leukemia","kind":"cancer","name":"Hairy cell leukaemia","route":"/cancers/hairy-cell-leukemia/"}],"indications":["Hairy cell leukaemia (initially alpha-interferon-refractory; later untreated disease)"],"years":[1991],"firstYear":1991,"regions":["US"],"target":{"key":"target","id":"ada","name":"Adenosine deaminase (ADA)","href":"/targets/ada/"},"companies":[]},{"drug":{"id":"pilocarpine","kind":"drug","name":"Pilocarpine","route":"/drugs/pilocarpine/"},"status":"approved","modality":"Cholinergic agonist (small molecule) for radiation-induced dry mouth","cancers":[{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"},{"id":"nasopharyngeal","kind":"cancer","name":"Nasopharyngeal carcinoma","route":"/cancers/nasopharyngeal/"}],"indications":["Dry mouth caused by radiotherapy for head and neck cancer"],"years":[1994],"firstYear":1994,"regions":["US"],"companies":[{"id":"eisai","kind":"company","name":"Eisai","route":"/companies/eisai/"}]},{"drug":{"id":"anastrozole","kind":"drug","name":"Anastrozole","route":"/drugs/anastrozole/"},"brand":"Arimidex","status":"approved","modality":"Oral non-steroidal aromatase inhibitor","cancers":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"ductal-carcinoma-in-situ","kind":"cancer","name":"Ductal carcinoma in situ (DCIS)","route":"/cancers/ductal-carcinoma-in-situ/"}],"indications":["Advanced breast cancer in postmenopausal women after tamoxifen","Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer"],"years":[1995,2002],"firstYear":1995,"regions":["US"],"target":{"key":"target","id":"aromatase","name":"Aromatase (CYP19A1)","href":"/targets/aromatase/"},"companies":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"}]},{"drug":{"id":"bicalutamide","kind":"drug","name":"Bicalutamide","route":"/drugs/bicalutamide/"},"brand":"Casodex","status":"approved","modality":"Oral first-generation non-steroidal antiandrogen","cancers":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"salivary-duct-carcinoma","kind":"cancer","name":"Salivary duct carcinoma","route":"/cancers/salivary-duct-carcinoma/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"indications":["Metastatic prostate cancer with LHRH analogue","Advanced prostate cancer; 150 mg for locally advanced"],"years":[1995],"firstYear":1995,"regions":["US","EU"],"target":{"key":"target","id":"androgen-receptor","name":"Androgen receptor","href":"/targets/androgen-receptor/"},"companies":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"}]},{"drug":{"id":"acitretin","kind":"drug","name":"Acitretin","route":"/drugs/acitretin/"},"brand":"Soriatane","status":"approved","modality":"Oral systemic retinoid","cancers":[{"id":"cutaneous-scc","kind":"cancer","name":"Cutaneous squamous cell carcinoma","route":"/cancers/cutaneous-scc/"}],"indications":["Severe psoriasis (oncology use as chemoprevention of squamous cell carcinoma is off-label)"],"years":[1996],"firstYear":1996,"regions":["US"],"target":{"key":"target","id":"rara+rxr","name":"Retinoic acid receptor alpha x Retinoid X receptor","href":"/targets/rara/"},"companies":[]},{"drug":{"id":"cabergoline","kind":"drug","name":"Cabergoline","route":"/drugs/cabergoline/"},"brand":"Dostinex","status":"approved","modality":"Oral long-acting dopamine D2 receptor agonist","cancers":[{"id":"pituitary-tumours","kind":"cancer","name":"Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma","route":"/cancers/pituitary-tumours/"}],"indications":["Hyperprolactinaemic disorders, idiopathic or due to pituitary adenomas"],"years":[1996],"firstYear":1996,"regions":["US"],"target":{"key":"target","id":"drd2","name":"Dopamine D2 receptor","href":"/targets/drd2/"},"companies":[{"id":"pfizer","kind":"company","name":"Pfizer (incl. 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Risk is highest in bulky CLL and high-count AML, which is why venetoclax starts at a tiny dose and ramps up over weeks.","category":"Side effects","from":[{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"}]}],"events":[{"group":"Diarrhoea","drugs":35,"maxGrade3":40,"maxAnyGrade":95,"examples":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"}]},{"group":"Tiredness (fatigue)","drugs":33,"maxGrade3":13,"maxAnyGrade":69,"examples":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"axitinib","kind":"drug","name":"Axitinib","route":"/drugs/axitinib/"}]},{"group":"Nausea or 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syndrome","drugs":11,"maxGrade3":17,"maxAnyGrade":60,"examples":[{"id":"axitinib","kind":"drug","name":"Axitinib","route":"/drugs/axitinib/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"fruquintinib","kind":"drug","name":"Fruquintinib","route":"/drugs/fruquintinib/"}]}],"drugsWithToxicity":75},"resistance":[{"id":"egfr-tki","drugClass":"EGFR tyrosine kinase inhibitors (osimertinib)","tldr":"Lung cancers on osimertinib escape by mutating the drug's binding site, switching on a bypass receptor (MET), or changing cell type entirely.","route":"/resistance/#egfr-tki","exemplars":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"amivantamab","kind":"drug","name":"Amivantamab","route":"/drugs/amivantamab/"}],"mechanisms":[{"name":"On-target EGFR C797S","category":"on-target","categoryLabel":"On-target","how":"Mutation of the cysteine that osimertinib binds covalently; abolishes drug binding while EGFR stays active.","frequency":"~7 to 15% after first-line osimertinib","route":"/resistance/#egfr-tki-on-target-egfr-c797s"},{"name":"MET amplification / bypass","category":"bypass","categoryLabel":"Bypass","how":"Amplified MET signals to PI3K/MAPK independently of EGFR.","frequency":"~15 to 20%","route":"/resistance/#egfr-tki-met-amplification-bypass"},{"name":"Histologic transformation","category":"lineage","categoryLabel":"Lineage switch","how":"Conversion to small-cell lung cancer (RB1/TP53 co-loss) or squamous histology; EGFR mutation persists but the cell no longer depends on it.","frequency":"~5 to 15%","route":"/resistance/#egfr-tki-histologic-transformation"},{"name":"Pre-existing minor resistant clones","category":"other","categoryLabel":"Other","how":"Small subclones that already carry a resistance route expand under single-agent TKI; adding chemotherapy up front kills them before they take over.","route":"/resistance/#egfr-tki-pre-existing-minor-resistant-clones"}],"sources":[{"label":"FLAURA2 (NEJM 2023)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2306434"}]},{"id":"alk-tki","drugClass":"ALK tyrosine kinase inhibitors","tldr":"Each ALK drug generation was beaten by a new mutation in the kinase; lorlatinib covers nearly all of them, so resistance now runs through other pathways.","route":"/resistance/#alk-tki","exemplars":[{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"}],"mechanisms":[{"name":"Solvent-front G1202R and compound mutations","category":"on-target","categoryLabel":"On-target","how":"Steric clash blocks first- and second-generation inhibitors; compound mutations (G1202R + L1196M etc.) emerge after lorlatinib.","frequency":"G1202R in ~40% after second-generation TKIs","route":"/resistance/#alk-tki-solvent-front-g1202r-and-compound-mutations"},{"name":"Bypass signalling (MET, EGFR, KRAS)","category":"bypass","categoryLabel":"Bypass","how":"Alternative receptors or downstream mutations re-activate MAPK/PI3K.","route":"/resistance/#alk-tki-bypass-signalling-met-egfr-kras"}],"sources":[{"label":"CROWN 5-year (J Clin Oncol 2024)","url":"https://ascopubs.org/doi/10.1200/JCO.24.00581"}]},{"id":"cdk46-endocrine","drugClass":"CDK4/6 inhibitor + endocrine therapy","tldr":"Hormone-positive breast cancer escapes either by mutating the oestrogen receptor so it no longer needs oestrogen, or by rewiring the cell-cycle engine (RB loss, cyclin E) so CDK4/6 no longer matters.","route":"/resistance/#cdk46-endocrine","exemplars":[{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"},{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"elacestrant","kind":"drug","name":"Elacestrant","route":"/drugs/elacestrant/"},{"id":"vepdegestrant","kind":"drug","name":"Vepdegestrant","route":"/drugs/vepdegestrant/"}],"mechanisms":[{"name":"ESR1 ligand-binding-domain mutations","category":"on-target","categoryLabel":"On-target","how":"Y537S/D538G render ER constitutively active; arise under aromatase-inhibitor pressure, detectable in ctDNA.","frequency":"~30 to 40% after AI progression","route":"/resistance/#cdk46-endocrine-esr1-ligand-binding-domain-mutations"},{"name":"RB1 loss","category":"bypass","categoryLabel":"Bypass","how":"Without RB, CDK4/6 inhibition cannot arrest the cell cycle.","frequency":"~5 to 10% acquired","route":"/resistance/#cdk46-endocrine-rb1-loss"},{"name":"Cyclin E / CDK2 activation","category":"bypass","categoryLabel":"Bypass","how":"CCNE1 amplification or CDK2 activity bypasses the G1 block.","route":"/resistance/#cdk46-endocrine-cyclin-e-cdk2-activation"},{"name":"PI3K/AKT/mTOR activation","category":"bypass","categoryLabel":"Bypass","how":"PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.","frequency":"PIK3CA ~40% of HR+ disease","route":"/resistance/#cdk46-endocrine-pi3k-akt-mtor-activation"}],"sources":[{"label":"SERENA-6 (ASCO 2026 coverage, BCRF)","url":"https://www.bcrf.org/blog/asco-2026-key-takeaways/"}]},{"id":"parp-inhibitor","drugClass":"PARP inhibitors","tldr":"Tumours that lost BRCA can regain repair by re-mutating BRCA back into working order, or by finding another way to protect their DNA.","route":"/resistance/#parp-inhibitor","exemplars":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}],"mechanisms":[{"name":"BRCA1/2 reversion mutations","category":"bypass","categoryLabel":"Bypass","how":"Secondary mutations restore the open reading frame and homologous recombination; also confers platinum resistance.","frequency":"~20 to 40% of PARPi-resistant ovarian cancer","route":"/resistance/#parp-inhibitor-brca1-2-reversion-mutations"},{"name":"Restoration of HR via 53BP1/Shieldin loss","category":"bypass","categoryLabel":"Bypass","how":"Loss of end-protection factors lets BRCA1-deficient cells resect DNA ends and repair by HR.","route":"/resistance/#parp-inhibitor-restoration-of-hr-via-53bp1-shieldin-loss"},{"name":"Replication fork protection and PARP1 loss","category":"on-target","categoryLabel":"On-target","how":"Stabilised forks tolerate PARP trapping; PARP1 mutations abolish trapping.","route":"/resistance/#parp-inhibitor-replication-fork-protection-and-parp1-loss"},{"name":"Drug efflux (ABCB1)","category":"pharmacology","categoryLabel":"Pharmacology","how":"Olaparib and rucaparib are P-gp substrates.","route":"/resistance/#parp-inhibitor-drug-efflux-abcb1"}],"sources":[{"label":"SOLO-1 7-year OS (J Clin Oncol 2023)","url":"https://ascopubs.org/doi/10.1200/JCO.22.01549"}]},{"id":"kras-g12c","drugClass":"KRAS G12C inhibitors","tldr":"Blocking one RAS mutant makes the cell turn up every upstream receptor and often mutate KRAS again; that is why responses are short and why combinations and pan-RAS drugs followed.","route":"/resistance/#kras-g12c","exemplars":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"}],"mechanisms":[{"name":"Adaptive RTK feedback (EGFR, others)","category":"bypass","categoryLabel":"Bypass","how":"Relief of ERK-mediated negative feedback re-activates receptors within hours, producing new wild-type KRAS-GTP the drug cannot bind.","frequency":"Universal, especially in colorectal cancer","route":"/resistance/#kras-g12c-adaptive-rtk-feedback-egfr-others"},{"name":"Secondary KRAS mutations (Y96D, R68S, H95) and amplification","category":"on-target","categoryLabel":"On-target","how":"Alter the switch-II pocket or overwhelm the drug.","route":"/resistance/#kras-g12c-secondary-kras-mutations-y96d-r68s-h95-and-amplification"},{"name":"Bypass alterations (MET amplification, NRAS/BRAF mutations, RTK fusions)","category":"bypass","categoryLabel":"Bypass","how":"Alternative MAPK activation.","route":"/resistance/#kras-g12c-bypass-alterations-met-amplification-nras-braf-mutations-rtk-fusions"}],"sources":[{"label":"CodeBreaK 300 (NEJM 2023)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2308795"}]},{"id":"ar-pathway","drugClass":"Androgen receptor pathway inhibitors (abiraterone, enzalutamide)","tldr":"Prostate cancer keeps the androgen receptor working without hormones (amplification, splice variants), or abandons it and becomes a neuroendocrine cancer.","route":"/resistance/#ar-pathway","exemplars":[{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"},{"id":"pluvicto","kind":"drug","name":"Lutetium-177 vipivotide tetraxetan","route":"/drugs/pluvicto/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}],"mechanisms":[{"name":"AR amplification and ligand-binding-domain mutations","category":"on-target","categoryLabel":"On-target","how":"More receptor, or mutations (F877L, T878A) that turn antagonists into agonists.","frequency":"AR amplification ~30 to 50% of CRPC","route":"/resistance/#ar-pathway-ar-amplification-and-ligand-binding-domain-mutations"},{"name":"AR splice variants (AR-V7)","category":"on-target","categoryLabel":"On-target","how":"Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.","route":"/resistance/#ar-pathway-ar-splice-variants-ar-v7"},{"name":"Lineage plasticity to neuroendocrine prostate cancer","category":"lineage","categoryLabel":"Lineage switch","how":"RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.","frequency":"~15 to 20% of CRPC","route":"/resistance/#ar-pathway-lineage-plasticity-to-neuroendocrine-prostate-cancer"},{"name":"PI3K/AKT activation via PTEN loss","category":"bypass","categoryLabel":"Bypass","how":"Reciprocal feedback between AR and PI3K pathways.","frequency":"PTEN loss ~40% of mCRPC","route":"/resistance/#ar-pathway-pi3k-akt-activation-via-pten-loss"},{"name":"Glucocorticoid receptor substitution","category":"bypass","categoryLabel":"Bypass","how":"GR drives an AR-like transcriptional programme under enzalutamide.","route":"/resistance/#ar-pathway-glucocorticoid-receptor-substitution"}],"sources":[{"label":"CAPItello-281 (FDA approval Q2 2026, AACR digest)","url":"https://www.aacr.org/blog/2026/07/02/fda-approvals-in-oncology-april-june-2026/"}]}],"papers":[{"id":"paper-adaura-8-year-os-jto-2026","kind":"paper","name":"ADAURA: exploratory eight-year overall survival update for adjuvant osimertinib in resected EGFR-mutated stage IB to IIIA lung cancer","route":"/key-papers/paper-adaura-8-year-os-jto-2026/","year":2026,"journal":"Journal of Thoracic Oncology","paperType":"rct","tldr":"Eight years after surgery, about three in four patients who took osimertinib for three years were still alive, compared with under six in ten on placebo: the longest survival follow-up from any global adjuvant trial in EGFR-mutated lung cancer.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"paper-litespark-011-motzer-lancet-2026","kind":"paper","name":"Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial","route":"/key-papers/paper-litespark-011-motzer-lancet-2026/","year":2026,"journal":"The Lancet","paperType":"rct","tldr":"In 747 people whose advanced clear-cell kidney cancer had grown after immunotherapy, belzutifan plus lenvatinib kept the cancer from progressing for a median of 14.8 months against 10.7 with cabozantinib, but at this interim look the survival difference was not statistically significant.","via":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}]},{"id":"paper-guilford-antiparasitic-acupuncture-meridian-case-series-2026","kind":"paper","name":"Cancer therapy using antiparasitic medications guided by acupuncture meridian assessment: a case series of six patients","route":"/key-papers/paper-guilford-antiparasitic-acupuncture-meridian-case-series-2026/","year":2026,"journal":"Integrative Medicine (Encinitas)","paperType":"observational","tldr":"Six patients with advanced cancers treated over a decade with antiparasitic drugs chosen by measuring electrical conductance at acupuncture points were reported to have lived longer than expected; the method has no established basis and the series has no controls.","via":[{"id":"mebendazole","kind":"drug","name":"Mebendazole","route":"/drugs/mebendazole/"}]},{"id":"paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","kind":"paper","name":"Capivasertib plus paclitaxel as first-line treatment for metastatic triple-negative breast cancer: results from the randomised, global phase III CAPItello-290 trial","route":"/key-papers/paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026/","year":2026,"journal":"Annals of Oncology","paperType":"rct","tldr":"The 812-patient trial in which adding the AKT inhibitor capivasertib to first-line paclitaxel did not lengthen life in metastatic triple-negative breast cancer (17.7 versus 18.0 months), even in the 31 percent of patients whose tumours carried the pathway alterations it targets.","via":[{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"}]},{"id":"paper-flaura2-long-term-safety-lung-cancer-2026","kind":"paper","name":"FLAURA2: long-term safety of first-line osimertinib plus platinum-pemetrexed in EGFR-mutated advanced lung cancer","route":"/key-papers/paper-flaura2-long-term-safety-lung-cancer-2026/","year":2026,"journal":"Lung Cancer","paperType":"rct","tldr":"Side effects of the osimertinib plus chemotherapy combination were most frequent in the first four chemotherapy cycles and fell steadily once patients moved to maintenance and then to osimertinib alone; few had to stop osimertinib because of them.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"paper-rockwell-ivermectin-benzimidazole-prescribing-jama-netw-open-2026","kind":"paper","name":"Ivermectin-benzimidazole prescribing following celebrity endorsement","route":"/key-papers/paper-rockwell-ivermectin-benzimidazole-prescribing-jama-netw-open-2026/","year":2026,"journal":"JAMA Network Open","paperType":"observational","tldr":"After a January 2025 podcast promoted ivermectin with a dog dewormer as a cancer cure, US prescriptions of the combination doubled overall and rose 2.6-fold among people with cancer, most steeply in the South.","via":[{"id":"mebendazole","kind":"drug","name":"Mebendazole","route":"/drugs/mebendazole/"}]},{"id":"paper-krystal-12-plain-language-summary-future-oncol-2026","kind":"paper","name":"KRYSTAL-12 plain language summary: adagrasib for non-small-cell lung cancer with KRAS G12C mutations","route":"/key-papers/paper-krystal-12-plain-language-summary-future-oncol-2026/","year":2026,"journal":"Future Oncology","paperType":"review","tldr":"A plain-language account of the KRYSTAL-12 trial, written for patients and carers, explaining how adagrasib compared with docetaxel chemotherapy in previously treated KRAS G12C lung cancer.","via":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"}]},{"id":"paper-hulscher-ivermectin-mebendazole-cohort-anticancer-res-2026","kind":"paper","name":"Real-world clinical outcomes of ivermectin and mebendazole in cancer patients: results from a prospective observational cohort (with 2026 expression of concern)","route":"/key-papers/paper-hulscher-ivermectin-mebendazole-cohort-anticancer-res-2026/","year":2026,"journal":"Anticancer Research","paperType":"observational","tldr":"A telemedicine company's survey of patients it prescribed ivermectin and mebendazole reported that most felt better; the journal has attached an expression of concern while it checks whether the diagnoses, the regressions and the ethical approval can be verified.","via":[{"id":"mebendazole","kind":"drug","name":"Mebendazole","route":"/drugs/mebendazole/"}]},{"id":"paper-transcend-miller-nejm-2026","kind":"paper","name":"Setmelanotide for the treatment of acquired hypothalamic obesity (TRANSCEND)","route":"/key-papers/paper-transcend-miller-nejm-2026/","year":2026,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In children and adults whose severe weight gain followed damage to the hypothalamus, a year of daily setmelanotide injections cut body-mass index by 16.5 percent while placebo recipients gained 3.3 percent, and hunger fell more too.","via":[{"id":"setmelanotide","kind":"drug","name":"Setmelanotide","route":"/drugs/setmelanotide/"}]},{"id":"paper-olympia-6-year-update-ann-oncol-2026","kind":"paper","name":"Sustained benefit of adjuvant olaparib in women with germline BRCA1- and BRCA2-associated high-risk HER2-negative early breast cancer: updated results from the OlympiA phase III trial","route":"/key-papers/paper-olympia-6-year-update-ann-oncol-2026/","year":2026,"journal":"Annals of Oncology","paperType":"rct","tldr":"The six-year OlympiA update: the year of olaparib still cut relapse by 35 percent and death by 28 percent, six-year survival was 87.5 versus 83.2 percent, there were fewer new BRCA-related breast and ovarian cancers, and no excess of leukaemia.