{"id":"targeted-therapy-roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/","eras":[{"era":"1977-2001","title":"The idea of a target","description":"Tamoxifen blocked the oestrogen receptor and trastuzumab (1998) the HER2 protein, each with a test to find the patients whose tumours depended on them. Imatinib (2001) proved the concept in its purest form: a pill against BCR-ABL, the one enzyme chronic myeloid leukaemia cannot live without, that turned a fatal disease into a chronic one and made Brian Druker's Oregon clinic the birthplace of precision oncology.","status":"historic","refs":[{"id":"tamoxifen","kind":"drug","name":"Tamoxifen","route":"/drugs/tamoxifen/","status":"approved","tldr":"The original targeted cancer drug (1977): a pill that blocks oestrogen's effect on breast cancer and halves recurrence, still essential for premenopausal women."},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/","status":"approved","tldr":"The first targeted antibody for a solid tumour (1998), which turned HER2-positive breast cancer from the worst subtype into one of the most treatable."},{"id":"hera-b31-n9831","kind":"trial","name":"HERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab)","route":"/trials/hera-b31-n9831/","status":"positive","tldr":"Three trials reported together in 2005 showed that a year of trastuzumab after surgery cuts the risk of dying from HER2-positive breast cancer by about a third."},{"id":"toga","kind":"trial","name":"ToGA","route":"/trials/toga/","status":"positive","tldr":"The trial that brought the breast-cancer drug Herceptin to stomach cancer, the first targeted therapy to improve survival in this disease."},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/","status":"approved","tldr":"The drug that started the targeted therapy era in 2001, turning chronic myeloid leukaemia into a manageable condition with near-normal life expectancy."},{"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":"ohsu-knight","kind":"institution","name":"OHSU Knight Cancer Institute","route":"/institutions/ohsu-knight/","tldr":"Brian Druker's institute, where imatinib was proven in CML and precision oncology was born; now focused on early detection and functional genomics."},{"id":"companion-diagnostic","kind":"technology","name":"Companion diagnostics","route":"/technologies/companion-diagnostic/","status":"standard-of-care","tldr":"The test that decides whether a specific drug is right for you, approved together with the drug."}],"trials":[{"id":"hera-b31-n9831","name":"HERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab)","route":"/trials/hera-b31-n9831/","outcomes":[{"endpoint":"10-year overall survival (B-31/N9831)","unit":"%","arms":[{"name":"Chemotherapy + trastuzumab","n":2028,"value":84},{"name":"Chemotherapy alone","n":2018,"value":75.2}],"hr":0.63,"ci":[0.54,0.73],"source":"https://ascopubs.org/doi/10.1200/JCO.2014.55.5730"},{"endpoint":"Disease-free survival (B-31/N9831)","primary":true,"arms":[{"name":"Chemotherapy + trastuzumab"},{"name":"Chemotherapy alone"}],"hr":0.6,"ci":[0.53,0.68],"source":"https://doi.org/10.1056/NEJMoa052122"}],"setting":"Adjuvant HER2+ early breast cancer: one year of trastuzumab with or after chemotherapy vs chemotherapy alone","enrolled":9000,"enrolledBasis":"registry"},{"id":"toga","name":"ToGA","route":"/trials/toga/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Trastuzumab + chemotherapy","n":294,"value":13.8},{"name":"Chemotherapy","n":290,"value":11.1}],"hr":0.74,"ci":[0.6,0.91],"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61121-X/abstract"}],"setting":"First-line HER2-positive advanced gastric/GEJ adenocarcinoma: trastuzumab + cisplatin/fluoropyrimidine vs chemotherapy","enrolled":594,"enrolledBasis":"registry"}],"papers":[]},{"era":"2004-2013","title":"Oncogene addiction, and the resistance lesson","description":"EGFR mutations (2004) explained why gefitinib and erlotinib worked spectacularly in a minority of lung cancers; crizotinib for ALK (2011) and vemurafenib for BRAF (2011) followed within months of the target being found. Then nearly every responder relapsed: T790M in EGFR, gatekeeper mutations in ALK, MAPK reactivation in BRAF. Resistance became the central problem of the field, and reading it from a biopsy became the route to the next drug.","status":"historic","refs":[{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/","status":"approved","tldr":"The lung-cancer pill whose dramatic responses in a few patients led to the discovery of EGFR mutations in 2004."