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"paper-amplify-acalabrutinib-venetoclax-nejm-2025","kind":"paper","name":"AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients","route":"/key-papers/paper-amplify-acalabrutinib-venetoclax-nejm-2025/","year":2025,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In AMPLIFY, an all-oral, 14-month course of acalabrutinib plus venetoclax beat FCR or BR chemo-immunotherapy in fit CLL patients, offering a time-limited alternative to indefinite pills.","via":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"paper-roman-anderson-eclinicalmedicine-2025","kind":"paper","name":"Avasopasem manganese treatment for severe oral mucositis from chemoradiotherapy for locally advanced head and neck cancer: phase 3 randomized controlled trial (ROMAN)","route":"/key-papers/paper-roman-anderson-eclinicalmedicine-2025/","year":2025,"journal":"eClinicalMedicine","paperType":"rct","tldr":"Giving avasopasem before each radiotherapy session lowered the share of head and neck cancer patients who got severe mouth ulcers from 64 to 54 percent and cut how long the ulcers lasted from 18 days to 8, but the gain was smaller than hoped and the FDA wanted another trial.","via":[{"id":"avasopasem-manganese","kind":"drug","name":"Avasopasem manganese","route":"/drugs/avasopasem-manganese/"}]},{"id":"paper-beamion-lung-1-zongertinib-nejm-2025","kind":"paper","name":"Beamion LUNG-1: zongertinib in previously treated HER2-mutant non-small-cell lung cancer","route":"/key-papers/paper-beamion-lung-1-zongertinib-nejm-2025/","year":2025,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The oral HER2-selective kinase inhibitor zongertinib shrank tumours in about seven in ten patients with previously treated HER2-mutant lung cancer with little of the diarrhoea and rash that plagued earlier HER2 pills, becoming the first oral drug approved for this driver.","via":[{"id":"zongertinib","kind":"drug","name":"Zongertinib","route":"/drugs/zongertinib/"}]},{"id":"paper-breakwater-nejm-2025","kind":"paper","name":"BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer","route":"/key-papers/paper-breakwater-nejm-2025/","year":2025,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding a BRAF inhibitor and an EGFR antibody to first-line chemotherapy roughly doubled survival in BRAF V600E-mutated metastatic bowel cancer, one of the worst-prognosis subtypes.","via":[{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-cabinet-cabozantinib-nejm-2024","kind":"paper","name":"CABINET (Alliance A021602): cabozantinib for advanced neuroendocrine tumours","route":"/key-papers/paper-cabinet-cabozantinib-nejm-2024/","year":2025,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Cabozantinib delayed progression in previously treated advanced neuroendocrine tumours of both pancreatic and extra-pancreatic origin compared with placebo, adding a new option after somatostatin analogues, everolimus or radioligand therapy.","via":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"}]},{"id":"paper-cepheus-dara-vrd-natmed-2025","kind":"paper","name":"CEPHEUS: daratumumab quadruplet for newly diagnosed myeloma patients not having a transplant, with MRD-negativity as the main endpoint","route":"/key-papers/paper-cepheus-dara-vrd-natmed-2025/","year":2025,"journal":"Nature Medicine","paperType":"rct","tldr":"In patients who were transplant-ineligible or deferred transplant, the daratumumab quadruplet raised deep-remission rates from about 39% to 61% and cut progression risk by 43%.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-cll12-ibrutinib-early-stage-langerbeins-jco-2025","kind":"paper","name":"CLL12: ibrutinib in early-stage chronic lymphocytic leukaemia, a randomised placebo-controlled phase 3 trial","route":"/key-papers/paper-cll12-ibrutinib-early-stage-langerbeins-jco-2025/","year":2025,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Giving the pill ibrutinib to people with early, symptom-free chronic lymphocytic leukaemia delayed the disease but, after almost six years, did not help them live longer than placebo, so doctors should keep watching and waiting rather than treating early.","via":[{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"}]},{"id":"paper-leap-012-lancet-2025","kind":"paper","name":"LEAP-012: transarterial chemoembolisation with lenvatinib plus pembrolizumab versus placebo for unresectable non-metastatic hepatocellular carcinoma","route":"/key-papers/paper-leap-012-lancet-2025/","year":2025,"journal":"The Lancet","paperType":"rct","tldr":"Adding lenvatinib and pembrolizumab to chemoembolisation delayed progression in intermediate-stage liver cancer, the second trial to show that systemic therapy improves on embolisation alone, at the cost of more side effects.","via":[{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}]},{"id":"paper-gilene-ivermectin-toxicity-paediatric-oncology-2025","kind":"paper","name":"The threat of medical misinformation: a case of ivermectin toxicity in a pediatric oncology patient","route":"/key-papers/paper-gilene-ivermectin-toxicity-paediatric-oncology-2025/","year":2025,"journal":"Pediatric Blood & Cancer","paperType":"observational","tldr":"A letter describing severe ivermectin poisoning in a young patient with bone cancer who was also taking regorafenib, a cancer drug that shares the enzyme ivermectin is cleared by.","via":[{"id":"regorafenib","kind":"drug","name":"Regorafenib","route":"/drugs/regorafenib/"}]},{"id":"paper-duo-e-jco-2023","kind":"paper","name":"DUO-E: durvalumab with carboplatin-paclitaxel and maintenance durvalumab with or without olaparib in advanced endometrial cancer","route":"/key-papers/paper-duo-e-jco-2023/","year":2024,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Adding durvalumab to first-line chemotherapy delayed progression in advanced endometrial cancer, and adding the PARP inhibitor olaparib to durvalumab maintenance helped further in mismatch repair-proficient tumours.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"paper-zhou-j-thorac-oncol","kind":"paper","name":"Efficacy and Safety of KRASG12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study","route":"/key-papers/paper-zhou-j-thorac-oncol/","year":2024,"journal":"Journal of Thoracic Oncology","paperType":"observational","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 39127176 and published in Journal of Thoracic Oncology; the citing page links this DOI, which is how the record was matched.","via":[{"id":"fulzerasib","kind":"drug","name":"Fulzerasib","route":"/drugs/fulzerasib/"}]},{"id":"paper-firstmappp-sunitinib-metastatic-ppgl-baudin-lancet-2024","kind":"paper","name":"FIRSTMAPPP: sunitinib for metastatic progressive phaeochromocytomas and paragangliomas","route":"/key-papers/paper-firstmappp-sunitinib-metastatic-ppgl-baudin-lancet-2024/","year":2024,"journal":"The Lancet","paperType":"rct","tldr":"In the first randomised trial in these rare tumours, sunitinib kept 36 percent of patients free of progression at one year against 19 percent on placebo.","via":[{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-firstmappp-sunitinib-metastatic-ppgl-lancet-2024","kind":"paper","name":"FIRSTMAPPP: sunitinib for metastatic progressive pheochromocytomas and paragangliomas","route":"/key-papers/paper-firstmappp-sunitinib-metastatic-ppgl-lancet-2024/","year":2024,"journal":"The Lancet","paperType":"rct","tldr":"The first randomised trial ever completed in metastatic pheochromocytoma and paraganglioma found that the kinase inhibitor sunitinib roughly doubled the proportion of patients whose disease had not progressed at one year compared with placebo.","via":[{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-bedrosian-asco-sso-germline-testing-breast-jco-2024","kind":"paper","name":"Germline testing in patients with breast cancer: ASCO-Society of Surgical Oncology guideline","route":"/key-papers/paper-bedrosian-asco-sso-germline-testing-breast-jco-2024/","year":2024,"journal":"Journal of Clinical Oncology","paperType":"guideline","tldr":"The 2024 American guideline says every woman diagnosed with breast cancer at 65 or under should be offered BRCA1/2 testing, as should anyone who might be treated with a PARP inhibitor, whatever her family history.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}]},{"id":"paper-imerge-imetelstat-mds-lancet-2024","kind":"paper","name":"IMerge: imetelstat, a telomerase inhibitor, for transfusion-dependent lower-risk MDS after erythropoietin has failed","route":"/key-papers/paper-imerge-imetelstat-mds-lancet-2024/","year":2024,"journal":"The Lancet","paperType":"rct","tldr":"In IMerge, imetelstat, the first telomerase inhibitor to reach approval, freed about 40% of heavily transfused MDS patients from transfusions for eight weeks and 28% for six months, versus 15% and 3% with placebo.","via":[{"id":"imetelstat","kind":"drug","name":"Imetelstat","route":"/drugs/imetelstat/"}]},{"id":"paper-intuitt-nf2-brigatinib-plotkin-nejm-2024","kind":"paper","name":"INTUITT-NF2: brigatinib in NF2-related schwannomatosis with progressive tumours","route":"/key-papers/paper-intuitt-nf2-brigatinib-plotkin-nejm-2024/","year":2024,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"In people with the inherited condition NF2 whose nerve and brain-lining tumours were growing despite earlier treatment, the kinase inhibitor brigatinib shrank some tumours, slowed the growth of all types and improved hearing in a third of affected ears without serious toxicity.","via":[{"id":"brigatinib","kind":"drug","name":"Brigatinib","route":"/drugs/brigatinib/"}]},{"id":"paper-mariposa-nejm-2024","kind":"paper","name":"MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-mariposa-nejm-2024/","year":2024,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Combining an EGFR-MET bispecific antibody with a third-generation EGFR pill beat osimertinib alone, delaying progression by about seven months and later improving survival, at the cost of more side effects.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-morpho-gilteritinib-levis-jco-2024","kind":"paper","name":"MORPHO: gilteritinib as post-transplant maintenance for FLT3-ITD acute myeloid leukaemia","route":"/key-papers/paper-morpho-gilteritinib-levis-jco-2024/","year":2024,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Two years of the FLT3 blocker gilteritinib after a stem-cell transplant did not significantly reduce relapses across all patients, but it clearly did in the half whose highly sensitive blood tests still found traces of the leukaemia, one of the first results to support choosing post-transplant treatment by residual disease.","via":[{"id":"gilteritinib","kind":"drug","name":"Gilteritinib","route":"/drugs/gilteritinib/"}]},{"id":"paper-natalee-nejm-2024","kind":"paper","name":"NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer","route":"/key-papers/paper-natalee-nejm-2024/","year":2024,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Three years of the CDK4/6 inhibitor ribociclib added to hormone therapy reduced relapses in stage II-III hormone-receptor-positive breast cancer, including some node-negative patients.","via":[{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"},{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"paper-arrillaga-romany-j-clin-oncol","kind":"paper","name":"ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma","route":"/key-papers/paper-arrillaga-romany-j-clin-oncol/","year":2024,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 38335473 and published in Journal of Clinical Oncology; the citing page links this DOI, which is how the record was matched.","via":[{"id":"dordaviprone","kind":"drug","name":"Dordaviprone","route":"/drugs/dordaviprone/"}]},{"id":"paper-perseus-dara-vrd-transplant-nejm-2024","kind":"paper","name":"PERSEUS: daratumumab added to bortezomib-lenalidomide-dexamethasone around autologous transplant in newly diagnosed myeloma","route":"/key-papers/paper-perseus-dara-vrd-transplant-nejm-2024/","year":2024,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding daratumumab to the standard three-drug induction, transplant and maintenance cut progression or death by 58% and pushed MRD-negativity to three-quarters of patients.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024","kind":"paper","name":"TRIANGLE: ibrutinib with immunochemotherapy with or without autologous transplant versus immunochemotherapy and transplant in untreated mantle cell lymphoma","route":"/key-papers/paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024/","year":2024,"journal":"The Lancet","paperType":"rct","tldr":"Adding ibrutinib to first-line treatment for younger people with mantle cell lymphoma kept more of them free of treatment failure at three years, and the stem cell transplant that was standard was not shown to add benefit once ibrutinib was used.","via":[{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"}]},{"id":"paper-trident-1-repotrectinib-nejm-2024","kind":"paper","name":"TRIDENT-1: repotrectinib in ROS1 fusion-positive non-small-cell lung cancer","route":"/key-papers/paper-trident-1-repotrectinib-nejm-2024/","year":2024,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The next-generation ROS1 and TRK inhibitor repotrectinib shrank tumours in almost four in five untreated patients with ROS1-positive lung cancer, kept the disease under control for nearly three years, and worked in about four in ten patients after crizotinib including those with the resistant G2032R mutation.","via":[{"id":"repotrectinib","kind":"drug","name":"Repotrectinib","route":"/drugs/repotrectinib/"}]},{"id":"paper-a071401-brastianos-jco-2023","kind":"paper","name":"Alliance A071401: phase II trial of focal adhesion kinase inhibition in meningiomas with somatic NF2 mutations","route":"/key-papers/paper-a071401-brastianos-jco-2023/","year":2023,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"In the first trial to match meningioma patients to a drug by their tumour's mutation, a FAK-blocking tablet kept 83 percent of low-grade and 33 percent of higher-grade NF2-mutant tumours from progressing for six months, clearing the bar the trial had set.","via":[{"id":"gsk2256098","kind":"drug","name":"GSK2256098","route":"/drugs/gsk2256098/"}]},{"id":"paper-augment-101-revumenib-menin-nature-2023","kind":"paper","name":"AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation","route":"/key-papers/paper-augment-101-revumenib-menin-nature-2023/","year":2023,"journal":"Nature","paperType":"translational","tldr":"Blocking menin, a scaffold protein the leukaemia depends on, produced remissions in heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukaemia.","via":[{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}]},{"id":"paper-qin-lancet","kind":"paper","name":"Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study","route":"/key-papers/paper-qin-lancet/","year":2023,"journal":"The Lancet","paperType":"rct","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 37499670 and published in The Lancet; the citing page links this DOI, which is how the record was matched.","via":[{"id":"rivoceranib","kind":"drug","name":"Rivoceranib (apatinib)","route":"/drugs/rivoceranib/"}]},{"id":"paper-capitello-291-nejm-2023","kind":"paper","name":"CAPItello-291: capivasertib plus fulvestrant in hormone receptor-positive advanced breast cancer","route":"/key-papers/paper-capitello-291-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding the AKT inhibitor capivasertib to fulvestrant doubled the time to progression in advanced hormone receptor-positive breast cancer after aromatase inhibitor failure, with the largest gain in tumours with PIK3CA, AKT1 or PTEN alterations.","via":[{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"}]},{"id":"paper-cartitude-4-cilta-cel-nejm-2023","kind":"paper","name":"CARTITUDE-4: cilta-cel CAR-T versus standard combinations after one to three prior lines of myeloma therapy","route":"/key-papers/paper-cartitude-4-cilta-cel-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Moving BCMA CAR-T to the second line cut the risk of progression or death by 74% compared with standard triplets, and later improved overall survival.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","kind":"paper","name":"CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer","route":"/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The first KRAS-blocking pill shrank tumours in about one in five patients with heavily pretreated pancreatic cancer carrying the G12C mutation and controlled the disease in most for a few months. Modest as that is, it was the first direct hit on the gene that drives nearly every pancreatic cancer.","via":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}]},{"id":"paper-codebreak-200-lancet-2023","kind":"paper","name":"CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug","route":"/key-papers/paper-codebreak-200-lancet-2023/","year":2023,"journal":"The Lancet","paperType":"rct","tldr":"The first drug to directly block mutant KRAS beat docetaxel chemotherapy on delaying progression in KRAS G12C lung cancer, but only by about a month, and did not improve survival.","via":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}]},{"id":"paper-codebreak-300-nejm-2023","kind":"paper","name":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer","route":"/key-papers/paper-codebreak-300-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Combining a KRAS G12C inhibitor with an EGFR antibody produced responses in about a quarter of patients with heavily pretreated KRAS G12C bowel cancer, versus none with standard chemotherapy, and more than doubled the time to progression.","via":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}]},{"id":"paper-commands-luspatercept-mds-lancet-2023","kind":"paper","name":"COMMANDS: luspatercept versus epoetin alfa as first treatment for anaemia in lower-risk MDS needing transfusions","route":"/key-papers/paper-commands-luspatercept-mds-lancet-2023/","year":2023,"journal":"The Lancet","paperType":"rct","tldr":"In COMMANDS, luspatercept, a drug that frees late-stage red cell production from TGF-beta-family braking, freed 59% of transfusion-dependent MDS patients from transfusions for at least 12 weeks, against 31% with the standard erythropoietin injection.","via":[{"id":"imetelstat","kind":"drug","name":"Imetelstat","route":"/drugs/imetelstat/"}]},{"id":"paper-li-j-thorac-oncol","kind":"paper","name":"D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRAS G12C in Patients With NSCLC: Phase 1 Study Results","route":"/key-papers/paper-li-j-thorac-oncol/","year":2023,"journal":"Journal of Thoracic Oncology","paperType":"observational","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 36948246 and published in Journal of Thoracic Oncology; the citing page links this DOI, which is how the record was matched.","via":[{"id":"garsorasib","kind":"drug","name":"Garsorasib","route":"/drugs/garsorasib/"}]},{"id":"paper-hargrave-dabrafenib-trametinib-paediatric-hgg-jco-2023","kind":"paper","name":"Dabrafenib plus trametinib in relapsed or refractory BRAF V600-mutant paediatric high-grade glioma","route":"/key-papers/paper-hargrave-dabrafenib-trametinib-paediatric-hgg-jco-2023/","year":2023,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"In children whose BRAF V600-mutant high-grade glioma had relapsed, the combination of dabrafenib and trametinib shrank tumours in more than half and gave responses lasting well over a year, far better than historical chemotherapy.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-dreamseq-jco-2023","kind":"paper","name":"DREAMseq (ECOG-ACRIN EA6134): sequencing dabrafenib-trametinib and nivolumab-ipilimumab in BRAF-mutant metastatic melanoma","route":"/key-papers/paper-dreamseq-jco-2023/","year":2023,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Starting with nivolumab plus ipilimumab and switching to BRAF-MEK inhibitors at progression gave 20 percentage points better two-year survival than the reverse order in BRAF-mutant advanced melanoma, settling the question of which to use first.