},{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/","status":"approved","tldr":"Erlotinib was one of the first EGFR pills for lung cancer; it was approved before anyone knew EGFR mutations predicted who would respond, then redefined by them."},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/","tldr":"A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills."},{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/","status":"approved","tldr":"Crizotinib was the first ALK inhibitor, approved four years after ALK fusions were found in lung cancer; it was also the first drug for ROS1 lung cancer and for ALK-positive lymphoma and inflammatory myofibroblastic tumour in children."},{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/","tldr":"ALK is a gene fusion driver in about 4 to 5% of non-small-cell lung cancers that responds to a succession of ALK inhibitor pills. Lorlatinib kept about 60% of patients progression-free at five years, alectinib is approved after surgery, and neladalkib targets compound resistance mutations."},{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/","tldr":"BRAF is a signalling kinase mutated in half of melanomas; blocking it with two drugs at once became a template for targeted therapy."},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/","status":"approved","tldr":"Dabrafenib plus trametinib is the BRAF-plus-MEK pill combination, approved for BRAF V600E lung cancer and, since 2022, for any solid tumour with that mutation."},{"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."},{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/","tldr":"Nearly every targeted therapy stops working within months to a few years as the tumour adapts."},{"id":"gefitinib-chemo-tmh","kind":"trial","name":"Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)","route":"/trials/gefitinib-chemo-tmh/","status":"positive","tldr":"An Indian trial showed that adding standard chemotherapy to the cheap first-generation pill gefitinib doubled the time lung cancer stayed controlled and cut deaths by more than half."}],"trials":[{"id":"gefitinib-chemo-tmh","name":"Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)","route":"/trials/gefitinib-chemo-tmh/","outcomes":[{"endpoint":"Median progression-free survival","primary":true,"unit":"months","arms":[{"name":"Gefitinib + pemetrexed-carboplatin","n":174,"value":16},{"name":"Gefitinib","n":176,"value":8}],"hr":0.51,"p":"<0.001","source":"https://doi.org/10.1200/JCO.19.01154"}],"setting":"Untreated advanced EGFR-mutant non-small-cell lung cancer: gefitinib alone vs gefitinib plus pemetrexed and carboplatin","enrolled":350,"enrolledBasis":"registry"}],"papers":[]},{"era":"2014-2020","title":"Designed for resistance, the brain and the adjuvant setting","description":"Osimertinib was built to hit T790M and cross into the brain; alectinib and lorlatinib did the same for ALK. Given after surgery, the pills halved the risk of death in EGFR-mutant lung cancer (ADAURA) and sharply cut recurrence in ALK-positive disease (ALINA); LAURA extended them to after chemoradiation. Olaparib (2014) made an inherited BRCA defect a target in ovarian, breast and prostate cancer (SOLO-1, OlympiA, PROfound). Larotrectinib's approval for any NTRK-fusion tumour (2018) made the mutation, not the organ, the indication; RET (LIBRETTO-431) and ROS1 followed. COMBI-AD proved a year of BRAF-MEK pills after melanoma surgery halves relapse; DREAMseq settled that immunotherapy should come first.","status":"current","refs":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/","status":"approved","tldr":"Osimertinib (Tagrisso) is the standard pill for EGFR-mutant lung cancer, now also given after surgery and with chemotherapy or after chemoradiation."},{"id":"alectinib","kind":"drug","name":"Alectinib","route":"/drugs/alectinib/","status":"approved","tldr":"Alectinib is a well-tolerated ALK pill, standard first line for years and, since 2024, the first targeted therapy given after surgery for ALK-positive lung cancer."