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-embark-nejm-2023","kind":"paper","name":"EMBARK: enzalutamide with or without leuprolide in high-risk biochemically recurrent prostate cancer","route":"/key-papers/paper-embark-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In men whose PSA was rising fast after surgery or radiotherapy without visible metastases, enzalutamide with or without hormone injections delayed metastases by years compared with hormone injections alone, with treatment paused when the PSA fell to undetectable.","via":[{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}]},{"id":"paper-indigo-nejm-2023","kind":"paper","name":"INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma","route":"/key-papers/paper-indigo-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"An oral drug that blocks the mutant IDH enzyme more than doubled the time before slow-growing IDH-mutant brain tumours progressed, letting patients postpone radiotherapy and chemotherapy for years.","via":[{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","kind":"paper","name":"KRYSTAL-1: adagrasib in advanced solid tumours harbouring a KRAS G12C mutation, including pancreatic cancer","route":"/key-papers/paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023/","year":2023,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Adagrasib, the second KRAS G12C pill, shrank tumours in about a third of patients with pancreatic cancer and in two in five with bile duct cancer in this basket study, with disease control for several months.","via":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"}]},{"id":"paper-krystal-1-crc-yaeger-nejm-2023","kind":"paper","name":"KRYSTAL-1: adagrasib with or without cetuximab in KRAS G12C-mutated colorectal cancer","route":"/key-papers/paper-krystal-1-crc-yaeger-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The KRAS G12C inhibitor adagrasib on its own shrank about one in five previously treated colorectal cancers, but combined with the EGFR antibody cetuximab the response rate rose to nearly half, showing the two drugs are needed together in this disease.","via":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"}]},{"id":"paper-libretto-431-nejm-2023","kind":"paper","name":"LIBRETTO-431: first-line selpercatinib versus chemotherapy with or without pembrolizumab in RET fusion-positive lung cancer","route":"/key-papers/paper-libretto-431-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Given as first treatment, selpercatinib more than doubled the time to progression compared with platinum-pemetrexed chemotherapy plus pembrolizumab in RET fusion-positive lung cancer, and protected against brain metastases.","via":[{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"}]},{"id":"paper-libretto-531-nejm-2023","kind":"paper","name":"LIBRETTO-531: selpercatinib versus cabozantinib or vandetanib in advanced RET-mutant medullary thyroid cancer","route":"/key-papers/paper-libretto-531-nejm-2023/","year":2023,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"The selective RET inhibitor selpercatinib cut the risk of progression by more than 70 percent compared with the older multikinase drugs cabozantinib and vandetanib in RET-mutant medullary thyroid cancer, with fewer side effects.","via":[{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"}]},{"id":"paper-momentum-momelotinib-lancet-2023","kind":"paper","name":"MOMENTUM: momelotinib versus danazol for myelofibrosis patients with anaemia after a prior JAK inhibitor","route":"/key-papers/paper-momentum-momelotinib-lancet-2023/","year":2023,"journal":"The Lancet","paperType":"rct","tldr":"A JAK inhibitor that also blocks the anaemia-driving ACVR1 pathway improved symptoms and spleen size without worsening, and often improving, anaemia in previously treated patients.","via":[{"id":"momelotinib","kind":"drug","name":"Momelotinib","route":"/drugs/momelotinib/"},{"id":"pacritinib","kind":"drug","name":"Pacritinib","route":"/drugs/pacritinib/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"}]},{"id":"paper-mountaineer-lancet-oncol-2023","kind":"paper","name":"MOUNTAINEER: tucatinib plus trastuzumab for HER2-positive, RAS wild-type metastatic colorectal cancer","route":"/key-papers/paper-mountaineer-lancet-oncol-2023/","year":2023,"journal":"The Lancet Oncology","paperType":"observational","tldr":"The chemotherapy-free combination of tucatinib and trastuzumab shrank tumours in almost four in ten patients with previously treated HER2-positive colorectal cancer, with responses lasting about a year, and became the first approved HER2 regimen for the disease.","via":[{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"paper-pharos-encorafenib-binimetinib-riely-jco-2023","kind":"paper","name":"PHAROS: encorafenib plus binimetinib in BRAF V600E-mutant metastatic non-small-cell lung cancer","route":"/key-papers/paper-pharos-encorafenib-binimetinib-riely-jco-2023/","year":2023,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"A second BRAF and MEK inhibitor pair, encorafenib plus binimetinib, shrank tumours in three quarters of untreated and nearly half of previously treated patients with BRAF V600E lung cancer, giving a better-tolerated alternative to dabrafenib-trametinib.","via":[{"id":"binimetinib","kind":"drug","name":"Binimetinib","route":"/drugs/binimetinib/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"}]},{"id":"paper-pioneer-avapritinib-indolent-systemic-mastocytosis-nejm-evid-2023","kind":"paper","name":"PIONEER: avapritinib versus placebo in indolent systemic mastocytosis","route":"/key-papers/paper-pioneer-avapritinib-indolent-systemic-mastocytosis-nejm-evid-2023/","year":2023,"journal":"NEJM Evidence","paperType":"rct","tldr":"A low dose of the KIT inhibitor avapritinib eased the itching, flushing, gut and bone symptoms of indolent systemic mastocytosis more than placebo, the first drug shown to do so in a randomised trial.","via":[{"id":"avapritinib","kind":"drug","name":"Avapritinib","route":"/drugs/avapritinib/"}]},{"id":"paper-quantum-first-quizartinib-lancet-2023","kind":"paper","name":"QuANTUM-First: quizartinib added to intensive chemotherapy and continued as maintenance in newly diagnosed FLT3-ITD AML","route":"/key-papers/paper-quantum-first-quizartinib-lancet-2023/","year":2023,"journal":"The Lancet","paperType":"rct","tldr":"Adding the FLT3 inhibitor quizartinib to standard chemotherapy, and continuing it for up to three years, roughly doubled median survival in FLT3-ITD acute myeloid leukaemia.","via":[{"id":"gilteritinib","kind":"drug","name":"Gilteritinib","route":"/drugs/gilteritinib/"},{"id":"midostaurin","kind":"drug","name":"Midostaurin","route":"/drugs/midostaurin/"},{"id":"quizartinib","kind":"drug","name":"Quizartinib","route":"/drugs/quizartinib/"}]},{"id":"paper-aall1231-bortezomib-t-all-teachey-jco-2022","kind":"paper","name":"AALL1231: bortezomib in newly diagnosed T-cell acute lymphoblastic leukaemia and lymphoma, with cranial radiotherapy removed","route":"/key-papers/paper-aall1231-bortezomib-t-all-teachey-jco-2022/","year":2022,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"In children with T-cell leukaemia or lymphoma, adding bortezomib to chemotherapy did not significantly improve survival for the whole group but did for those with lymphoma, and the intensified chemotherapy let more than nine in ten avoid radiotherapy to the brain without more relapses.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-aaml1031-sorafenib-flt3-pollard-jco-2022","kind":"paper","name":"AAML1031: sorafenib combined with chemotherapy for children with high allelic ratio FLT3-ITD acute myeloid leukaemia","route":"/key-papers/paper-aaml1031-sorafenib-flt3-pollard-jco-2022/","year":2022,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Adding the kinase inhibitor sorafenib to chemotherapy improved event-free survival in children with high allelic ratio FLT3-ITD acute myeloid leukaemia compared with matched historical controls, the first FLT3-targeted result in paediatric leukaemia.","via":[{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"}]},{"id":"paper-agile-ivosidenib-azacitidine-nejm-2022","kind":"paper","name":"AGILE: ivosidenib plus azacitidine for newly diagnosed IDH1-mutated AML in patients unfit for intensive chemotherapy","route":"/key-papers/paper-agile-ivosidenib-azacitidine-nejm-2022/","year":2022,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding the IDH1 inhibitor ivosidenib to azacitidine tripled median survival, from 7.9 to 24 months, in older patients with IDH1-mutated AML.","via":[{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"paper-arasens-nejm-2022","kind":"paper","name":"ARASENS: darolutamide added to androgen deprivation and docetaxel in metastatic hormone-sensitive prostate cancer","route":"/key-papers/paper-arasens-nejm-2022/","year":2022,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding the androgen receptor inhibitor darolutamide to hormone therapy and docetaxel chemotherapy cut deaths by a third in metastatic hormone-sensitive prostate cancer, establishing triplet therapy for men fit for chemotherapy.","via":[{"id":"darolutamide","kind":"drug","name":"Darolutamide","route":"/drugs/darolutamide/"}]},{"id":"paper-emerald-elacestrant-jco-2022","kind":"paper","name":"EMERALD: elacestrant versus standard endocrine therapy after a CDK4/6 inhibitor","route":"/key-papers/paper-emerald-elacestrant-jco-2022/","year":2022,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"The oral oestrogen receptor degrader elacestrant delayed progression compared with standard hormone therapy in advanced breast cancer that had progressed on a CDK4/6 inhibitor, with the clearest benefit in tumours carrying an ESR1 mutation.","via":[{"id":"elacestrant","kind":"drug","name":"Elacestrant","route":"/drugs/elacestrant/"}]},{"id":"paper-gog-281-trametinib-lgsoc-gershenson-lancet-2022","kind":"paper","name":"GOG 281/LOGS: trametinib versus standard of care in recurrent low-grade serous ovarian cancer","route":"/key-papers/paper-gog-281-trametinib-lgsoc-gershenson-lancet-2022/","year":2022,"journal":"The Lancet","paperType":"rct","tldr":"The MEK inhibitor trametinib more than doubled the time to progression compared with chemotherapy or hormone therapy in recurrent low-grade serous ovarian cancer, the first positive randomised trial in this slow-growing, chemotherapy-resistant disease.","via":[{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-intrigue-ripretinib-vs-sunitinib-jco-2022","kind":"paper","name":"INTRIGUE: ripretinib versus sunitinib in advanced gastrointestinal stromal tumour after imatinib","route":"/key-papers/paper-intrigue-ripretinib-vs-sunitinib-jco-2022/","year":2022,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Ripretinib was not better than sunitinib as second-line treatment for gastrointestinal stromal tumour overall, but it was better tolerated and worked better in tumours with KIT exon 11 plus exon 17/18 secondary mutations, while sunitinib was better for exon 13/14 mutations.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"ripretinib","kind":"drug","name":"Ripretinib","route":"/drugs/ripretinib/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-keynote-775-nejm-2022","kind":"paper","name":"KEYNOTE-775: lenvatinib plus pembrolizumab versus chemotherapy for previously treated advanced endometrial cancer","route":"/key-papers/paper-keynote-775-nejm-2022/","year":2022,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"After platinum chemotherapy, the combination of the kinase inhibitor lenvatinib and pembrolizumab lengthened survival compared with doxorubicin or paclitaxel in advanced endometrial cancer, including in the mismatch repair-proficient majority.","via":[{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}]},{"id":"paper-geyer-brightness-4-year-follow-up-ann-oncol-2022","kind":"paper","name":"Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial","route":"/key-papers/paper-geyer-brightness-4-year-follow-up-ann-oncol-2022/","year":2022,"journal":"Annals of Oncology","paperType":"rct","tldr":"The 4.5-year follow-up of BrighTNess showing that adding carboplatin to pre-surgery chemotherapy in 634 women cut relapse or death by about 40 percent without more second cancers, while adding the PARP inhibitor veliparib added nothing.","via":[{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"paper-olympia-overall-survival-ann-oncol-2022","kind":"paper","name":"Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer","route":"/key-papers/paper-olympia-overall-survival-ann-oncol-2022/","year":2022,"journal":"Annals of Oncology","paperType":"rct","tldr":"The second planned analysis of OlympiA, at 3.5 years, in which a year of olaparib tablets after standard treatment cut deaths by 32 percent in women with an inherited BRCA fault, the first time a PARP inhibitor had lengthened life in early breast cancer.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP 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cancer","route":"/key-papers/paper-stampede-abiraterone-high-risk-attard-lancet-2022/","year":2022,"journal":"The Lancet","paperType":"rct","tldr":"Adding two years of abiraterone to hormone therapy and radiotherapy for high-risk localised or node-positive prostate cancer halved the risk of metastases and cut deaths by 40 percent, while adding enzalutamide on top brought only extra toxicity.","via":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}]},{"id":"paper-mansoori-mebendazole-gi-cancer-phase-2a-sci-rep-2021","kind":"paper","name":"A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer","route":"/key-papers/paper-mansoori-mebendazole-gi-cancer-phase-2a-sci-rep-2021/","year":2021,"journal":"Scientific Reports","paperType":"translational","tldr":"A Swedish trial gave mebendazole to ten people with advanced bowel and stomach cancers that had stopped responding to treatment; it was safe, but every patient's cancer kept growing, four of them unusually fast.","via":[{"id":"mebendazole","kind":"drug","name":"Mebendazole","route":"/drugs/mebendazole/"}]},{"id":"paper-ampect-nab-sirolimus-pecoma-wagner-jco-2021","kind":"paper","name":"AMPECT: nab-sirolimus for malignant perivascular epithelioid cell tumours","route":"/key-papers/paper-ampect-nab-sirolimus-pecoma-wagner-jco-2021/","year":2021,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Albumin-bound sirolimus shrank tumours in about four in ten patients with malignant PEComa, with responses lasting years and best results in tumours with TSC2 mutations, and became the first approved treatment for the disease.","via":[{"id":"sirolimus-albumin-bound","kind":"drug","name":"Sirolimus protein-bound particles","route":"/drugs/sirolimus-albumin-bound/"}]},{"id":"paper-arrow-pralsetinib-gainor-lancet-oncol-2021","kind":"paper","name":"ARROW: pralsetinib for RET fusion-positive non-small-cell lung cancer","route":"/key-papers/paper-arrow-pralsetinib-gainor-lancet-oncol-2021/","year":2021,"journal":"The Lancet Oncology","paperType":"observational","tldr":"Pralsetinib, a second selective RET inhibitor, shrank tumours in 61 percent of previously treated and 70 percent of untreated patients with RET fusion-positive lung cancer, giving an alternative to selpercatinib.","via":[{"id":"pralsetinib","kind":"drug","name":"Pralsetinib","route":"/drugs/pralsetinib/"}]},{"id":"paper-rockstar-blood-2021","kind":"paper","name":"Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study","route":"/key-papers/paper-rockstar-blood-2021/","year":2021,"journal":"Blood","paperType":"rct","tldr":"The primary report of ROCKstar: about three in four patients with chronic graft-versus-host disease that had failed at least two treatments responded to belumosudil at either dose, and responses lasted about a year.","via":[{"id":"belumosudil","kind":"drug","name":"Belumosudil","route":"/drugs/belumosudil/"}]},{"id":"paper-belzutifan-vhl-jonasch-nejm-2021","kind":"paper","name":"Belzutifan for renal cell carcinoma and other tumours in von Hippel-Lindau disease","route":"/key-papers/paper-belzutifan-vhl-jonasch-nejm-2021/","year":2021,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The oral HIF-2 alpha inhibitor belzutifan shrank kidney cancers in about half of people with von Hippel-Lindau disease and also shrank their brain and spinal haemangioblastomas and pancreatic tumours, letting many avoid repeated operations.","via":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"}]},{"id":"paper-clear-nejm-2021","kind":"paper","name":"CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer","route":"/key-papers/paper-clear-nejm-2021/","year":2021,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Combining the multi-kinase inhibitor lenvatinib with pembrolizumab more than doubled the time to progression compared with sunitinib in advanced clear-cell kidney cancer and improved survival, with 71% of patients responding.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-explorer-avapritinib-advanced-systemic-mastocytosis-nat-med-2021","kind":"paper","name":"EXPLORER: safety and efficacy of avapritinib in advanced systemic mastocytosis (phase 1)","route":"/key-papers/paper-explorer-avapritinib-advanced-systemic-mastocytosis-nat-med-2021/","year":2021,"journal":"Nature Medicine","paperType":"observational","tldr":"The first study of avapritinib, a drug designed to hit the KIT D816V mutation that drives most mastocytosis, produced responses in three quarters of patients with advanced disease and set the dose for later trials.","via":[{"id":"avapritinib","kind":"drug","name":"Avapritinib","route":"/drugs/avapritinib/"}]},{"id":"paper-drug-dosing-conundrum-nejm-2021","kind":"paper","name":"FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high","route":"/key-papers/paper-drug-dosing-conundrum-nejm-2021/","year":2021,"journal":"New England Journal of Medicine","paperType":"review","tldr":"FDA oncology leaders argued that the maximum tolerated dose paradigm inherited from chemotherapy produces targeted drugs and immunotherapies dosed far above what is needed, using sotorasib (960 mg vs 240 mg) as the case study, and launched Project Optimus to require dose optimisation before approval.","via":[{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-nifty-liposomal-irinotecan-lancet-oncol-2021","kind":"paper","name":"Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study","route":"/key-papers/paper-nifty-liposomal-irinotecan-lancet-oncol-2021/","year":2021,"journal":"The Lancet Oncology","paperType":"rct","tldr":"In a Korean trial, adding liposomal irinotecan to fluorouracil held second-line bile duct and gallbladder cancer still for about seven months rather than six weeks, at the cost of more low blood counts.","via":[{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/"}]},{"id":"paper-magnolia-zanubrutinib-mzl-ccr-2021","kind":"paper","name":"MAGNOLIA: zanubrutinib in relapsed or refractory marginal zone lymphoma","route":"/key-papers/paper-magnolia-zanubrutinib-mzl-ccr-2021/","year":2021,"journal":"Clinical Cancer Research","paperType":"observational","tldr":"The BTK inhibitor zanubrutinib produced responses in about two thirds of patients with relapsed marginal zone lymphoma across all subtypes with few of the cardiac side effects seen with ibrutinib, leading to its approval.","via":[{"id":"zanubrutinib","kind":"drug","name":"Zanubrutinib","route":"/drugs/zanubrutinib/"}]},{"id":"paper-olympia-nejm-2021","kind":"paper","name":"OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer","route":"/key-papers/paper-olympia-nejm-2021/","year":2021,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In women born with a BRCA1 or BRCA2 mutation whose early breast cancer was high risk, a year of the PARP inhibitor olaparib after standard treatment cut relapses by more than 40% and later improved survival.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"paper-papmet-pal-lancet-2021","kind":"paper","name":"PAPMET (SWOG 1500): cabozantinib versus sunitinib for metastatic papillary renal cell carcinoma","route":"/key-papers/paper-papmet-pal-lancet-2021/","year":2021,"journal":"The Lancet","paperType":"rct","tldr":"In the first randomised trial to show a benefit in papillary kidney cancer, the MET-targeting kinase inhibitor cabozantinib delayed progression and tripled the response rate compared with sunitinib, while two other MET inhibitors did not.","via":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"savolitinib","kind":"drug","name":"Savolitinib","route":"/drugs/savolitinib/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-pathfinder-avapritinib-advanced-systemic-mastocytosis-nat-med-2021","kind":"paper","name":"PATHFINDER: efficacy and safety of avapritinib in advanced systemic mastocytosis (phase 2 interim analysis)","route":"/key-papers/paper-pathfinder-avapritinib-advanced-systemic-mastocytosis-nat-med-2021/","year":2021,"journal":"Nature Medicine","paperType":"observational","tldr":"The confirmatory trial of avapritinib in advanced systemic mastocytosis again showed responses in three quarters of patients, with the drug clearing marrow mast cells and normalising tryptase in many, and it became the standard first-line targeted therapy.","via":[{"id":"avapritinib","kind":"drug","name":"Avapritinib","route":"/drugs/avapritinib/"}]},{"id":"paper-aaml1031-bortezomib-aplenc-haematologica-2020","kind":"paper","name":"AAML1031: bortezomib with standard chemotherapy for children with acute myeloid leukaemia does not improve outcomes","route":"/key-papers/paper-aaml1031-bortezomib-aplenc-haematologica-2020/","year":2020,"journal":"Haematologica","paperType":"rct","tldr":"Adding the proteasome inhibitor bortezomib to standard chemotherapy for children with newly diagnosed acute myeloid leukaemia did not help them live longer or relapse less, and it caused more nerve damage and intensive care admissions.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-adaura-nejm-2020","kind":"paper","name":"ADAURA: three years of osimertinib after surgery for EGFR-mutated lung cancer","route":"/key-papers/paper-adaura-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"After surgery for early-stage EGFR-mutated lung cancer, three years of osimertinib cut recurrences by about 80% and later reduced deaths by half.