},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/","status":"approved","tldr":"An ALK inhibitor with the longest disease control ever recorded for a targeted lung cancer pill: 60% progression-free at five years."},{"id":"adaura","kind":"trial","name":"ADAURA","route":"/trials/adaura/","status":"positive","tldr":"Showed a targeted pill after lung cancer surgery halves the risk of death, the first such result for a targeted therapy."},{"id":"alina","kind":"trial","name":"ALINA","route":"/trials/alina/","status":"positive","tldr":"Showed that giving an ALK pill after surgery, instead of chemotherapy, sharply reduces recurrence, including in the brain."},{"id":"laura","kind":"trial","name":"LAURA","route":"/trials/laura/","status":"positive","tldr":"For stage III lung cancers with an EGFR mutation, a targeted pill after chemoradiation cut progression by more than 80%."},{"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":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/","status":"approved","tldr":"Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer."},{"id":"solo-1","kind":"trial","name":"SOLO-1","route":"/trials/solo-1/","status":"positive","tldr":"Two years of an olaparib pill after chemotherapy made a large share of women with BRCA-mutated ovarian cancer long-term survivors."},{"id":"olympia","kind":"trial","name":"OlympiA","route":"/trials/olympia/","status":"positive","tldr":"Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations."},{"id":"profound","kind":"trial","name":"PROfound","route":"/trials/profound/","status":"positive","tldr":"The first biomarker-selected trial in prostate cancer to improve survival, using a PARP inhibitor in men with BRCA-type mutations."},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/","tldr":"DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum."},{"id":"larotrectinib","kind":"drug","name":"Larotrectinib","route":"/drugs/larotrectinib/","status":"approved","tldr":"The first drug approved for a gene fusion regardless of where the cancer started; it works in about 75% of NTRK-fusion cancers, from infant fibrosarcoma to salivary and thyroid cancers."},{"id":"entrectinib","kind":"drug","name":"Entrectinib","route":"/drugs/entrectinib/","status":"approved","tldr":"Entrectinib (Rozlytrek) is a pill for NTRK-fusion cancers and ROS1 lung cancer that reaches brain metastases."},{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/","status":"approved","tldr":"Selpercatinib is a selective RET inhibitor approved for any tumour with a RET fusion, with a further label update in July 2026."},{"id":"libretto-431","kind":"trial","name":"LIBRETTO-431","route":"/trials/libretto-431/","status":"positive","tldr":"Proved that a RET pill is better than chemotherapy with or without immunotherapy as first treatment for RET-fusion lung cancer."},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/","tldr":"A tumour-agnostic approval lets a drug be used for any cancer carrying a specific molecular feature, regardless of where it started."},{"id":"ntrk","kind":"target","name":"NTRK","route":"/targets/ntrk/","tldr":"Rare gene fusions found across dozens of cancer types; the first target where a drug was approved for any tumour carrying it."},{"id":"ret","kind":"target","name":"RET","route":"/targets/ret/","tldr":"RET is a kinase altered in thyroid cancer and a small slice of lung cancer, treatable with one selective pill regardless of where the tumour is."},{"id":"ros1","kind":"target","name":"ROS1","route":"/targets/ros1/","tldr":"A gene fusion in about 1-2% of lung cancers that responds for years to targeted pills, now in their third generation."},{"id":"combi-ad","kind":"trial","name":"COMBI-AD","route":"/trials/combi-ad/","status":"positive","tldr":"A year of two targeted pills after surgery halves the risk of relapse in BRAF-mutant melanoma, and the benefit is still visible a decade later."},{"id":"dreamseq","kind":"trial","name":"DREAMseq (ECOG-ACRIN EA6134)","route":"/trials/dreamseq/","status":"positive","tldr":"Settled the order question: for BRAF-mutant melanoma, start with immunotherapy and save the targeted pills for later."