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-anbl1221-expansion-dinutuximab-gm-csf-mody-jco-2020","kind":"paper","name":"ANBL1221 expansion: irinotecan, temozolomide and dinutuximab with GM-CSF in refractory or relapsed neuroblastoma","route":"/key-papers/paper-anbl1221-expansion-dinutuximab-gm-csf-mody-jco-2020/","year":2020,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Across 53 children treated with irinotecan, temozolomide and dinutuximab for relapsed neuroblastoma, four in ten had their tumours shrink and 85 percent were alive a year later, confirming the combination as the standard salvage treatment.","via":[{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/"}]},{"id":"paper-schmid-pakt-capivasertib-tnbc-jco-2020","kind":"paper","name":"Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial","route":"/key-papers/paper-schmid-pakt-capivasertib-tnbc-jco-2020/","year":2020,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Adding capivasertib to first-line paclitaxel improved survival in metastatic triple-negative cancer from 12.6 to 19.1 months, with the largest gain in the fifth of patients whose tumours carried a PIK3CA, AKT1 or PTEN alteration.","via":[{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"}]},{"id":"paper-crown-nejm-2020","kind":"paper","name":"CROWN: lorlatinib versus crizotinib as first treatment for ALK-positive lung cancer","route":"/key-papers/paper-crown-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"The third-generation ALK inhibitor lorlatinib kept ALK-positive lung cancer under control for years longer than crizotinib and largely prevented brain metastases; at five years most patients on lorlatinib had still not progressed.","via":[{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-dasatinib-vs-imatinib-ph-positive-all-shen-jama-oncol-2020","kind":"paper","name":"Dasatinib versus imatinib with chemotherapy for paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (CCCG-ALL-2015)","route":"/key-papers/paper-dasatinib-vs-imatinib-ph-positive-all-shen-jama-oncol-2020/","year":2020,"journal":"JAMA Oncology","paperType":"rct","tldr":"In Chinese children with Philadelphia-positive leukaemia, dasatinib given at a high dose with chemotherapy improved four-year event-free survival compared with imatinib and reduced central nervous system relapses, without cranial irradiation or routine transplant.","via":[{"id":"dasatinib","kind":"drug","name":"Dasatinib","route":"/drugs/dasatinib/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"paper-elevate-tn-acalabrutinib-lancet-2020","kind":"paper","name":"ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL","route":"/key-papers/paper-elevate-tn-acalabrutinib-lancet-2020/","year":2020,"journal":"The Lancet","paperType":"rct","tldr":"In ELEVATE-TN, acalabrutinib, a second-generation BTK inhibitor, with or without an antibody, cut the risk of progression by 80-90% compared with chlorambucil-obinutuzumab in older or unfit patients with CLL.","via":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"zanubrutinib","kind":"drug","name":"Zanubrutinib","route":"/drugs/zanubrutinib/"}]},{"id":"paper-doebele-entrectinib-ntrk-lancet-oncol-2020","kind":"paper","name":"Entrectinib in NTRK fusion-positive solid tumours: integrated analysis of three trials","route":"/key-papers/paper-doebele-entrectinib-ntrk-lancet-oncol-2020/","year":2020,"journal":"The Lancet Oncology","paperType":"observational","tldr":"Entrectinib, a TRK and ROS1 inhibitor that enters the brain, shrank tumours in more than half of patients with NTRK fusion-positive cancers of ten types and controlled brain metastases, leading to a tumour-agnostic approval alongside larotrectinib.","via":[{"id":"entrectinib","kind":"drug","name":"Entrectinib","route":"/drugs/entrectinib/"}]},{"id":"paper-drilon-entrectinib-ros1-lancet-oncol-2020","kind":"paper","name":"Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three trials","route":"/key-papers/paper-drilon-entrectinib-ros1-lancet-oncol-2020/","year":2020,"journal":"The Lancet Oncology","paperType":"observational","tldr":"Entrectinib shrank tumours in more than three quarters of patients with ROS1-positive lung cancer and, unlike crizotinib, controlled brain metastases in most patients who had them, earning approval as a first-line option.","via":[{"id":"entrectinib","kind":"drug","name":"Entrectinib","route":"/drugs/entrectinib/"}]},{"id":"paper-erdheim-chester-disease-consensus-recommendations-blood-2020","kind":"paper","name":"Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis and treatment in the molecular 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fusions, the first targeted drug approved for the disease.","via":[{"id":"pemigatinib","kind":"drug","name":"Pemigatinib","route":"/drugs/pemigatinib/"}]},{"id":"paper-geometry-mono-1-capmatinib-nejm-2020","kind":"paper","name":"GEOMETRY mono-1: capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer","route":"/key-papers/paper-geometry-mono-1-capmatinib-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The MET inhibitor capmatinib shrank tumours in two thirds of untreated and four in ten previously treated patients with MET exon 14-skipping lung cancer, leading to the first approval for this driver, while MET-amplified tumours responded only at very high copy number.","via":[{"id":"capmatinib","kind":"drug","name":"Capmatinib","route":"/drugs/capmatinib/"}]},{"id":"paper-her2climb-brain-lin-jco-2020","kind":"paper","name":"HER2CLIMB brain metastases analysis: intracranial efficacy and survival with 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benefited.","via":[{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"paper-invictus-ripretinib-lancet-oncol-2020","kind":"paper","name":"INVICTUS: ripretinib in advanced gastrointestinal stromal tumours after three or more prior kinase inhibitors","route":"/key-papers/paper-invictus-ripretinib-lancet-oncol-2020/","year":2020,"journal":"The Lancet Oncology","paperType":"rct","tldr":"The switch-control KIT inhibitor ripretinib lengthened progression-free survival from one to six months and improved survival compared with placebo in gastrointestinal stromal tumours that had failed imatinib, sunitinib and regorafenib.","via":[{"id":"ripretinib","kind":"drug","name":"Ripretinib","route":"/drugs/ripretinib/"}]},{"id":"paper-libretto-001-selpercatinib-nsclc-nejm-2020","kind":"paper","name":"LIBRETTO-001: selpercatinib in RET fusion-positive non-small-cell lung cancer","route":"/key-papers/paper-libretto-001-selpercatinib-nsclc-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The selective RET inhibitor selpercatinib shrank tumours in 64 percent of previously treated and 85 percent of untreated patients with RET fusion-positive lung cancer, including brain metastases, and led to the first approval for this driver.","via":[{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"}]},{"id":"paper-asco-hereditary-breast-cancer-guideline-jco-2020","kind":"paper","name":"Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline","route":"/key-papers/paper-asco-hereditary-breast-cancer-guideline-jco-2020/","year":2020,"journal":"Journal of Clinical Oncology","paperType":"guideline","tldr":"The 2020 joint US guideline for breast cancer in people who carry an inherited fault in BRCA1, BRCA2 or another risk gene: breast-conserving surgery is allowed, bilateral mastectomy should be discussed, platinum beats taxanes in advanced disease and PARP inhibitors beat single-agent chemotherapy.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"paper-monarche-jco-2020","kind":"paper","name":"monarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancer","route":"/key-papers/paper-monarche-jco-2020/","year":2020,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Adding two years of the CDK4/6 inhibitor abemaciclib to standard hormone therapy after surgery cut the risk of the cancer coming back by a quarter in women with node-positive, high-risk disease.","via":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"paper-navigator-avapritinib-heinrich-lancet-oncol-2020","kind":"paper","name":"NAVIGATOR: avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour","route":"/key-papers/paper-navigator-avapritinib-heinrich-lancet-oncol-2020/","year":2020,"journal":"The Lancet Oncology","paperType":"observational","tldr":"Avapritinib shrank tumours in almost nine in ten patients with PDGFRA D842V-mutant gastrointestinal stromal tumour, a subtype completely resistant to imatinib and every other kinase inhibitor, and became its first effective treatment.","via":[{"id":"avapritinib","kind":"drug","name":"Avapritinib","route":"/drugs/avapritinib/"}]},{"id":"paper-profound-nejm-2020","kind":"paper","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","route":"/key-papers/paper-profound-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In men with metastatic castration-resistant prostate cancer carrying BRCA1, BRCA2 or ATM alterations who had progressed on hormonal therapy, the PARP inhibitor olaparib delayed progression and lengthened survival compared with another hormonal agent.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"paper-remora-lenvatinib-thymic-carcinoma-lancet-oncol-2020","kind":"paper","name":"REMORA: lenvatinib in advanced or metastatic thymic 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most common side effects.","via":[{"id":"mebendazole","kind":"drug","name":"Mebendazole","route":"/drugs/mebendazole/"}]},{"id":"paper-gordan-j-clin-oncol","kind":"paper","name":"Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline","route":"/key-papers/paper-gordan-j-clin-oncol/","year":2020,"journal":"Journal of Clinical Oncology","paperType":"guideline","tldr":"Paper cited by one trial page and one treatment page, indexed on Europe PMC as PubMed record 33197225 and published in Journal of Clinical Oncology; the citing pages link this DOI, which is how the record was matched.","via":[{"id":"donafenib","kind":"drug","name":"Donafenib","route":"/drugs/donafenib/"}]},{"id":"paper-viale-a-venetoclax-azacitidine-nejm-2020","kind":"paper","name":"VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy","route":"/key-papers/paper-viale-a-venetoclax-azacitidine-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding the BCL-2 inhibitor venetoclax to azacitidine more than doubled remission rates and extended median survival from 9.6 to 14.7 months in unfit AML patients.","via":[{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"paper-vision-tepotinib-paik-nejm-2020","kind":"paper","name":"VISION: tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations","route":"/key-papers/paper-vision-tepotinib-paik-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The once-daily MET inhibitor tepotinib shrank tumours in about half of patients with MET exon 14-skipping lung cancer, detected either in tissue or in a blood test, supporting approval and the use of liquid biopsy to find the alteration.","via":[{"id":"tepotinib","kind":"drug","name":"Tepotinib","route":"/drugs/tepotinib/"}]},{"id":"paper-zuma-2-brexu-cel-mantle-cell-nejm-2020","kind":"paper","name":"ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors","route":"/key-papers/paper-zuma-2-brexu-cel-mantle-cell-nejm-2020/","year":2020,"journal":"New England Journal of Medicine","paperType":"translational","tldr":"In mantle cell lymphoma that had stopped responding to BTK inhibitors, a single CAR-T infusion produced responses in 93% of patients and complete remissions in two-thirds.","via":[{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/"}]},{"id":"paper-admiral-gilteritinib-flt3-nejm-2019","kind":"paper","name":"ADMIRAL: gilteritinib pills versus chemotherapy for relapsed FLT3-mutated acute myeloid leukaemia","route":"/key-papers/paper-admiral-gilteritinib-flt3-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"An oral FLT3 inhibitor extended survival compared with salvage chemotherapy in relapsed AML with a FLT3 mutation, doubling the remission rate.","via":[{"id":"gilteritinib","kind":"drug","name":"Gilteritinib","route":"/drugs/gilteritinib/"},{"id":"midostaurin","kind":"drug","name":"Midostaurin","route":"/drugs/midostaurin/"},{"id":"quizartinib","kind":"drug","name":"Quizartinib","route":"/drugs/quizartinib/"}]},{"id":"paper-aramis-nejm-2019","kind":"paper","name":"ARAMIS: darolutamide in non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-aramis-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Darolutamide, an androgen receptor inhibitor that barely enters the brain, delayed metastases by nearly two years in men with non-metastatic castration-resistant prostate cancer with side effects close to placebo, and later showed a survival benefit.","via":[{"id":"darolutamide","kind":"drug","name":"Darolutamide","route":"/drugs/darolutamide/"}]},{"id":"paper-beacon-crc-kopetz-nejm-2019","kind":"paper","name":"BEACON CRC: encorafenib and cetuximab with or without binimetinib in BRAF V600E-mutated colorectal cancer","route":"/key-papers/paper-beacon-crc-kopetz-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Blocking BRAF with encorafenib and EGFR with cetuximab lengthened survival compared with standard chemotherapy in previously treated BRAF V600E-mutant colorectal cancer, the first targeted regimen to work in this poor-prognosis group.","via":[{"id":"binimetinib","kind":"drug","name":"Binimetinib","route":"/drugs/binimetinib/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"}]},{"id":"paper-cassiopeia-lancet-2019","kind":"paper","name":"CASSIOPEIA: daratumumab added to bortezomib, thalidomide and dexamethasone before and after transplant in newly diagnosed myeloma","route":"/key-papers/paper-cassiopeia-lancet-2019/","year":2019,"journal":"The Lancet","paperType":"rct","tldr":"Adding the antibody daratumumab to a standard three-drug induction and consolidation around autologous transplant deepened responses and delayed progression in newly diagnosed myeloma, establishing four-drug induction.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-cll14-venetoclax-obinutuzumab-nejm-2019","kind":"paper","name":"CLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patients","route":"/key-papers/paper-cll14-venetoclax-obinutuzumab-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"A fixed one-year course of two targeted drugs kept CLL under control far longer than chemo-immunotherapy, and most patients had no detectable disease when treatment stopped.","via":[{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019","kind":"paper","name":"Jones 2019: NRG1 gene fusions are recurrent, clinically actionable rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma","route":"/key-papers/paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019/","year":2019,"journal":"Clinical Cancer Research","paperType":"translational","tldr":"In a Canadian programme sequencing the genomes of advanced pancreatic cancers in real time, tumours without a KRAS mutation repeatedly carried NRG1 fusions, and patients treated with HER-family blockers on the strength of that finding responded. It showed that fusion testing in KRAS wild-type disease changes treatment.","via":[{"id":"afatinib","kind":"drug","name":"Afatinib","route":"/drugs/afatinib/"}]},{"id":"paper-keynote-426-nejm-2019","kind":"paper","name":"KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma","route":"/key-papers/paper-keynote-426-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Combining pembrolizumab with the kinase inhibitor axitinib lengthened survival and delayed progression compared with sunitinib as first treatment for advanced clear cell kidney cancer, across all risk groups.","via":[{"id":"axitinib","kind":"drug","name":"Axitinib","route":"/drugs/axitinib/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-paola-1-nejm-2019","kind":"paper","name":"PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours","route":"/key-papers/paper-paola-1-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding the PARP inhibitor olaparib to bevacizumab after first-line chemotherapy for advanced ovarian cancer roughly doubled the time without progression in women whose tumours had defective DNA repair, but did nothing for those without it.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"paper-tap-lancet","kind":"paper","name":"Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial","route":"/key-papers/paper-tap-lancet/","year":2019,"journal":"The Lancet","paperType":"rct","tldr":"Paper cited by one cancer page, one trial page, one treatment page and one target page, indexed on Europe PMC as PubMed record 31229240 and published in The Lancet; the citing pages link this DOI, which is how the record was matched.","via":[{"id":"pexidartinib","kind":"drug","name":"Pexidartinib","route":"/drugs/pexidartinib/"}]},{"id":"paper-tchekmedyian-lenvatinib-adenoid-cystic-jco-2019","kind":"paper","name":"Phase 2 study of lenvatinib in progressive, recurrent or metastatic adenoid cystic carcinoma","route":"/key-papers/paper-tchekmedyian-lenvatinib-adenoid-cystic-jco-2019/","year":2019,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"The multikinase inhibitor lenvatinib shrank tumours in about one in six patients with progressing adenoid cystic carcinoma and stabilised most of the rest, making it one of the few active drugs for this slow but relentless salivary cancer.","via":[{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}]},{"id":"paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","kind":"paper","name":"POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer","route":"/key-papers/paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In patients with inherited BRCA mutations whose pancreatic cancer had been held in check by platinum chemotherapy, switching to the tablet olaparib roughly doubled the time before the disease grew again compared with placebo. It was the first biomarker-driven approval in pancreatic cancer.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"paper-prima-niraparib-nejm-2019","kind":"paper","name":"PRIMA: niraparib maintenance in newly diagnosed advanced ovarian cancer","route":"/key-papers/paper-prima-niraparib-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Niraparib maintenance after first-line chemotherapy delayed progression in newly diagnosed advanced ovarian cancer whether or not the tumour had a homologous recombination deficiency, though the gain was much larger when it did.","via":[{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"}]},{"id":"paper-solar-1-alpelisib-nejm-2019","kind":"paper","name":"SOLAR-1: alpelisib plus fulvestrant for PIK3CA-mutated hormone receptor-positive advanced breast cancer","route":"/key-papers/paper-solar-1-alpelisib-nejm-2019/","year":2019,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Alpelisib, a pill blocking the mutated PI3K-alpha enzyme, nearly doubled the time to progression when added to fulvestrant in advanced breast cancer carrying a PIK3CA mutation, at the cost of high blood sugar and rash.","via":[{"id":"alpelisib","kind":"drug","name":"Alpelisib","route":"/drugs/alpelisib/"}]},{"id":"paper-jiang-lancet-oncol","kind":"paper","name":"Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial","route":"/key-papers/paper-jiang-lancet-oncol/","year":2019,"journal":"The Lancet Oncology","paperType":"rct","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 31036468 and published in The Lancet Oncology; the citing page links this DOI, which is how the record was matched.","via":[{"id":"tucidinostat","kind":"drug","name":"Tucidinostat (chidamide)","route":"/drugs/tucidinostat/"}]},{"id":"paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019","kind":"paper","name":"Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: an international observational study","route":"/key-papers/paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019/","year":2019,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"In children with life-threatening Langerhans cell histiocytosis that had not responded to chemotherapy, the BRAF inhibitor vemurafenib brought the disease under control in nearly all of them, though it usually returned when the drug was stopped.","via":[{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}]},{"id":"paper-checkmate-214-nejm-2018","kind":"paper","name":"CheckMate 214: nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma","route":"/key-papers/paper-checkmate-214-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Dual immunotherapy with nivolumab and ipilimumab lengthened survival compared with sunitinib in intermediate- and poor-risk advanced kidney cancer, with about one in ten patients achieving a complete response that has proved durable over years.","via":[{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-columbus-lancet-oncol-2018","kind":"paper","name":"COLUMBUS: encorafenib plus binimetinib versus vemurafenib or encorafenib in BRAF-mutant melanoma","route":"/key-papers/paper-columbus-lancet-oncol-2018/","year":2018,"journal":"The Lancet Oncology","paperType":"rct","tldr":"The third BRAF-MEK combination, encorafenib plus binimetinib, delayed progression more than vemurafenib and produced the longest median survival of any targeted regimen in BRAF-mutant melanoma, with less fever than dabrafenib-trametinib.","via":[{"id":"binimetinib","kind":"drug","name":"Binimetinib","route":"/drugs/binimetinib/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}]},{"id":"paper-rosai-dorfman-destombes-consensus-recommendations-blood-2018","kind":"paper","name":"Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease","route":"/key-papers/paper-rosai-dorfman-destombes-consensus-recommendations-blood-2018/","year":2018,"journal":"Blood","paperType":"guideline","tldr":"The first expert guidance on Rosai-Dorfman disease: how to confirm the diagnosis, which patients can be watched, and which need surgery, steroids, chemotherapy or targeted treatment.","via":[{"id":"cobimetinib","kind":"drug","name":"Cobimetinib","route":"/drugs/cobimetinib/"}]},{"id":"paper-subbiah-dabrafenib-trametinib-atc-jco-2018","kind":"paper","name":"Dabrafenib and trametinib in BRAF V600E-mutant anaplastic thyroid cancer (ROAR)","route":"/key-papers/paper-subbiah-dabrafenib-trametinib-atc-jco-2018/","year":2018,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"In one of the most lethal cancers known, dabrafenib plus trametinib shrank BRAF-mutant anaplastic thyroid cancer in about two thirds of patients, leading to the first ever drug approval for the disease.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-ivosidenib-idh1-dinardo-nejm-2018","kind":"paper","name":"Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory acute myeloid leukaemia","route":"/key-papers/paper-ivosidenib-idh1-dinardo-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The oral IDH1 inhibitor ivosidenib put about a third of patients with relapsed or refractory IDH1-mutated acute myeloid leukaemia into remission, with some clearing the mutation altogether, leading to its approval.","via":[{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/"}]},{"id":"paper-traina-enzalutamide-ar-tnbc-jco-2018","kind":"paper","name":"Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer","route":"/key-papers/paper-traina-enzalutamide-ar-tnbc-jco-2018/","year":2018,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Enzalutamide gave clinical benefit at 16 weeks to a quarter of women with androgen receptor-expressing triple-negative breast cancer, a third among those with 10% or more staining, with fatigue the only common severe side effect.","via":[{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}]},{"id":"paper-esphall2010-continuous-imatinib-biondi-lancet-haematol-2018","kind":"paper","name":"EsPhALL2010: continuous imatinib with chemotherapy in paediatric Philadelphia chromosome-positive ALL","route":"/key-papers/paper-esphall2010-continuous-imatinib-biondi-lancet-haematol-2018/","year":2018,"journal":"The Lancet Haematology","paperType":"observational","tldr":"Giving children with Philadelphia-positive leukaemia the pill imatinib continuously from the second week of treatment allowed fewer of them to need a transplant, with survival similar to the earlier study that used short courses, but at the cost of more serious toxicity during intensive treatment blocks.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Starting with the third-generation EGFR drug osimertinib, rather than saving it for later, kept EGFR-mutated lung cancer under control for almost twice as long and later helped patients live longer.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018","kind":"paper","name":"Heining 2018: NRG1 fusions in KRAS wild-type pancreatic cancer","route":"/key-papers/paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018/","year":2018,"journal":"Cancer Discovery","paperType":"translational","tldr":"Whole-genome and RNA sequencing of pancreatic cancers in younger patients found that most of the tumours without a KRAS mutation instead carried a fusion of the NRG1 gene, and two patients given a HER-family blocker responded. It established NRG1 fusions as the driver to look for in KRAS wild-type pancreatic cancer.","via":[{"id":"afatinib","kind":"drug","name":"Afatinib","route":"/drugs/afatinib/"}]},{"id":"paper-archer-1050-os-jco-2018","kind":"paper","name":"Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations","route":"/key-papers/paper-archer-1050-os-jco-2018/","year":2018,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"The mature survival analysis of ARCHER 1050: patients on dacomitinib lived a median of 34.1 months against 26.8 months on gefitinib, the first survival gain for a second-generation EGFR inhibitor over a standard one.","via":[{"id":"dacomitinib","kind":"drug","name":"Dacomitinib","route":"/drugs/dacomitinib/"},{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"}]},{"id":"paper-drilon-larotrectinib-nejm-2018","kind":"paper","name":"Larotrectinib in TRK fusion-positive cancers in adults and children","route":"/key-papers/paper-drilon-larotrectinib-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The selective TRK inhibitor larotrectinib shrank tumours in three quarters of patients with NTRK fusions across 17 different cancer types and ages from infancy to old age, leading to the first tumour-agnostic approval of a targeted drug.","via":[{"id":"larotrectinib","kind":"drug","name":"Larotrectinib","route":"/drugs/larotrectinib/"}]},{"id":"paper-mavoric-mogamulizumab-lancet-oncol-2018","kind":"paper","name":"MAVORIC: mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma","route":"/key-papers/paper-mavoric-mogamulizumab-lancet-oncol-2018/","year":2018,"journal":"The Lancet Oncology","paperType":"rct","tldr":"The anti-CCR4 antibody mogamulizumab doubled the time to progression compared with vorinostat in previously treated mycosis fungoides and Sezary syndrome, with particularly strong activity in the blood, and became the first antibody approved for these lymphomas.","via":[{"id":"vorinostat","kind":"drug","name":"Vorinostat","route":"/drugs/vorinostat/"}]},{"id":"paper-murano-venetoclax-rituximab-nejm-2018","kind":"paper","name":"MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL","route":"/key-papers/paper-murano-venetoclax-rituximab-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In relapsed CLL, a time-limited venetoclax-rituximab course cut progression risk by more than 80% compared with bendamustine-rituximab and later improved survival.","via":[{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"paper-prosper-nejm-2018","kind":"paper","name":"PROSPER: enzalutamide in men with non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-prosper-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Enzalutamide delayed metastases by almost two years in men with rapidly rising PSA on hormone therapy and no visible spread, and longer follow-up showed it also lengthened survival.","via":[{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}]},{"id":"paper-reflect-lenvatinib-lancet-2018","kind":"paper","name":"REFLECT: lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma","route":"/key-papers/paper-reflect-lenvatinib-lancet-2018/","year":2018,"journal":"The Lancet","paperType":"rct","tldr":"Lenvatinib matched sorafenib for survival in advanced liver cancer while shrinking tumours far more often and delaying progression longer, making it the first new first-line option in ten years.","via":[{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"},{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"}]},{"id":"paper-brock-n-engl-j-med","kind":"paper","name":"Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss","route":"/key-papers/paper-brock-n-engl-j-med/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Paper cited by two cancer pages and one treatment page, indexed on Europe PMC as PubMed record 29924955 and published in New England Journal of Medicine; the citing pages link this DOI, which is how the record was matched.","via":[{"id":"sodium-thiosulfate","kind":"drug","name":"Sodium thiosulfate (otoprotectant)","route":"/drugs/sodium-thiosulfate/"}]},{"id":"paper-solo-1-nejm-2018","kind":"paper","name":"SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer","route":"/key-papers/paper-solo-1-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In women with newly diagnosed advanced BRCA-mutated ovarian cancer who had responded to chemotherapy, two years of the PARP inhibitor olaparib kept far more of them free of progression than placebo, and the effect persisted for years after the tablets stopped. It moved PARP inhibitors into first-line maintenance and made BRCA testing at diagnosis routine.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"paper-spartan-nejm-2018","kind":"paper","name":"SPARTAN: apalutamide for non-metastatic castration-resistant prostate cancer","route":"/key-papers/paper-spartan-nejm-2018/","year":2018,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In men whose PSA was rising rapidly on hormone therapy but who had no visible metastases, apalutamide delayed the appearance of metastases by two years and later showed a survival benefit.","via":[{"id":"apalutamide","kind":"drug","name":"Apalutamide","route":"/drugs/apalutamide/"}]},{"id":"paper-ve-basket-vemurafenib-erdheim-chester-lch-jama-oncol-2018","kind":"paper","name":"VE-BASKET: vemurafenib for BRAF V600-mutant Erdheim-Chester disease and Langerhans cell histiocytosis","route":"/key-papers/paper-ve-basket-vemurafenib-erdheim-chester-lch-jama-oncol-2018/","year":2018,"journal":"JAMA Oncology","paperType":"observational","tldr":"The BRAF inhibitor vemurafenib shrank disease in most adults with BRAF-mutant Erdheim-Chester disease, and the responses lasted, leading to the first drug approval for this histiocytosis.","via":[{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}]},{"id":"paper-anbl1221-irinotecan-temozolomide-dinutuximab-mody-lancet-oncol-2017","kind":"paper","name":"ANBL1221: irinotecan-temozolomide with temsirolimus or dinutuximab in relapsed or refractory neuroblastoma","route":"/key-papers/paper-anbl1221-irinotecan-temozolomide-dinutuximab-mody-lancet-oncol-2017/","year":2017,"journal":"The Lancet Oncology","paperType":"rct","tldr":"In children whose neuroblastoma had come back, adding the anti-GD2 antibody dinutuximab to irinotecan and temozolomide shrank the cancer in half of them, while adding temsirolimus almost never did.","via":[{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/"},{"id":"temsirolimus","kind":"drug","name":"Temsirolimus","route":"/drugs/temsirolimus/"}]},{"id":"paper-alta-jco-2017","kind":"paper","name":"Brigatinib in patients with crizotinib-refractory ALK-positive non-small-cell lung cancer: a randomized, multicenter phase II trial (ALTA)","route":"/key-papers/paper-alta-jco-2017/","year":2017,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"The primary report of ALTA: after crizotinib, brigatinib shrank tumours in about half of patients, more so at the 180 mg dose after a week at 90 mg, and held the disease for around a year.","via":[{"id":"brigatinib","kind":"drug","name":"Brigatinib","route":"/drugs/brigatinib/"}]},{"id":"paper-combi-ad-nejm-2017","kind":"paper","name":"COMBI-AD: adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma","route":"/key-papers/paper-combi-ad-nejm-2017/","year":2017,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"A year of dabrafenib plus trametinib after surgery for stage III BRAF-mutant melanoma cut the risk of relapse by more than half, giving patients with BRAF mutations a targeted alternative to adjuvant immunotherapy.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-planchard-dabrafenib-trametinib-first-line-lancet-oncol-2017","kind":"paper","name":"Dabrafenib plus trametinib in previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer","route":"/key-papers/paper-planchard-dabrafenib-trametinib-first-line-lancet-oncol-2017/","year":2017,"journal":"The Lancet Oncology","paperType":"observational","tldr":"Used as first treatment, dabrafenib plus trametinib shrank tumours in almost two thirds of patients with BRAF V600E-mutant lung cancer and controlled the disease for over a year, supporting its use before chemotherapy.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-archer-1050-lancet-oncol-2017","kind":"paper","name":"Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial","route":"/key-papers/paper-archer-1050-lancet-oncol-2017/","year":2017,"journal":"The Lancet Oncology","paperType":"rct","tldr":"The primary report of ARCHER 1050: dacomitinib held untreated EGFR-mutant lung cancer for a median of 14.7 months against 9.2 months on gefitinib, at the cost of more rash and diarrhoea.","via":[{"id":"dacomitinib","kind":"drug","name":"Dacomitinib","route":"/drugs/dacomitinib/"},{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"}]},{"id":"paper-enasidenib-idh2-stein-blood-2017","kind":"paper","name":"Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukaemia","route":"/key-papers/paper-enasidenib-idh2-stein-blood-2017/","year":2017,"journal":"Blood","paperType":"observational","tldr":"Enasidenib, a pill blocking the mutant IDH2 enzyme, produced responses in about four in ten patients with relapsed IDH2-mutated acute myeloid leukaemia by making the leukaemic cells mature, and became the first IDH-targeted drug approved.","via":[{"id":"enasidenib","kind":"drug","name":"Enasidenib","route":"/drugs/enasidenib/"}]},{"id":"paper-ascend-4-lancet-2017","kind":"paper","name":"First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study","route":"/key-papers/paper-ascend-4-lancet-2017/","year":2017,"journal":"The Lancet","paperType":"rct","tldr":"The primary report of ASCEND-4: untreated ALK-positive lung cancer stayed under control for a median of 16.6 months on ceritinib against 8.1 months on platinum chemotherapy.","via":[{"id":"ceritinib","kind":"drug","name":"Ceritinib","route":"/drugs/ceritinib/"}]},{"id":"paper-ifm-2009-attal-nejm-2017","kind":"paper","name":"IFM 2009: lenalidomide, bortezomib and dexamethasone with or without upfront transplantation for myeloma","route":"/key-papers/paper-ifm-2009-attal-nejm-2017/","year":2017,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding an early autologous stem cell transplant to modern three-drug therapy delayed relapse in newly diagnosed myeloma, though overall survival was similar because patients in the drug-only arm could have a transplant later.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-kim-lotus-ipatasertib-tnbc-lancet-oncol-2017","kind":"paper","name":"Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial","route":"/key-papers/paper-kim-lotus-ipatasertib-tnbc-lancet-oncol-2017/","year":2017,"journal":"The Lancet Oncology","paperType":"rct","tldr":"Adding the AKT inhibitor ipatasertib to first-line paclitaxel lengthened the time before metastatic triple-negative cancer grew from 4.9 to 6.2 months, the first randomised support for AKT-directed therapy in the disease.","via":[{"id":"ipatasertib","kind":"drug","name":"Ipatasertib","route":"/drugs/ipatasertib/"}]},{"id":"paper-olympiad-nejm-2017","kind":"paper","name":"OlympiAD: olaparib versus chemotherapy in metastatic breast cancer with a germline BRCA mutation","route":"/key-papers/paper-olympiad-nejm-2017/","year":2017,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In women with metastatic HER2-negative breast cancer and an inherited BRCA mutation, the PARP inhibitor tablet olaparib delayed progression by almost three months compared with chemotherapy and caused fewer severe side effects.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"paper-ratify-midostaurin-nejm-2017","kind":"paper","name":"RATIFY: midostaurin added to chemotherapy for acute myeloid leukaemia with a FLT3 mutation","route":"/key-papers/paper-ratify-midostaurin-nejm-2017/","year":2017,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Adding the FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy, then as maintenance, lengthened survival in adults under 60 with FLT3-mutated acute myeloid leukaemia, the first targeted drug to do so.","via":[{"id":"midostaurin","kind":"drug","name":"Midostaurin","route":"/drugs/midostaurin/"}]},{"id":"paper-jo-idh2-r172-mutations-snuc-mod-pathol-2017","kind":"paper","name":"Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma","route":"/key-papers/paper-jo-idh2-r172-mutations-snuc-mod-pathol-2017/","year":2017,"journal":"Modern Pathology","paperType":"translational","tldr":"Sequencing showed that most sinonasal undifferentiated carcinomas, a cancer long defined only by what it is not, carry a mutation in the IDH2 gene found in no other head and neck cancer, giving the disease a molecular identity, a diagnostic antibody test and a possible drug target.","via":[{"id":"enasidenib","kind":"drug","name":"Enasidenib","route":"/drugs/enasidenib/"}]},{"id":"paper-stampede-abiraterone-nejm-2017","kind":"paper","name":"STAMPEDE: adding abiraterone to hormone therapy at diagnosis of advanced prostate cancer","route":"/key-papers/paper-stampede-abiraterone-nejm-2017/","year":2017,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Giving the hormone-pathway drug abiraterone from the start, alongside standard testosterone suppression, cut deaths by more than a third in men newly diagnosed with high-risk or metastatic prostate cancer.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"},{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"}]},{"id":"paper-aspen-armstrong-lancet-oncol-2016","kind":"paper","name":"ASPEN: everolimus versus sunitinib in metastatic non-clear cell renal cell carcinoma","route":"/key-papers/paper-aspen-armstrong-lancet-oncol-2016/","year":2016,"journal":"The Lancet Oncology","paperType":"rct","tldr":"In the first randomised trial dedicated to non-clear cell kidney cancers, sunitinib delayed progression more than everolimus overall, though chromophobe tumours appeared to fare better on everolimus.","via":[{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-planchard-dabrafenib-trametinib-braf-nsclc-lancet-oncol-2016","kind":"paper","name":"Dabrafenib plus trametinib in previously treated BRAF V600E-mutant metastatic non-small-cell lung cancer","route":"/key-papers/paper-planchard-dabrafenib-trametinib-braf-nsclc-lancet-oncol-2016/","year":2016,"journal":"The Lancet Oncology","paperType":"observational","tldr":"Combining a BRAF inhibitor with a MEK inhibitor shrank tumours in about two thirds of previously treated patients with BRAF V600E-mutant lung cancer, far more than BRAF inhibition alone, leading to the first approval for this driver.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-gotlib-midostaurin-advanced-systemic-mastocytosis-nejm-2016","kind":"paper","name":"Efficacy and safety of midostaurin in advanced systemic mastocytosis","route":"/key-papers/paper-gotlib-midostaurin-advanced-systemic-mastocytosis-nejm-2016/","year":2016,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The multi-kinase inhibitor midostaurin shrank the mast cell burden and reversed organ damage in six in ten patients with advanced systemic mastocytosis, becoming the first approved targeted drug for the disease.","via":[{"id":"midostaurin","kind":"drug","name":"Midostaurin","route":"/drugs/midostaurin/"}]},{"id":"paper-eribulin-liposarcoma-schoffski-lancet-2016","kind":"paper","name":"Eribulin versus dacarbazine in previously treated advanced liposarcoma or leiomyosarcoma","route":"/key-papers/paper-eribulin-liposarcoma-schoffski-lancet-2016/","year":2016,"journal":"The Lancet","paperType":"rct","tldr":"Eribulin lengthened survival by two months compared with dacarbazine in previously treated liposarcoma and leiomyosarcoma, with the entire benefit in liposarcoma, where survival improved by seven months, leading to its approval for that subtype.","via":[{"id":"eribulin","kind":"drug","name":"Eribulin","route":"/drugs/eribulin/"}]},{"id":"paper-heracles-lancet-oncol-2016","kind":"paper","name":"HERACLES: trastuzumab and lapatinib in HER2-amplified, KRAS wild-type metastatic colorectal cancer","route":"/key-papers/paper-heracles-lancet-oncol-2016/","year":2016,"journal":"The Lancet Oncology","paperType":"observational","tldr":"This small Italian trial was the first to show that HER2-amplified colorectal cancer responds to dual HER2 blockade, establishing HER2 as a genuine drug target in a disease where it had been ignored.","via":[{"id":"lapatinib","kind":"drug","name":"Lapatinib","route":"/drugs/lapatinib/"}]},{"id":"paper-royer-plasma-cell-leukaemia-ifm-jco-2016","kind":"paper","name":"IFM 2006 prospective trial: bortezomib-based induction and transplantation for primary plasma cell leukaemia","route":"/key-papers/paper-royer-plasma-cell-leukaemia-ifm-jco-2016/","year":2016,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"The first prospective trial dedicated to plasma cell leukaemia showed that a bortezomib-based four-drug induction followed by stem cell transplantation could produce remissions in most patients, though relapse remained the rule.","via":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"}]},{"id":"paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-hammel-jama-2016","kind":"paper","name":"LAP07: chemoradiotherapy versus chemotherapy after four months of gemcitabine in locally advanced pancreatic cancer","route":"/key-papers/paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-hammel-jama-2016/","year":2016,"journal":"JAMA","paperType":"rct","tldr":"Adding radiotherapy after four months of chemotherapy did not help people with unresectable, non-metastatic pancreatic cancer live longer, though it delayed local growth; adding erlotinib to gemcitabine did not help either.","via":[{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"}]},{"id":"paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-jama-2016","kind":"paper","name":"LAP07: chemoradiotherapy versus continued chemotherapy for locally advanced pancreatic cancer controlled after four months of gemcitabine","route":"/key-papers/paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-jama-2016/","year":2016,"journal":"JAMA","paperType":"rct","tldr":"Adding radiotherapy after four months of chemotherapy did not help patients with inoperable pancreatic cancer confined to the pancreas live longer, though it delayed regrowth at the original site. Nor did adding the pill erlotinib to gemcitabine. The result pushed radiotherapy out of the routine pathway for locally advanced disease.","via":[{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"}]},{"id":"paper-radiant-4-everolimus-lancet-2016","kind":"paper","name":"RADIANT-4: everolimus for advanced non-functional neuroendocrine tumours of the lung or gastrointestinal tract","route":"/key-papers/paper-radiant-4-everolimus-lancet-2016/","year":2016,"journal":"The Lancet","paperType":"rct","tldr":"Everolimus more than doubled the time to progression in advanced non-functioning neuroendocrine tumours of the lung and gut, the first drug with randomised evidence in lung carcinoids.","via":[{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"}]},{"id":"paper-bolt-sonidegib-migden-lancet-oncol-2015","kind":"paper","name":"BOLT: two doses of sonidegib in locally advanced or metastatic basal cell carcinoma","route":"/key-papers/paper-bolt-sonidegib-migden-lancet-oncol-2015/","year":2015,"journal":"The Lancet Oncology","paperType":"rct","tldr":"Sonidegib, a second hedgehog inhibitor, shrank tumours in about 40 percent of patients with locally advanced basal cell carcinoma at the lower 200 mg dose with fewer side effects than the higher dose, and was approved as an alternative to vismodegib.","via":[{"id":"sonidegib","kind":"drug","name":"Sonidegib","route":"/drugs/sonidegib/"}]},{"id":"paper-combi-d-long-lancet-2015","kind":"paper","name":"COMBI-d: dabrafenib and trametinib versus dabrafenib alone for BRAF V600-mutant melanoma","route":"/key-papers/paper-combi-d-long-lancet-2015/","year":2015,"journal":"The Lancet","paperType":"rct","tldr":"Adding the MEK inhibitor trametinib to the BRAF inhibitor dabrafenib lengthened survival and reduced the skin cancers caused by BRAF inhibition alone in metastatic BRAF-mutant melanoma, establishing dual blockade as the standard for targeted therapy.","via":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}]},{"id":"paper-ibis-i-tamoxifen-lancet-oncol-2015","kind":"paper","name":"IBIS-I: five years of tamoxifen keeps preventing breast cancer for at least 20 years","route":"/key-papers/paper-ibis-i-tamoxifen-lancet-oncol-2015/","year":2015,"journal":"Lancet Oncology","paperType":"rct","tldr":"In women at increased risk, 5 years of tamoxifen reduced breast cancer by 29% over a median 16 years of follow-up, with the benefit continuing long after the pills stopped, but no reduction in breast cancer deaths.","via":[{"id":"tamoxifen","kind":"drug","name":"Tamoxifen","route":"/drugs/tamoxifen/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"paper-couch-tnbc-germline-17-genes-jco-2015","kind":"paper","name":"Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer","route":"/key-papers/paper-couch-tnbc-germline-17-genes-jco-2015/","year":2015,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Testing 1,824 women with triple-negative breast cancer regardless of family history found an inherited cancer-gene mutation in one in seven: BRCA1 in 8.5%, BRCA2 in 2.7% and other repair genes in 3.7%, which is why every TNBC patient is now offered germline testing.