}],"trials":[{"id":"adaura","name":"ADAURA","route":"/trials/adaura/","outcomes":[{"endpoint":"Disease-free survival, stage II to IIIA","primary":true,"unit":"months","arms":[{"name":"Osimertinib","n":233,"note":"Median DFS not reached with osimertinib at the primary analysis"},{"name":"Placebo","n":237,"value":19.6}],"hr":0.17,"ci":[0.11,0.26],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2027071"},{"endpoint":"Overall survival at 5 years, stage II to IIIA","unit":"%","arms":[{"name":"Osimertinib","value":85},{"name":"Placebo","value":73}],"hr":0.49,"ci":[0.33,0.73],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2304594"},{"endpoint":"Overall survival at 5 years, stage IB to IIIA","unit":"%","arms":[{"name":"Osimertinib","value":88},{"name":"Placebo","value":78}],"hr":0.49,"ci":[0.34,0.7],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2304594"},{"endpoint":"8-year overall survival, stage II to IIIA","unit":"%","arms":[{"name":"Osimertinib","value":74,"note":"Post hoc exploratory update, data cut-off 4 May 2026"},{"name":"Placebo","value":58}],"hr":0.53,"ci":[0.38,0.75],"source":"https://doi.org/10.1016/j.jtho.2026.104179"},{"endpoint":"8-year overall survival, stage IB to IIIA","unit":"%","arms":[{"name":"Osimertinib","value":79,"note":"Post hoc exploratory update, data cut-off 4 May 2026"},{"name":"Placebo","value":64}],"hr":0.52,"ci":[0.39,0.71],"source":"https://doi.org/10.1016/j.jtho.2026.104179"}],"setting":"Adjuvant osimertinib 3 years after resection of stage IB-IIIA EGFR-mutant NSCLC","enrolled":682,"enrolledBasis":"registry"},{"id":"alina","name":"ALINA","route":"/trials/alina/","outcomes":[{"endpoint":"Disease-free survival, stage II to IIIA","primary":true,"unit":"months","arms":[{"name":"Alectinib","n":116,"note":"Median not reached"},{"name":"Platinum chemotherapy","n":115,"value":44.4}],"hr":0.24,"ci":[0.13,0.45],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2310532"}],"setting":"Adjuvant alectinib 2 years vs platinum chemotherapy after resection of stage IB (≥4 cm)-IIIA ALK-positive NSCLC","enrolled":257,"enrolledBasis":"registry"},{"id":"laura","name":"LAURA","route":"/trials/laura/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Osimertinib","n":143,"value":39.1},{"name":"Placebo","n":73,"value":5.6}],"hr":0.16,"ci":[0.1,0.24],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2402614"}],"setting":"Unresectable stage III EGFR-mutant NSCLC after chemoradiation: osimertinib until progression vs placebo","enrolled":216,"enrolledBasis":"registry"},{"id":"solo-1","name":"SOLO-1","route":"/trials/solo-1/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"HR","arms":[{"name":"Olaparib","n":260},{"name":"Placebo","n":131}],"hr":0.3,"ci":[0.23,0.41],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1810858"},{"endpoint":"Overall survival at 7 years","unit":"%","arms":[{"name":"Olaparib","value":67},{"name":"Placebo","value":46.5}],"hr":0.55,"ci":[0.4,0.76],"source":"https://ascopubs.org/doi/10.1200/JCO.22.01549"}],"setting":"Newly diagnosed advanced BRCA-mutated ovarian cancer in response to platinum chemotherapy: olaparib maintenance for 2 years vs placebo","enrolled":391,"enrolledNote":"ClinicalTrials.gov lists 450 participants (actual); the NEJM 2018 primary analysis randomised 391 patients (260 olaparib, 131 placebo).","enrolledBasis":"randomised"},{"id":"olympia","name":"OlympiA","route":"/trials/olympia/","outcomes":[{"endpoint":"Invasive disease-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Olaparib","n":921,"value":85.9},{"name":"Placebo","n":915,"value":77.1}],"hr":0.58,"ci":[0.41,0.82],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2105215"},{"endpoint":"Overall survival at 4 years","unit":"%","arms":[{"name":"Olaparib","value":89.8},{"name":"Placebo","value":86.4}],"hr":0.68,"ci":[0.47,0.97],"p":"0.009","source":"https://www.annalsofoncology.org/article/S0923-7534(22)04165-7/fulltext"},{"endpoint":"Overall survival at 6 years","unit":"%","arms":[{"name":"Olaparib","value":87.5},{"name":"Placebo","value":83.2}],"hr":0.72,"ci":[0.56,0.93],"source":"https://clinicaltrials.gov/study/NCT02032823"}],"setting":"Adjuvant olaparib for one year in germline BRCA-mutated, HER2-negative, high-risk early breast cancer","enrolled":1837,"enrolledBasis":"registry"},{"id":"profound","name":"PROfound","route":"/trials/profound/","outcomes":[{"endpoint":"Radiographic progression-free survival, cohort A (BRCA1/2, ATM)","primary":true,"unit":"months","arms":[{"name":"Olaparib","n":162,"value":7.4},{"name":"Enzalutamide or