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}]},{"id":"paper-select-lenvatinib-nejm-2015","kind":"paper","name":"SELECT: lenvatinib versus placebo in radioiodine-refractory differentiated thyroid cancer","route":"/key-papers/paper-select-lenvatinib-nejm-2015/","year":2015,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"The multikinase inhibitor lenvatinib delayed progression by almost fifteen months compared with placebo in iodine-refractory differentiated thyroid cancer and shrank tumours in two thirds of patients, becoming the preferred drug for this disease.","via":[{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}]},{"id":"paper-storm-adjuvant-sorafenib-bruix-lancet-oncol-2015","kind":"paper","name":"STORM: adjuvant sorafenib after resection or ablation of hepatocellular carcinoma","route":"/key-papers/paper-storm-adjuvant-sorafenib-bruix-lancet-oncol-2015/","year":2015,"journal":"The Lancet Oncology","paperType":"rct","tldr":"Four years of sorafenib after curative surgery or ablation for liver cancer did not delay recurrence or lengthen survival, and caused substantial toxicity, closing the door on kinase inhibitors as adjuvant therapy.","via":[{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"}]},{"id":"paper-esmo-thymic-epithelial-tumours-guideline-ann-oncol-2015","kind":"paper","name":"Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","route":"/key-papers/paper-esmo-thymic-epithelial-tumours-guideline-ann-oncol-2015/","year":2015,"journal":"Annals of Oncology","paperType":"guideline","tldr":"The European guideline for thymoma and thymic carcinoma, built on the French RYTHMIC network's experience: complete surgery where possible, radiotherapy for invasive tumours and platinum chemotherapy for disease that cannot be removed.","via":[{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-robinson-vismodegib-shh-medulloblastoma-jco-2015","kind":"paper","name":"Vismodegib in recurrent sonic hedgehog-subgroup medulloblastoma (PBTC-025B and PBTC-032)","route":"/key-papers/paper-robinson-vismodegib-shh-medulloblastoma-jco-2015/","year":2015,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"The hedgehog pathway inhibitor vismodegib produced responses in recurrent SHH-subgroup medulloblastoma but not in other subgroups, and only in tumours whose mutation lay upstream of the drug's target, showing that molecular subgrouping must guide its use.","via":[{"id":"vismodegib","kind":"drug","name":"Vismodegib","route":"/drugs/vismodegib/"}]},{"id":"paper-shaw-crizotinib-ros1-nejm-2014","kind":"paper","name":"Crizotinib in ROS1-rearranged non-small-cell lung cancer","route":"/key-papers/paper-shaw-crizotinib-ros1-nejm-2014/","year":2014,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"Crizotinib shrank tumours in almost three quarters of patients with ROS1-rearranged lung cancer and controlled the disease for a median of 19 months, establishing ROS1 as a targetable driver and leading to the first approval.","via":[{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"}]},{"id":"paper-decision-sorafenib-lancet-2014","kind":"paper","name":"DECISION: sorafenib in radioactive iodine-refractory differentiated thyroid cancer","route":"/key-papers/paper-decision-sorafenib-lancet-2014/","year":2014,"journal":"The Lancet","paperType":"rct","tldr":"Sorafenib was the first drug shown to delay progression in iodine-refractory differentiated thyroid cancer, adding about five months compared with placebo and opening the era of kinase inhibitors for the disease.","via":[{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"}]},{"id":"paper-solomon-n-engl-j-med","kind":"paper","name":"First-line crizotinib versus chemotherapy in ALK-positive lung cancer","route":"/key-papers/paper-solomon-n-engl-j-med/","year":2014,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 25470694 and published in New England Journal of Medicine; the citing page links this DOI, which is how the record was matched.","via":[{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"}]},{"id":"paper-exam-cabozantinib-mtc-elisei-jco-2013","kind":"paper","name":"EXAM: cabozantinib in progressive medullary thyroid cancer","route":"/key-papers/paper-exam-cabozantinib-mtc-elisei-jco-2013/","year":2013,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Cabozantinib, a kinase inhibitor blocking RET, MET and VEGF receptors, delayed progression by more than seven months compared with placebo in progressive medullary thyroid cancer, at the cost of considerable toxicity.","via":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"}]},{"id":"paper-grid-regorafenib-gist-lancet-2013","kind":"paper","name":"GRID: regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib","route":"/key-papers/paper-grid-regorafenib-gist-lancet-2013/","year":2013,"journal":"The Lancet","paperType":"rct","tldr":"Regorafenib delayed progression by almost four months compared with placebo in gastrointestinal stromal tumours resistant to both imatinib and sunitinib, giving patients a third line of targeted therapy.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"regorafenib","kind":"drug","name":"Regorafenib","route":"/drugs/regorafenib/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}]},{"id":"paper-shi-lancet-oncol","kind":"paper","name":"Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial","route":"/key-papers/paper-shi-lancet-oncol/","year":2013,"journal":"The Lancet Oncology","paperType":"rct","tldr":"Paper cited by one treatment page, indexed on Europe PMC as PubMed record 23948351 and published in The Lancet Oncology; the citing page links this DOI, which is how the record was matched.","via":[{"id":"icotinib","kind":"drug","name":"Icotinib","route":"/drugs/icotinib/"}]},{"id":"paper-hodi-imatinib-kit-melanoma-jco-2013","kind":"paper","name":"Imatinib for melanomas harbouring mutationally activated or amplified KIT arising on mucosal, acral and chronically sun-damaged skin","route":"/key-papers/paper-hodi-imatinib-kit-melanoma-jco-2013/","year":2013,"journal":"Journal of Clinical Oncology","paperType":"observational","tldr":"Imatinib shrank tumours in about a third of patients with melanoma carrying KIT mutations, but only in those with mutations in specific exons, defining a small targetable subgroup among mucosal and acral melanomas.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/","year":2013,"journal":"Nature","paperType":"basic","tldr":"Using disulfide-tethering screens, Shokat's laboratory found small molecules that bind covalently to the mutant cysteine of KRAS G12C in a previously unknown pocket beneath switch II, locking the oncoprotein in its inactive GDP-bound state.","via":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"paper-pace-ponatinib-nejm-2013","kind":"paper","name":"PACE: ponatinib in Philadelphia chromosome-positive leukaemias resistant to earlier tyrosine kinase inhibitors","route":"/key-papers/paper-pace-ponatinib-nejm-2013/","year":2013,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"Ponatinib produced deep responses in patients with chronic myeloid leukaemia or Philadelphia-positive acute lymphoblastic leukaemia whose disease had resisted other kinase inhibitors, including the T315I mutation that no other drug could reach.","via":[{"id":"ponatinib","kind":"drug","name":"Ponatinib","route":"/drugs/ponatinib/"}]},{"id":"paper-gucalp-bicalutamide-ar-positive-tbcrc011-ccr-2013","kind":"paper","name":"Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer","route":"/key-papers/paper-gucalp-bicalutamide-ar-positive-tbcrc011-ccr-2013/","year":2013,"journal":"Clinical Cancer Research","paperType":"rct","tldr":"Screening 424 women with ER-negative breast cancer found androgen receptor in 12%; the prostate drug bicalutamide held the disease stable for six months in 19% of them, the first clinical proof that the LAR subtype can be treated through its receptor.","via":[{"id":"bicalutamide","kind":"drug","name":"Bicalutamide","route":"/drugs/bicalutamide/"}]},{"id":"paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","kind":"paper","name":"COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis","route":"/key-papers/paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012/","year":2012,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Ruxolitinib shrank the enlarged spleen by more than a third in 42% of myelofibrosis patients versus under 1% on placebo, and halved symptom scores in nearly half.","via":[{"id":"fedratinib","kind":"drug","name":"Fedratinib","route":"/drugs/fedratinib/"},{"id":"momelotinib","kind":"drug","name":"Momelotinib","route":"/drugs/momelotinib/"},{"id":"pacritinib","kind":"drug","name":"Pacritinib","route":"/drugs/pacritinib/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"}]},{"id":"paper-comfort-ii-ruxolitinib-best-available-therapy-harrison-nejm-2012","kind":"paper","name":"COMFORT-II: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis","route":"/key-papers/paper-comfort-ii-ruxolitinib-best-available-therapy-harrison-nejm-2012/","year":2012,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"In this European trial, ruxolitinib shrank the spleen by more than a third in 28 percent of people with myelofibrosis after 48 weeks while no patient on the best alternative treatment achieved that, and symptoms and quality of life improved.","via":[{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"}]},{"id":"paper-erivance-vismodegib-sekulic-nejm-2012","kind":"paper","name":"ERIVANCE BCC: efficacy and safety of vismodegib in advanced basal cell carcinoma","route":"/key-papers/paper-erivance-vismodegib-sekulic-nejm-2012/","year":2012,"journal":"New England Journal of Medicine","paperType":"observational","tldr":"The hedgehog pathway inhibitor vismodegib shrank tumours in 43 percent of patients with locally advanced and 30 percent with metastatic basal cell carcinoma, becoming the first drug approved for advanced basal cell carcinoma.","via":[{"id":"vismodegib","kind":"drug","name":"Vismodegib","route":"/drugs/vismodegib/"}]},{"id":"paper-esphall-imatinib-biondi-lancet-oncol-2012","kind":"paper","name":"EsPhALL: imatinib after induction for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukaemia","route":"/key-papers/paper-esphall-imatinib-biondi-lancet-oncol-2012/","year":2012,"journal":"The Lancet Oncology","paperType":"rct","tldr":"In this European trial, adding intermittent imatinib to intensive chemotherapy for childhood Philadelphia-positive leukaemia improved disease-free survival in good-risk patients and supported its use in every child with the disease.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"paper-ssg-xviii-adjuvant-imatinib-joensuu-jama-2012","kind":"paper","name":"SSG XVIII/AIO: one versus three years of adjuvant imatinib for operable gastrointestinal stromal tumour","route":"/key-papers/paper-ssg-xviii-adjuvant-imatinib-joensuu-jama-2012/","year":2012,"journal":"JAMA","paperType":"rct","tldr":"Three years of imatinib after surgery for high-risk gastrointestinal stromal tumour reduced recurrences and deaths compared with one year, setting the standard duration of adjuvant therapy.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"paper-zeta-vandetanib-mtc-wells-jco-2012","kind":"paper","name":"ZETA: vandetanib in locally advanced or metastatic medullary thyroid cancer","route":"/key-papers/paper-zeta-vandetanib-mtc-wells-jco-2012/","year":2012,"journal":"Journal of Clinical Oncology","paperType":"rct","tldr":"Vandetanib was the first drug shown to delay progression in medullary thyroid cancer, roughly doubling progression-free survival compared with placebo, and became the first approved therapy for the disease.","via":[{"id":"vandetanib","kind":"drug","name":"Vandetanib","route":"/drugs/vandetanib/"}]},{"id":"paper-chapman-vemurafenib-nejm-2011","kind":"paper","name":"BRIM-3: improved survival with vemurafenib in melanoma with BRAF V600E mutation","route":"/key-papers/paper-chapman-vemurafenib-nejm-2011/","year":2011,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"Vemurafenib, the first drug targeting the BRAF V600E mutation, reduced deaths by 63 percent compared with dacarbazine chemotherapy in metastatic melanoma, launching targeted therapy in the disease.","via":[{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}]},{"id":"paper-conroy-folfirinox-pancreatic-nejm-2011","kind":"paper","name":"Conroy 2011: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer (PRODIGE 4/ACCORD 11)","route":"/key-papers/paper-conroy-folfirinox-pancreatic-nejm-2011/","year":2011,"journal":"New England Journal of Medicine","paperType":"rct","tldr":"A four-drug chemotherapy combination gave fit patients with metastatic pancreatic cancer clearly longer survival than the standard gemcitabine, the first real improvement in the disease in over a decade, at the cost of more side effects.","via":[{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal 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evidence","status":"current","step":4,"route":"/roadmaps/survivorship-roadmap/#story-step-3","refs":[{"id":"sodium-thiosulfate","kind":"drug","name":"Sodium thiosulfate (otoprotectant)","route":"/drugs/sodium-thiosulfate/"}]},{"roadmap":{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"},"era":"1977-2001","title":"The idea of a target","status":"historic","step":1,"route":"/roadmaps/targeted-therapy-roadmap/#story-step-0","refs":[{"id":"tamoxifen","kind":"drug","name":"Tamoxifen","route":"/drugs/tamoxifen/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"roadmap":{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"},"era":"2004-2013","title":"Oncogene addiction, and the resistance lesson","status":"historic","step":2,"route":"/roadmaps/targeted-therapy-roadmap/#story-step-1","refs":[{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"},{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"},{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"}]},{"roadmap":{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"},"era":"2014-2020","title":"Designed for resistance, the brain and the adjuvant 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fall","route":"/roadmaps/targeted-therapy-roadmap/"},"era":"2021-2026","title":"The undruggable drivers fall","status":"current","step":4,"route":"/roadmaps/targeted-therapy-roadmap/#story-step-3","refs":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"divarasib","kind":"drug","name":"Divarasib","route":"/drugs/divarasib/"},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/"},{"id":"mrtx1133","kind":"drug","name":"MRTX1133","route":"/drugs/mrtx1133/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"elironrasib","kind":"drug","name":"Elironrasib","route":"/drugs/elironrasib/"},{"id":"olomorasib","kind":"drug","name":"Olomorasib","route":"/drugs/olomorasib/"},{"id":"lazertinib","kind":"drug","name":"Lazertinib","route":"/drugs/lazertinib/"}]},{"roadmap":{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"},"era":"2026-2030","title":"Fourth generations, degraders and switching on a blood test","status":"emerging","step":5,"route":"/roadmaps/targeted-therapy-roadmap/#story-step-4","refs":[{"id":"neladalkib","kind":"drug","name":"Neladalkib","route":"/drugs/neladalkib/"},{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/"}]},{"roadmap":{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"},"era":"2030+","title":"Forecasting resistance instead of waiting for it","status":"speculative","step":7,"route":"/roadmaps/targeted-therapy-roadmap/#story-step-6","refs":[{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","route":"/drugs/eprenetapopt/"}]},{"roadmap":{"id":"tnbc-history","kind":"roadmap","name":"TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line","route":"/roadmaps/tnbc-history/"},"era":"2018-2020","title":"Immunotherapy and PARP arrive","status":"historic","step":2,"route":"/roadmaps/tnbc-history/#story-step-1","refs":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}]},{"roadmap":{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"},"era":"2017-2026","title":"PARP inhibition for germline BRCA carriers","status":"current","step":9,"route":"/roadmaps/tnbc-roadmap/#story-step-8","refs":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"roadmap":{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"},"era":"2020-2026","title":"Antibody-drug conjugates move from third line to first","status":"current","step":11,"route":"/roadmaps/tnbc-roadmap/#story-step-10","refs":[{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"}]}],"ideas":[{"id":"idea-molecular-class-adjuvant-endometrial","kind":"idea","name":"Molecular-class-directed adjuvant therapy in endometrial cancer","route":"/ideas/idea-molecular-class-adjuvant-endometrial/","maturity":"being-tested-at-scale","tldr":"Give adjuvant treatment by the tumour's molecular class rather than by stage and grade: nothing for POLE-mutated, immunotherapy for MMRd, chemotherapy plus targeted agents for p53-abnormal, hormones for NSMP.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"idea-mrd-guided-stop-cll","kind":"idea","name":"MRD-guided treatment duration in CLL","route":"/ideas/idea-mrd-guided-stop-cll/","maturity":"being-tested-at-scale","tldr":"Instead of a fixed 12 or 15 months, stop each patient's therapy when their blood shows no detectable leukaemia, and restart if it returns.","via":[{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"},{"id":"zanubrutinib","kind":"drug","name":"Zanubrutinib","route":"/drugs/zanubrutinib/"}]},{"id":"idea-cost-pooled-procurement-essential","kind":"idea","name":"Pool purchasing of essential cancer medicines across countries","route":"/ideas/idea-cost-pooled-procurement-essential/","maturity":"being-tested-at-scale","tldr":"Small countries pay more for the same generic chemotherapy because they buy alone; the PAHO Strategic Fund and the WHO essential medicines list show that buying together brings prices down and keeps supply steady.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"letrozole","kind":"drug","name":"Letrozole (and other aromatase inhibitors)","route":"/drugs/letrozole/"},{"id":"tamoxifen","kind":"drug","name":"Tamoxifen","route":"/drugs/tamoxifen/"}]},{"id":"idea-reg-pooled-procurement-adult-essentials","kind":"idea","name":"Pooled international procurement of essential adult cancer medicines","route":"/ideas/idea-reg-pooled-procurement-adult-essentials/","maturity":"being-tested-at-scale","tldr":"Countries buying cancer drugs alone pay more and face shortages. Buying together, as they already do for childhood cancer drugs and vaccines, cuts prices and secures supply.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"idea-cost-low-dose-abiraterone-food","kind":"idea","name":"Prescribe a quarter dose of abiraterone with breakfast","route":"/ideas/idea-cost-low-dose-abiraterone-food/","maturity":"being-tested-at-scale","tldr":"Taking 250 mg of abiraterone with a low-fat breakfast gives the same PSA response and testosterone suppression as the standard 1,000 mg fasting, because food increases absorption several-fold, so a quarter of the drug treats each man. The label still says fasting and no company promotes the food-effect dose, so adoption is patchy.","via":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"}]},{"id":"idea-tr1-public-dose-reduction-trials-of-approved-drugs","kind":"idea","name":"Publicly funded dose-reduction trials of expensive approved drugs","route":"/ideas/idea-tr1-public-dose-reduction-trials-of-approved-drugs/","maturity":"being-tested-at-scale","tldr":"Some expensive approved cancer drugs probably work as well at lower doses, as reduced-dose abiraterone with food and extended-interval checkpoint inhibitors suggest. Companies will not test this, so payers should fund randomised non-inferiority trials prioritised by spend and pharmacology, and use the results in reimbursement.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-reg-public-deescalation-trials-for-cost","kind":"idea","name":"Publicly funded trials of lower and less frequent doses of expensive cancer drugs","route":"/ideas/idea-reg-public-deescalation-trials-for-cost/","maturity":"being-tested-at-scale","tldr":"Abiraterone at a quarter dose with food matches full-dose exposure, and pembrolizumab and nivolumab can be given at longer intervals, but no manufacturer will fund trials that cut its own revenue. A public 'value trials' fund would run non-inferiority trials of lower doses and longer intervals for the highest-spend cancer drugs, with payers committing to adopt positive results.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-tr1-randomised-dose-comparison-before-pivotal","kind":"idea","name":"Randomise at least two doses in phase 2 before any pivotal trial","route":"/ideas/idea-tr1-randomised-dose-comparison-before-pivotal/","maturity":"being-tested-at-scale","tldr":"Cancer drugs are usually tested at the highest dose patients can stand, and that dose sticks for life. Comparing two or more doses head-to-head before the big trial would find doses that work as well with fewer side effects.","via":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-cost-transparent-generic-pricing","kind":"idea","name":"Transparent cost-plus pricing for every oral oncology generic","route":"/ideas/idea-cost-transparent-generic-pricing/","maturity":"being-tested-at-scale","tldr":"Generic imatinib and abiraterone can cost patients hundreds of dollars a month through insurance yet be sold at cost plus a fixed markup by transparent pharmacies; making that the default channel for oral cancer generics would save patients and plans money.","via":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"letrozole","kind":"drug","name":"Letrozole (and other aromatase inhibitors)","route":"/drugs/letrozole/"},{"id":"tamoxifen","kind":"drug","name":"Tamoxifen","route":"/drugs/tamoxifen/"}]},{"id":"idea-transplant-free-ph-all","kind":"idea","name":"Transplant-free Ph-positive ALL for MRD-negative adults","route":"/ideas/idea-transplant-free-ph-all/","maturity":"being-tested-at-scale","tldr":"If a pill plus immunotherapy makes the leukaemia undetectable, can most adults safely skip a bone-marrow transplant?","via":[{"id":"dasatinib","kind":"drug","name":"Dasatinib","route":"/drugs/dasatinib/"},{"id":"ponatinib","kind":"drug","name":"Ponatinib","route":"/drugs/ponatinib/"}]},{"id":"idea-bio1-ctdna-clone-report","kind":"idea","name":"A clone report from blood at every treatment cycle","route":"/ideas/idea-bio1-ctdna-clone-report/","maturity":"early-clinical","tldr":"Blood tests can already detect tumour DNA. Reporting which sub-populations of the tumour are growing or shrinking, cycle by cycle, would turn the test into an evolution monitor.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-reg-generic-targeted-therapy-drup","kind":"idea","name":"A DRUP-style protocol for off-label generic targeted drugs in rare tumours","route":"/ideas/idea-reg-generic-targeted-therapy-drup/","maturity":"early-clinical","tldr":"Cheap generic versions of targeted cancer drugs like imatinib exist, but patients with rare tumours carrying the matching mutation often cannot get them. A structured programme would treat them and collect the evidence.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-bio1-upfront-bypass-combination","kind":"idea","name":"Add the second drug on day one when the escape route is predictable","route":"/ideas/idea-bio1-upfront-bypass-combination/","maturity":"early-clinical","tldr":"If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}]},{"id":"idea-tr1-sex-stratified-pk-and-dosing","kind":"idea","name":"Analyse and dose by sex: women get more toxicity from many cancer drugs at the same dose","route":"/ideas/idea-tr1-sex-stratified-pk-and-dosing/","maturity":"early-clinical","tldr":"Women get more severe side effects than men at identical doses of fluorouracil, several kinase inhibitors and immune checkpoint inhibitors in pooled analyses. Trials should pre-specify sex-stratified drug level and toxicity analyses and, where they differ, run sex-specific dose-finding and label accordingly.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-moon-closed-loop-adaptive-therapy","kind":"idea","name":"Autonomous closed-loop adaptive therapy driven by blood tests and evolutionary models","route":"/ideas/idea-moon-closed-loop-adaptive-therapy/","maturity":"early-clinical","tldr":"Rather than giving the same dose until the cancer grows, measure tumour DNA in blood every few weeks and let a validated algorithm raise, lower, pause or switch drugs to keep the cancer suppressed for longer.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-adjuvant-selection-rcc","kind":"idea","name":"Biomarker-selected adjuvant therapy in RCC (ctDNA, CAIX PET, gene signatures)","route":"/ideas/idea-adjuvant-selection-rcc/","maturity":"early-clinical","tldr":"Adjuvant immunotherapy after kidney cancer surgery is given to everyone at high pathological risk although most would never relapse, so a year of toxicity is spread across the whole group to help a minority. A biomarker such as CAIX PET or kidney-specific tumour DNA could pick out the few who need it.","via":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"}]},{"id":"idea-bio2-autophagy-block-mrd","kind":"idea","name":"Block the recycling that keeps dormant cells alive","route":"/ideas/idea-bio2-autophagy-block-mrd/","maturity":"early-clinical","tldr":"Sleeping cancer cells survive by recycling their own contents. An old malaria drug blocks that recycling and is being tested in people with no visible cancer but detectable residual cells.","via":[{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"}]},{"id":"idea-atc-triplet-io","kind":"idea","name":"BRAF/MEK plus PD-1 blockade as standard for BRAF-mutant anaplastic thyroid cancer","route":"/ideas/idea-atc-triplet-io/","maturity":"early-clinical","tldr":"Add immunotherapy to the two targeted pills in the most aggressive thyroid cancer, because the combination has produced multi-year survivors in early series.","via":[{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"}]},{"id":"idea-tr1-brain-mets-default-included","kind":"idea","name":"Brain metastases included by default in every solid-tumour trial","route":"/ideas/idea-tr1-brain-mets-default-included/","maturity":"early-clinical","tldr":"Up to a fifth of people with advanced solid tumours have cancer in the brain and are usually barred from trials. Letting in those whose brain disease is treated, stable or symptom-free would widen trials and tell us whether drugs work in the brain.","via":[{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"idea-btk-degrader-frontline","kind":"idea","name":"BTK degraders to pre-empt resistance in frontline CLL","route":"/ideas/idea-btk-degrader-frontline/","maturity":"early-clinical","tldr":"If destroying BTK works when every inhibitor has failed, using it first might stop resistance from ever emerging.","via":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"idea-acc-cardiometabolic-clinic-hormone-therapy","kind":"idea","name":"Cardiometabolic screening and treatment for survivors on long-term hormone therapy","route":"/ideas/idea-acc-cardiometabolic-clinic-hormone-therapy/","maturity":"early-clinical","tldr":"Hormone-blocking treatments for prostate and breast cancer, taken for years, raise the risk of diabetes, heart disease and bone fractures. Survivors on these drugs should get the same preventive care as diabetics.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"},{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"}]},{"id":"idea-cdk4-selective-first-line","kind":"idea","name":"CDK4-selective inhibitors as the new first-line backbone","route":"/ideas/idea-cdk4-selective-first-line/","maturity":"early-clinical","tldr":"If a CDK4-only drug matches CDK4/6 inhibitors on efficacy with less neutropenia, continuous dosing and better adherence could translate into longer control.","via":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"atirmociclib","kind":"drug","name":"Atirmociclib","route":"/drugs/atirmociclib/"},{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"}]},{"id":"idea-pv-clone-directed-therapy","kind":"idea","name":"Clearing the JAK2 clone in polycythaemia vera: interferon plus mutant-selective inhibitors as a route to treatment-free remission","route":"/ideas/idea-pv-clone-directed-therapy/","maturity":"early-clinical","tldr":"Today's PV drugs control blood counts but leave the mutant cells in place. Interferon is the one treatment that shrinks the clone, and the first JAK2 V617F-selective inhibitors have entered trials; combining the two could aim at molecular remission, the way imatinib did for CML.","via":[{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-bio1-pan-ras-covalent-g12d","kind":"idea","name":"Covalent chemistry for the RAS mutations that still have no drug","route":"/ideas/idea-bio1-pan-ras-covalent-g12d/","maturity":"early-clinical","tldr":"One RAS mutation can now be drugged because it offers a reactive handle. Most RAS mutations do not, so new chemistry is needed to grab other amino acids.","via":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}]},{"id":"idea-btc-ctdna-fgfr-resistance","kind":"idea","name":"ctDNA-guided switching among FGFR inhibitors","route":"/ideas/idea-btc-ctdna-fgfr-resistance/","maturity":"early-clinical","tldr":"Track FGFR2 resistance mutations in blood and switch to the next-generation inhibitor that still covers them, before the scan shows progression.","via":[{"id":"futibatinib","kind":"drug","name":"Futibatinib","route":"/drugs/futibatinib/"},{"id":"pemigatinib","kind":"drug","name":"Pemigatinib","route":"/drugs/pemigatinib/"},{"id":"tinengotinib","kind":"drug","name":"Tinengotinib","route":"/drugs/tinengotinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-tr1-patient-reported-toxicity-dose-algorithms","kind":"idea","name":"Dose adjustments driven by patients' own symptom reports, tested against clinician judgement","route":"/ideas/idea-tr1-patient-reported-toxicity-dose-algorithms/","maturity":"early-clinical","tldr":"Patients report symptoms on their phone each week; a set of rules turns severe or worsening symptoms into a dose hold or reduction before the next clinic visit. This could keep people on treatment longer and feeling better.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-cost-shorter-course-trials","kind":"idea","name":"Fund trials that test shorter courses of the most expensive adjuvant drugs","route":"/ideas/idea-cost-shorter-course-trials/","maturity":"early-clinical","tldr":"The PERSEPHONE trial showed six months of trastuzumab after surgery is as good as twelve, halving the drug cost; no company will run such trials, so public funders and charities must.","via":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"idea-bio2-mechanism-defined-baskets","kind":"idea","name":"Group trials by broken mechanism, not by organ or single mutation","route":"/ideas/idea-bio2-mechanism-defined-baskets/","maturity":"early-clinical","tldr":"Rare cancers often share a broken cellular machine even when they arise in different organs. Grouping patients by that shared fault makes trials possible.","via":[{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-prev-frail-elderly-primary-endocrine-breast","kind":"idea","name":"Hormone tablets instead of surgery for small breast cancers in the frail over-80s","route":"/ideas/idea-prev-frail-elderly-primary-endocrine-breast/","maturity":"early-clinical","tldr":"Frail women over 80 with small hormone-sensitive breast cancers may do as well with a daily tablet as with surgery. A trial would define who can safely avoid the operation.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-dormancy-maintenance-therapy","kind":"idea","name":"Keep them asleep: dormancy maintenance as adjuvant therapy","route":"/ideas/idea-dormancy-maintenance-therapy/","maturity":"early-clinical","tldr":"Instead of trying to kill every hidden cancer cell after surgery, keep them dormant for life with low-toxicity drugs, the way extended hormone therapy already does in breast cancer.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-reg-secondary-patent-thicket-limits","kind":"idea","name":"Limit secondary patents and pay-for-delay so cancer generics arrive on time","route":"/ideas/idea-reg-secondary-patent-thicket-limits/","maturity":"early-clinical","tldr":"Companies extend monopolies on cancer drugs with dozens of minor patents and deals that pay generic makers to stay out. Closing these loopholes would bring cheaper versions years earlier.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"idea-prev-low-dose-tamoxifen-uptake","kind":"idea","name":"Low-dose tamoxifen for high-risk women, prescribed by pharmacists and nurses","route":"/ideas/idea-prev-low-dose-tamoxifen-uptake/","maturity":"early-clinical","tldr":"A 5 mg tamoxifen dose halves breast cancer recurrence after precancer with far fewer side effects than the full dose. Almost nobody is prescribed it. Change who can prescribe.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-reg-global-dose-optimisation-guideline","kind":"idea","name":"Make pre-approval dose optimisation an ICH standard so it is done once worldwide","route":"/ideas/idea-reg-global-dose-optimisation-guideline/","maturity":"early-clinical","tldr":"The FDA now asks companies to find the right dose of a cancer drug before approval. If every regulator asked the same way, companies would do it once and doses would match worldwide.","via":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}]},{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","route":"/ideas/idea-immunotherapy-mss-crc/","maturity":"early-clinical","tldr":"Ninety-five percent of bowel cancers ignore immunotherapy. Combinations that heat the tumour up (targeted drugs, radiation, new checkpoints) are the main hope.","via":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}]},{"id":"idea-tr1-therapeutic-drug-monitoring-for-oral-tkis","kind":"idea","name":"Measure blood levels of oral targeted drugs and adjust doses to a target range","route":"/ideas/idea-tr1-therapeutic-drug-monitoring-for-oral-tkis/","maturity":"early-clinical","tldr":"Blood levels of oral cancer pills vary several-fold between people on the same dose, so some are under-treated and others poisoned. Checking levels and adjusting the dose, as is routine for some antibiotics, could fix both.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-reg-patent-pool-oncology-eml","kind":"idea","name":"Medicines Patent Pool licences for every patented cancer drug on the WHO list","route":"/ideas/idea-reg-patent-pool-oncology-eml/","maturity":"early-clinical","tldr":"Companies can license their patents to generic makers for poorer countries through a UN-backed pool, as happened for HIV. Only one cancer drug has been licensed so far; the whole essential list should be.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-menin-infant-all","kind":"idea","name":"Menin inhibitors for infant KMT2A-rearranged ALL","route":"/ideas/idea-menin-infant-all/","maturity":"early-clinical","tldr":"Infant leukaemia is driven almost entirely by KMT2A fusions, which menin inhibitors were built to attack. Add them to the new blinatumomab-containing backbone.","via":[{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}]},{"id":"idea-moon-individualised-dosing-all-oral-drugs","kind":"idea","name":"Model-informed individual dosing with drug-level monitoring for every oral cancer drug","route":"/ideas/idea-moon-individualised-dosing-all-oral-drugs/","maturity":"early-clinical","tldr":"People differ several-fold in how they absorb and clear cancer pills. Measure blood levels and adjust each person's dose, as is routine for some antibiotics and transplant drugs.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-ctdna-switch-generalised","kind":"idea","name":"Molecular-progression switching beyond ESR1","route":"/ideas/idea-ctdna-switch-generalised/","maturity":"early-clinical","tldr":"SERENA-6 showed you can act on a blood test before the scan changes. The same logic could apply to PIK3CA, AKT1, or HER2 mutations emerging on treatment.","via":[{"id":"camizestrant","kind":"drug","name":"Camizestrant","route":"/drugs/camizestrant/"},{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"}]},{"id":"idea-shared-kras-vaccine-adjuvant","kind":"idea","name":"Off-the-shelf KRAS vaccines after pancreatic cancer surgery","route":"/ideas/idea-shared-kras-vaccine-adjuvant/","maturity":"early-clinical","tldr":"Almost every pancreatic cancer shares one of a handful of KRAS mutations. A pre-made vaccine against them could be given to every patient after surgery.","via":[{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}]},{"id":"idea-bio1-drug-holiday-resensitisation","kind":"idea","name":"Pause a failed drug so the tumour becomes sensitive to it again","route":"/ideas/idea-bio1-drug-holiday-resensitisation/","maturity":"early-clinical","tldr":"Resistant cancer cells can become dependent on the drug they resisted, as shown for BRAF-inhibitor-resistant melanoma in mice. Stopping the drug for a defined washout and then rechallenging, while tracking the resistance allele in blood tumour DNA, could make the tumour vulnerable to it once more.","via":[{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-reg-indication-specific-pricing","kind":"idea","name":"Pay a different price for the same cancer drug depending on the indication","route":"/ideas/idea-reg-indication-specific-pricing/","maturity":"early-clinical","tldr":"One immunotherapy may add years of life in one cancer and weeks in another, yet costs the same. Prices should track the benefit in each use.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"idea-fund-payer-funded-pragmatic-trials","kind":"idea","name":"Payers fund trials of cheaper, shorter or lower-dose versions of expensive treatments","route":"/ideas/idea-fund-payer-funded-pragmatic-trials/","maturity":"early-clinical","tldr":"Health insurers and national health systems have every reason to find out whether half the dose or half the duration of a costly drug works as well. They would fund those trials directly and keep the savings.","via":[{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"}]},{"id":"idea-acc-pharmacist-interaction-review-oral-anticancer","kind":"idea","name":"Pharmacist interaction check before every oral cancer-drug prescription","route":"/ideas/idea-acc-pharmacist-interaction-review-oral-anticancer/","maturity":"early-clinical","tldr":"Oral kinase inhibitors, CDK4/6 inhibitors and hormonal agents interact with proton pump inhibitors, anticoagulants, statins and antiarrhythmics, and are increasingly prescribed to older patients taking all of them. A mandatory oncology pharmacist review at initiation, dose change and refill, with a structured monitoring plan, would catch these interactions systematically.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"}]},{"id":"idea-moon-pooled-procurement-licensing-pool","kind":"idea","name":"Pooled procurement and voluntary licensing for essential cancer medicines in low-income countries","route":"/ideas/idea-moon-pooled-procurement-licensing-pool/","maturity":"early-clinical","tldr":"Buy essential cancer drugs for many countries at once and license newer ones to generic makers, as was done for HIV, so prices fall to what those health systems can pay.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"idea-moon-post-approval-dose-deescalation","kind":"idea","name":"Randomised lower-dose trials for approved drugs with quality of life as the primary endpoint","route":"/ideas/idea-moon-post-approval-dose-deescalation/","maturity":"early-clinical","tldr":"Many cancer drugs are approved at the highest dose patients could stand, not the best dose. Run trials that test lower doses on approved drugs and measure how patients feel.","via":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}]},{"id":"idea-ras-inhibitor-neoadjuvant-pdac","kind":"idea","name":"RAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable","route":"/ideas/idea-ras-inhibitor-neoadjuvant-pdac/","maturity":"early-clinical","tldr":"If daraxonrasib shrinks metastatic tumours this well, use it before surgery to make more locally advanced tumours operable.","via":[{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/"},{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}]},{"id":"idea-tr1-response-adapted-dose-reduction","kind":"idea","name":"Reduce the dose once the cancer responds: response-adapted de-escalation trials","route":"/ideas/idea-tr1-response-adapted-dose-reduction/","maturity":"early-clinical","tldr":"The dose needed to shrink a tumour may be higher than the dose needed to keep it from growing back. Trials that lower the dose once a response is achieved could reduce long-term side effects without losing control.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-tr1-model-based-dose-finding-with-late-toxicity","kind":"idea","name":"Retire the 3+3: model-based dose finding that counts late and chronic side effects","route":"/ideas/idea-tr1-model-based-dose-finding-with-late-toxicity/","maturity":"early-clinical","tldr":"The traditional way of finding a dose looks only at severe side effects in the first month. Modern statistical designs can use all patients' data and count the grumbling, long-lasting problems that make people quit months later.