abiraterone","n":83,"value":3.6}],"hr":0.34,"ci":[0.25,0.47],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1911440"},{"endpoint":"Overall survival, cohort A","unit":"months","arms":[{"name":"Olaparib","value":19.1},{"name":"Enzalutamide or abiraterone","value":14.7}],"hr":0.69,"ci":[0.5,0.97],"p":"0.02","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2022485"}],"setting":"mCRPC with HRR gene alterations after ARPI: olaparib vs enzalutamide/abiraterone switch","enrolled":387,"enrolledBasis":"registry"},{"id":"libretto-431","name":"LIBRETTO-431","route":"/trials/libretto-431/","outcomes":[{"endpoint":"Progression-free survival (BICR), ITT-pembrolizumab population","primary":true,"unit":"months","arms":[{"name":"Selpercatinib","n":129,"value":24.8},{"name":"Platinum-pemetrexed ± pembrolizumab","n":83,"value":11.2}],"hr":0.46,"ci":[0.31,0.7],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2309457"}],"setting":"First-line RET-fusion advanced NSCLC: selpercatinib vs platinum-pemetrexed ± pembrolizumab","enrolled":261,"enrolledBasis":"registry"},{"id":"combi-ad","name":"COMBI-AD","route":"/trials/combi-ad/","outcomes":[{"endpoint":"Relapse-free survival at 10 years","primary":true,"unit":"%","arms":[{"name":"Dabrafenib + trametinib","value":48},{"name":"Placebo","value":32}],"source":"https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9500"},{"endpoint":"Distant metastasis-free survival at 10 years","unit":"%","arms":[{"name":"Dabrafenib + trametinib","value":63},{"name":"Placebo","value":48}],"source":"https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9500"}],"setting":"Resected stage III BRAF V600-mutant melanoma: adjuvant dabrafenib + trametinib 1 year vs placebo","enrolled":870,"enrolledBasis":"registry"},{"id":"dreamseq","name":"DREAMseq (ECOG-ACRIN EA6134)","route":"/trials/dreamseq/","outcomes":[{"endpoint":"Overall survival at 2 years","primary":true,"unit":"%","arms":[{"name":"Immunotherapy first","value":71.8},{"name":"Targeted therapy first","value":51.5}],"p":"0.010","source":"https://ascopubs.org/doi/10.1200/JCO.22.01763"}],"setting":"Untreated BRAF V600 metastatic melanoma: nivolumab + ipilimumab then dabrafenib + trametinib at progression, vs the reverse sequence","enrolled":267,"enrolledBasis":"registry"}],"papers":[]},{"era":"2021-2026","title":"The undruggable drivers fall","description":"KRAS, mutated in a quarter of cancers and called undruggable for forty years, yielded to sotorasib (2021) and adagrasib, which lock the G12C mutant in its off state; CodeBreaK 200 and KRYSTAL-12 showed they beat chemotherapy, and divarasib beat both head to head (Krascendo 1). The G12D mutation, the commonest in pancreatic cancer, has its first drug in zoldonrasib, and daraxonrasib inhibits every RAS in its active state (RASolute 302). Elsewhere belzutifan drugged HIF-2, menin inhibitors reached leukaemia, and vepdegestrant (2026) became the first approved PROTAC, removing its target rather than blocking it. MARIPOSA and FLAURA2 showed that combinations beat osimertinib alone.","status":"current","refs":[{"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":"kras","kind":"target","name":"KRAS","route":"/targets/kras/","tldr":"KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021."},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/","status":"approved","tldr":"Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure."},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/","status":"approved","tldr":"Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer."},{"id":"codebreak-200","kind":"trial","name":"CodeBreaK 200","route":"/trials/codebreak-200/","status":"positive","tldr":"The first randomised trial of a KRAS drug: better than chemotherapy on progression, not on survival."},{"id":"krystal-12","kind":"trial","name":"KRYSTAL-12","route":"/trials/krystal-12/","status":"positive","tldr":"Confirmed that the KRAS pill adagrasib beats chemotherapy after first-line treatment, though the gain is modest."},{"id":"divarasib","kind":"drug","name":"Divarasib","route":"/drugs/divarasib/","status":"phase-3","tldr":"Divarasib is Roche's KRAS G12C pill, the first to beat the two approved KRAS drugs head-to-head (July 2026)."},{"id":"krascendo-1","kind":"trial","name":"Krascendo 1","route":"/trials/krascendo-1/","status":"positive","tldr":"The first head-to-head trial among KRAS drugs: Roche's divarasib beat the two approved pills on progression and survival."