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-shortened-venetoclax","kind":"idea","name":"Shorter venetoclax courses in unfit AML","route":"/ideas/idea-shortened-venetoclax/","maturity":"early-clinical","tldr":"Give venetoclax for 7 or 14 days per cycle instead of 28 to cut infections and low blood counts without losing the benefit.","via":[{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}]},{"id":"idea-tr1-start-low-titrate-up-oral-agents","kind":"idea","name":"Start low and step up: individualised titration of oral cancer drugs, randomised","route":"/ideas/idea-tr1-start-low-titrate-up-oral-agents/","maturity":"early-clinical","tldr":"Instead of starting everyone on the full dose and cutting back after side effects, start lower and increase in patients who tolerate it. This keeps more people on treatment and is how blood-pressure drugs are given.","via":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"idea-cns-first-adc-strategy","kind":"idea","name":"Systemic-first management of HER2-positive brain metastases","route":"/ideas/idea-cns-first-adc-strategy/","maturity":"early-clinical","tldr":"With Enhertu and tucatinib controlling brain metastases in most patients, radiation could be reserved for those who do not respond, sparing cognitive side effects.","via":[{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"idea-tr1-intermittent-dosing-to-delay-resistance","kind":"idea","name":"Test intermittent dosing of targeted drugs to delay resistance, with honest priors","route":"/ideas/idea-tr1-intermittent-dosing-to-delay-resistance/","maturity":"early-clinical","tldr":"Giving a targeted drug in pulses rather than continuously might slow the emergence of resistant cells and reduce side effects. Early results are mixed, so this needs careful trials with clear rules for when to try it.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-bio2-epigenetic-priming-cold-tumours","kind":"idea","name":"Unmask hidden antigens with a short epigenetic course before immunotherapy","route":"/ideas/idea-bio2-epigenetic-priming-cold-tumours/","maturity":"early-clinical","tldr":"Low doses of drugs that change how DNA is packaged can make cancer cells display more of what marks them as abnormal, potentially waking up immunotherapy in cold tumours.","via":[{"id":"mevrometostat","kind":"drug","name":"Mevrometostat","route":"/drugs/mevrometostat/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-tr1-food-effect-dose-reduction","kind":"idea","name":"Use food effects to cut the dose and cost of oral drugs that absorb better with meals","route":"/ideas/idea-tr1-food-effect-dose-reduction/","maturity":"early-clinical","tldr":"Some cancer pills are absorbed several times better with food, but the label says take them fasting at a high dose. Taking a quarter of the dose with breakfast can give the same drug levels at a quarter of the price.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"}]},{"id":"idea-bio2-vascular-normalisation-window","kind":"idea","name":"Use imaging to find the window when tumour blood vessels are working properly","route":"/ideas/idea-bio2-vascular-normalisation-window/","maturity":"early-clinical","tldr":"Low doses of anti-blood-vessel drugs briefly make tumour vessels work better, which helps immune cells and other drugs get in. Scans can find that window for each patient.","via":[{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}]},{"id":"idea-cost-voluntary-licensing-oncology","kind":"idea","name":"Voluntary licences and price caps for patented cancer drugs in low-income countries","route":"/ideas/idea-cost-voluntary-licensing-oncology/","maturity":"early-clinical","tldr":"India's 2012 compulsory licence on sorafenib cut its price by about 97% and its 2019 cap on trade margins lowered the shelf price of 42 cancer drugs; voluntary licences through a patent pool would achieve the same without a fight.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"}]},{"id":"idea-tr2-hrd-functional-standard","kind":"idea","name":"A functional test for homologous recombination deficiency validated across laboratories","route":"/ideas/idea-tr2-hrd-functional-standard/","maturity":"preclinical-evidence","tldr":"Tests for 'HRD', which decide who gets PARP inhibitors, rely on genomic scars that reflect the tumour's past, not its present. A test of current DNA-repair function would be better, but needs standardising.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"idea-bio1-epigenetic-persister-blockade","kind":"idea","name":"Block the chemical switch that lets cells hide from treatment","route":"/ideas/idea-bio1-epigenetic-persister-blockade/","maturity":"preclinical-evidence","tldr":"Cells that survive treatment do so by changing which genes they use, not their DNA. Drugs that block that change may stop survivors from forming at all.","via":[{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-tr2-resistance-mechanism-baskets","kind":"idea","name":"Combination baskets defined by resistance mechanism rather than by cancer type","route":"/ideas/idea-tr2-resistance-mechanism-baskets/","maturity":"preclinical-evidence","tldr":"Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.","via":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"}]},{"id":"idea-moon-dormancy-eradication-programme","kind":"idea","name":"Eradicate dormant cancer cells: a programme to wake and kill or lock asleep disseminated cells","route":"/ideas/idea-moon-dormancy-eradication-programme/","maturity":"preclinical-evidence","tldr":"Many relapses come from cancer cells that hid dormant for years. Find drugs that either force them awake so chemotherapy kills them, or keep them asleep for life.","via":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-bio2-pro-dormancy-therapy","kind":"idea","name":"Keep dormant cells asleep instead of trying to kill them","route":"/ideas/idea-bio2-pro-dormancy-therapy/","maturity":"preclinical-evidence","tldr":"If we cannot kill sleeping cancer cells, we could try to keep them asleep for life. That would turn residual cancer into a harmless passenger.","via":[{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-ferroptosis-persisters","kind":"idea","name":"Kill drug-tolerant persisters through ferroptosis","route":"/ideas/idea-ferroptosis-persisters/","maturity":"preclinical-evidence","tldr":"The cells that survive targeted therapy change shape and become unusually dependent on an antioxidant enzyme, GPX4. Hitting them in that window might stop resistance before it evolves.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-bio1-apobec-inhibitor-adjunct","kind":"idea","name":"Slow the tumour's mutation engine with APOBEC inhibitors during targeted therapy","route":"/ideas/idea-bio1-apobec-inhibitor-adjunct/","maturity":"preclinical-evidence","tldr":"Subsets of lung, bladder and breast cancers carry raised APOBEC enzyme activity that keeps generating new mutations, feeding resistance. Blocking APOBEC3 alongside a targeted drug aims not to kill cells but to slow the rate at which resistant variants arise; the inhibitors are still in discovery.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-tr2-alternating-vs-concurrent","kind":"idea","name":"Test alternating drug schedules against giving both drugs at once","route":"/ideas/idea-tr2-alternating-vs-concurrent/","maturity":"preclinical-evidence","tldr":"Two drugs might work better given in turns rather than together, with less toxicity. Almost no trial has tested this.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-bio1-immunopeptidome-timing","kind":"idea","name":"Time immunotherapy to the moment targeted drugs make tumours visible","route":"/ideas/idea-bio1-immunopeptidome-timing/","maturity":"preclinical-evidence","tldr":"Targeted drugs briefly make cancer cells easier for the immune system to spot. Giving immunotherapy exactly in that window, rather than at the same time, may work better.","via":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"}]},{"id":"idea-bio2-transferrin-shuttle-adc","kind":"idea","name":"Use the brain's own transport door to carry antibody drugs across","route":"/ideas/idea-bio2-transferrin-shuttle-adc/","maturity":"preclinical-evidence","tldr":"The brain imports iron through the transferrin receptor. Antibody shuttle domains that bind that receptor raise brain exposure roughly ten to fifty-fold in primates and are already used in clinical Alzheimer's antibodies; the same engineering could carry antibody-drug conjugates or T-cell engagers to brain metastases.","via":[{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"idea-chip-risk-modifiers","kind":"idea","name":"Which patients' blood clones will become leukaemia after treatment?","route":"/ideas/idea-chip-risk-modifiers/","maturity":"preclinical-evidence","tldr":"PARP inhibitors, platinum, and radioligand drugs can push pre-existing blood-cell clones toward leukaemia in a few patients. Predicting who could let us choose therapies more safely.","via":[{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"idea-tnbc-uk-trial-access-and-germline-testing-audit","kind":"idea","name":"A UK audit of trial access and germline testing uptake in triple-negative breast cancer","route":"/ideas/idea-tnbc-uk-trial-access-and-germline-testing-audit/","maturity":"speculative","tldr":"Every triple-negative patient under 60 in the UK should be offered a BRCA test at diagnosis because the result now changes treatment, and many should be offered a trial, but no one publishes how many are. A national audit through existing cancer registration and genomic laboratory data would show the gap by region before anyone tries to close it.","via":[{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}]},{"id":"idea-bio1-molecular-progression-add-on","kind":"idea","name":"Add a drug when the blood test turns, without stopping the one that works","route":"/ideas/idea-bio1-molecular-progression-add-on/","maturity":"speculative","tldr":"When a resistance mutation first appears in the blood, the current drug is often still controlling most of the tumour. Adding a second drug rather than swapping may keep both under control.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-bio1-condensate-disruptors","kind":"idea","name":"Break up the liquid droplets where oncogenic transcription happens","route":"/ideas/idea-bio1-condensate-disruptors/","maturity":"speculative","tldr":"Some cancer-driving proteins gather into droplet-like blobs inside the nucleus to switch genes on. Drugs that dissolve those blobs might switch the cancer programme off.","via":[{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-bio1-ctdna-adaptive-tki","kind":"idea","name":"ctDNA-guided dose holidays for lung cancer targeted therapy","route":"/ideas/idea-bio1-ctdna-adaptive-tki/","maturity":"speculative","tldr":"Use tumour DNA in the blood as the signal to pause and restart a lung cancer pill, keeping the tumour in check while slowing the rise of resistant cells.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-ctdna-guided-parp-duration","kind":"idea","name":"ctDNA-guided duration of PARP maintenance","route":"/ideas/idea-ctdna-guided-parp-duration/","maturity":"speculative","tldr":"Stop PARP inhibitors early in women whose blood shows no residual tumour DNA, and extend or switch in those whose ctDNA persists or reverts BRCA.","via":[{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}]},{"id":"idea-bio2-paediatric-first-development","kind":"idea","name":"Develop drugs in children first when the target is a children's target","route":"/ideas/idea-bio2-paediatric-first-development/","maturity":"speculative","tldr":"Children wait years for drugs because adult trials come first, even when the target belongs to a childhood cancer. Some drugs should start with children.","via":[{"id":"dordaviprone","kind":"drug","name":"Dordaviprone","route":"/drugs/dordaviprone/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"tovorafenib","kind":"drug","name":"Tovorafenib","route":"/drugs/tovorafenib/"}]},{"id":"idea-fund-duration-trial-exclusivity","kind":"idea","name":"Extra exclusivity for sponsors who run treatment-duration and de-escalation trials","route":"/ideas/idea-fund-duration-trial-exclusivity/","maturity":"speculative","tldr":"Companies lose money when they prove a shorter course works, so they never test it. Give them a modest reward, such as extra months of exclusivity, when they do.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}]},{"id":"idea-tr1-factorial-dose-finding-for-combinations","kind":"idea","name":"Factorial dose finding for drug combinations instead of full dose of everything","route":"/ideas/idea-tr1-factorial-dose-finding-for-combinations/","maturity":"speculative","tldr":"When two cancer drugs are combined, each is usually given at its full single-agent dose, which often proves too toxic. Testing a grid of dose pairs would find combinations that work with tolerable side effects.","via":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]},{"id":"idea-bio1-evolution-forecasting","kind":"idea","name":"Forecast the next resistance mutation like the weather","route":"/ideas/idea-bio1-evolution-forecasting/","maturity":"speculative","tldr":"Flu vaccines are chosen by predicting which virus strains will dominate next season. The same forecasting maths could predict which resistance mutation a patient's tumour will develop next.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}]},{"id":"idea-nl-glp1-adjuvant-hr-breast","kind":"idea","name":"GLP-1 receptor agonists as adjuvant weight-loss therapy in HR-positive breast cancer","route":"/ideas/idea-nl-glp1-adjuvant-hr-breast/","maturity":"speculative","tldr":"Coaching-based weight loss did not clearly cut breast cancer recurrence in BWEL, perhaps because the weight loss was too small. Drugs that produce three times as much weight loss could settle whether weight itself matters.","via":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"letrozole","kind":"drug","name":"Letrozole (and other aromatase inhibitors)","route":"/drugs/letrozole/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-late-recurrence-interception","kind":"idea","name":"Intercepting late recurrence with ctDNA surveillance and oral SERDs","route":"/ideas/idea-late-recurrence-interception/","maturity":"speculative","tldr":"Half of hormone-positive recurrences happen after year five. Blood tests during long-term follow-up could find them early and an oral SERD might stop them.","via":[{"id":"camizestrant","kind":"drug","name":"Camizestrant","route":"/drugs/camizestrant/"},{"id":"giredestrant","kind":"drug","name":"Giredestrant","route":"/drugs/giredestrant/"}]},{"id":"idea-desmoid-intermittent-dosing","kind":"idea","name":"Intermittent or stop-and-restart nirogacestat in desmoid tumours","route":"/ideas/idea-desmoid-intermittent-dosing/","maturity":"speculative","tldr":"Desmoid tumours are not cancers and often stop growing on their own; treating them indefinitely with a drug that causes ovarian failure may be more than needed.","via":[{"id":"nirogacestat","kind":"drug","name":"Nirogacestat","route":"/drugs/nirogacestat/"}]},{"id":"idea-bio2-brain-met-prevention-trials","kind":"idea","name":"Prevention trials aimed only at brain metastasis","route":"/ideas/idea-bio2-brain-met-prevention-trials/","maturity":"speculative","tldr":"Some cancers reach the brain in up to a quarter of patients. Prevention trials could aim specifically at stopping that, instead of treating it once it has happened.","via":[{"id":"alectinib","kind":"drug","name":"Alectinib","route":"/drugs/alectinib/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"idea-bio1-alternating-schedules","kind":"idea","name":"Rotate between drugs on a fixed schedule instead of waiting for failure","route":"/ideas/idea-bio1-alternating-schedules/","maturity":"speculative","tldr":"Hospitals rotate antibiotics to stop bacteria adapting. Cycling between two cancer drugs on a set schedule, rather than using one until it fails, might work the same way.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]},{"id":"idea-bio1-first-strike-second-strike","kind":"idea","name":"Switch drugs at maximum response, not at relapse","route":"/ideas/idea-bio1-first-strike-second-strike/","maturity":"speculative","tldr":"Species go extinct when a second disaster hits a population already shrunk by a first one. Apply the same logic: hit the tumour with a different kind of drug when it is smallest, rather than waiting for it to grow back.","via":[{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"}]},{"id":"idea-bio1-epigenetic-silencing-in-vivo","kind":"idea","name":"Switch off an undruggable oncogene permanently with epigenetic editing","route":"/ideas/idea-bio1-epigenetic-silencing-in-vivo/","maturity":"speculative","tldr":"Instead of blocking a cancer protein, add a chemical off-switch to its gene so the cell stops making it. Early versions of this tool are being tested in other diseases.","via":[{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"}]},{"id":"idea-acc-eml-listing-price-commitments","kind":"idea","name":"Tie WHO essential-medicines listing to a published tiered price and supply pledge","route":"/ideas/idea-acc-eml-listing-price-commitments/","maturity":"speculative","tldr":"When a cancer drug is added to the WHO essential medicines list, the maker should publicly commit to a low price and reliable supply for poorer countries, or the listing is withheld.","via":[{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"}]},{"id":"idea-fund-brain-metastases-programme","kind":"idea","name":"Treat brain metastases as a disease with its own trials programme","route":"/ideas/idea-fund-brain-metastases-programme/","maturity":"speculative","tldr":"A fifth of patients with solid tumours develop brain metastases and are usually excluded from trials. This would fund a programme that studies and treats them as a disease in their own right.","via":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"}]},{"id":"idea-bio2-mrd-guided-endocrine-duration","kind":"idea","name":"Use residual disease tests to decide who needs ten years of hormone therapy","route":"/ideas/idea-bio2-mrd-guided-endocrine-duration/","maturity":"speculative","tldr":"Extended hormone therapy after breast cancer prevents late recurrence in a minority of women while imposing joint pain, bone loss and sexual side-effects on everyone for a decade. A sensitive residual disease blood test at year five, repeated annually, could show who can safely stop.","via":[{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"}]}],"manufacturing":{"sites":[],"capabilities":[],"chain":{"id":"small-molecules","name":"Small molecules and sterile generics","summary":"API synthesis, tablets and sterile vials. The 2023 cisplatin and carboplatin shortage and the BCG shortage are the worked examples.","route":"/manufacturing/#chain-small-molecules","technologies":[{"id":"small-molecule-api-synthesis","kind":"technology","name":"Small-molecule API synthesis","route":"/technologies/small-molecule-api-synthesis/"},{"id":"oral-solid-dose-manufacturing","kind":"technology","name":"Oral solid dose manufacturing (tablets and capsules)","route":"/technologies/oral-solid-dose-manufacturing/"},{"id":"sterile-injectable-generics-manufacturing","kind":"technology","name":"Generic sterile injectables (the 2023 platinum shortage)","route":"/technologies/sterile-injectable-generics-manufacturing/"},{"id":"sterile-fill-finish","kind":"technology","name":"Sterile fill-finish and lyophilisation","route":"/technologies/sterile-fill-finish/"},{"id":"bcg-vaccine-manufacturing","kind":"technology","name":"BCG manufacturing and the bladder cancer BCG shortage","route":"/technologies/bcg-vaccine-manufacturing/"},{"id":"generic-drug-shortage-response","kind":"technology","name":"Generic oncology drug supply and shortage mitigation","route":"/technologies/generic-drug-shortage-response/"},{"id":"pharmaceutical-gmp-inspections","kind":"technology","name":"GMP, inspections, Form 483s and warning letters","route":"/technologies/pharmaceutical-gmp-inspections/"}],"companies":[{"id":"intas","kind":"company","name":"Intas Pharmaceuticals (Accord Healthcare)","route":"/companies/intas/"},{"id":"teva","kind":"company","name":"Teva Pharmaceuticals","route":"/companies/teva/"},{"id":"fresenius-kabi","kind":"company","name":"Fresenius Kabi","route":"/companies/fresenius-kabi/"},{"id":"pfizer","kind":"company","name":"Pfizer (incl. 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(MSD)","route":"/companies/merck/"}],"products":[{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"oxaliplatin","kind":"drug","name":"Oxaliplatin","route":"/drugs/oxaliplatin/"},{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/"},{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/"},{"id":"bcg-intravesical","kind":"drug","name":"Intravesical BCG","route":"/drugs/bcg-intravesical/"}]},"technologies":[{"id":"small-molecule-api-synthesis","kind":"technology","name":"Small-molecule API synthesis","route":"/technologies/small-molecule-api-synthesis/","tldr":"Before a tablet or a vial exists, the active drug itself has to be made: many chemical steps in reactors, or extraction from a plant, at a handful of factories most patients never hear of. When one of those factories stops, whole cancer drugs disappear."}]},"drugs":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"abexinostat","kind":"drug","name":"Abexinostat","route":"/drugs/abexinostat/"},{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"absk061","kind":"drug","name":"ABSK061","route":"/drugs/absk061/"},{"id":"abt-301","kind":"drug","name":"ABT-301","route":"/drugs/abt-301/"},{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"acitretin","kind":"drug","name":"Acitretin","route":"/drugs/acitretin/"},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"adavosertib","kind":"drug","name":"Adavosertib","route":"/drugs/adavosertib/"},{"id":"adu-s100","kind":"drug","name":"ADU-S100 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section is read from existing corpus records and names them (from, via, exemplars, refs); a section with nothing behind it is empty. Medicines of a format are the open drug engine's (/pipeline/engine/); technologies are listed in src/lib/modular-formats.ts. CC BY-NC 4.0, attribute Data from OnCo (onco.cc). Not medical advice."}