},{"id":"codebreak-300","kind":"trial","name":"CodeBreaK 300","route":"/trials/codebreak-300/","status":"positive","tldr":"CodeBreaK 300 showed that a KRAS drug needs an EGFR antibody partner to work in colorectal cancer."},{"id":"zoldonrasib","kind":"drug","name":"Zoldonrasib","route":"/drugs/zoldonrasib/","status":"phase-2","tldr":"The first drug aimed specifically at KRAS G12D, the single most common mutation in pancreatic cancer. Early combination data in 2026 showed half of previously treated patients responding."},{"id":"mrtx1133","kind":"drug","name":"MRTX1133","route":"/drugs/mrtx1133/","status":"phase-1","tldr":"MRTX1133 was the first potent chemical tool against KRAS G12D, and proved the mutation could be drugged even though it lacks the reactive handle G12C has."},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"rasolute-302","kind":"trial","name":"RASolute 302","route":"/trials/rasolute-302/","status":"positive","tldr":"The trial that nearly doubled survival in previously treated pancreatic cancer, presented in the ASCO 2026 plenary. The biggest result in the disease's history."},{"id":"elironrasib","kind":"drug","name":"Elironrasib","route":"/drugs/elironrasib/","status":"phase-2","tldr":"A next-generation KRAS G12C drug that hits the active form of the protein, from the same company as daraxonrasib."},{"id":"olomorasib","kind":"drug","name":"Olomorasib","route":"/drugs/olomorasib/","status":"phase-3","tldr":"Olomorasib is Lilly's KRAS G12C pill, designed to combine safely with immunotherapy in first-line lung cancer."},{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/","tldr":"The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer."},{"id":"litespark-005","kind":"trial","name":"LITESPARK-005","route":"/trials/litespark-005/","status":"positive","tldr":"The HIF-2α inhibitor beat the old standard everolimus after immunotherapy and targeted therapy had failed, with durable responses in a subset."},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/","status":"approved","tldr":"Instead of blocking a protein, these drugs tag it for the cell's own garbage disposal, removing it entirely."},{"id":"vepdegestrant","kind":"drug","name":"Vepdegestrant","route":"/drugs/vepdegestrant/","status":"approved","tldr":"Vepdegestrant is the first PROTAC ever approved (2026): a pill that tags the oestrogen receptor for destruction, for breast cancers with ESR1 mutations."},{"id":"veritac-2","kind":"trial","name":"VERITAC-2","route":"/trials/veritac-2/","status":"mixed","tldr":"The trial that got the first PROTAC approved, with benefit only in tumours with ESR1 mutations."},{"id":"mariposa","kind":"trial","name":"MARIPOSA","route":"/trials/mariposa/","status":"positive","tldr":"The first regimen to beat osimertinib in EGFR-mutant lung cancer, with a survival benefit exceeding a year."},{"id":"amivantamab","kind":"drug","name":"Amivantamab","route":"/drugs/amivantamab/","status":"approved","tldr":"A two-armed antibody that blocks EGFR and its escape partner MET, now first-line for EGFR-mutant lung cancer with lazertinib."},{"id":"lazertinib","kind":"drug","name":"Lazertinib","route":"/drugs/lazertinib/","status":"approved","tldr":"A third-generation EGFR pill used together with amivantamab as the first regimen to beat osimertinib in EGFR-mutant lung cancer."},{"id":"flaura2","kind":"trial","name":"FLAURA2","route":"/trials/flaura2/","status":"positive","tldr":"Adding chemotherapy to osimertinib extended both progression-free and, in 2025, overall survival."}],"trials":[{"id":"codebreak-200","name":"CodeBreaK 200","route":"/trials/codebreak-200/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Sotorasib","n":171,"value":5.6},{"name":"Docetaxel","n":174,"value":4.5}],"hr":0.66,"ci":[0.51,0.86],"p":"0.0017","source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00221-0/fulltext"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sotorasib","value":10.6,"note":"Not significant; crossover permitted"},{"name":"Docetaxel","value":11.3}],"hr":1.01,"source":"https://doi.org/10.1016/S0140-6736(23)00221-0"}],"setting":"Previously treated KRAS G12C NSCLC: sotorasib vs docetaxel","enrolled":345,"enrolledBasis":"registry"},{"id":"krystal-12","name":"KRYSTAL-12","route":"/trials/krystal-12/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Adagrasib","n":301,"value":5.5},{"name":"Docetaxel","n":152,"value":3.8}],"hr":0.58,"ci":[0.45,0.76],"p":"<0.0001","source":"https://clinicaltrials.gov/study/NCT04685135"}],"setting":"Previously treated KRAS G12C NSCLC: adagrasib vs docetaxel","enrolled":453,"enrolledBasis":"registry"},{"id":"krascendo-1","name":"Krascendo 1","route":"/trials/krascendo-1/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Divarasib","note":"Primary endpoint met with a statistically significant, clinically meaningful improvement per the sponsor (topline 2 July 2026); medians and hazard ratio pending presentation."},{"name":"Sotorasib or adagrasib"}],"source":"https://clinicaltrials.gov/study/NCT06497556"},{"endpoint":"Overall survival (interim)","unit":"months","arms":[{"name":"Divarasib","note":"Statistically significant OS improvement at the interim analysis per the sponsor; numbers pending."},{"name":"Sotorasib or adagrasib"}],"source":"https://clinicaltrials.gov/study/NCT06497556"}],"setting":"Previously treated KRAS G12C NSCLC: divarasib vs sotorasib or adagrasib","enrolled":338,"enrolledBasis":"registry"},{"id":"codebreak-300","name":"CodeBreaK 300","route":"/trials/codebreak-300/","outcomes":[{"endpoint":"Progression-free survival (BICR), sotorasib 960 mg + panitumumab","primary":true,"unit":"months","arms":[{"name":"Sotorasib 960 mg + panitumumab","n":53,"value":5.6},{"name":"Trifluridine-tipiracil or regorafenib","n":54,"value":2.2}],"hr":0.49,"ci":[0.3,0.8],"p":"0.006","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2308795"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sotorasib 960 mg + panitumumab","value":26.4},{"name":"Trifluridine-tipiracil or regorafenib","value":0}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2308795"}],"setting":"KRAS G12C colorectal cancer, previously treated: sotorasib + panitumumab vs standard of care","enrolled":160,"enrolledBasis":"registry"},{"id":"rasolute-302","name":"RASolute 302","route":"/trials/rasolute-302/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Daraxonrasib","value":13.2},{"name":"Chemotherapy (gemcitabine/nab-paclitaxel or mFOLFOX6)","value":6.7}],"hr":0.4,"source":"https://clinicaltrials.gov/study/NCT06625320"},{"endpoint":"Progression-free survival by blinded independent central review (overall population)","unit":"months","arms":[{"name":"Daraxonrasib","n":248,"value":7.2,"note":"95% CI 5.7 to 7.5"},{"name":"Chemotherapy (mFOLFIRINOX, gemcitabine/nab-paclitaxel, FOLFOX or liposomal irinotecan with 5-FU/LV)","n":252,"value":3.6,"note":"95% CI 2.9 to 4.2"}],"hr":0.49,"ci":[0.38,0.64],"p":"<0.0001","source":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22RASONQUE%22"},{"endpoint":"Objective response rate by blinded independent central review (overall population)","unit":"%","arms":[{"name":"Daraxonrasib","n":248,"value":30,"note":"95% CI 25 to 36"},{"name":"Chemotherapy","n":252,"value":11,"note":"95% CI 7 to 15"}],"p":"<0.0001","source":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22RASONQUE%22"}],"setting":"Metastatic PDAC after one prior line of chemotherapy: daraxonrasib vs investigator's choice chemotherapy","enrolled":500,"enrolledBasis":"registry"},{"id":"litespark-005","name":"LITESPARK-005","route":"/trials/litespark-005/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"arms":[{"name":"Belzutifan","n":374},{"name":"Everolimus","n":372}],"hr":0.75,"ci":[0.63,0.9],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2313906"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Belzutifan","value":22.7},{"name":"Everolimus","value":3.5}],"source":"https://doi.org/10.1056/NEJMoa2313906"}],"setting":"Advanced clear-cell RCC after PD-1/PD-L1 and VEGF-TKI: belzutifan vs everolimus","enrolled":755,"enrolledBasis":"registry"},{"id":"veritac-2","name":"VERITAC-2","route":"/trials/veritac-2/","outcomes":[{"endpoint":"Progression-free survival, ESR1-mutant (BICR)","primary":true,"unit":"months","arms":[{"name":"Vepdegestrant","n":136,"value":5},{"name":"Fulvestrant","n":134,"value":2.1}],"hr":0.57,"ci":[0.42,0.77],"p":"<0.001","source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA1000"},{"endpoint":"Progression-free survival, ITT","primary":true,"unit":"months","arms":[{"name":"Vepdegestrant","n":313,"value":3.7,"note":"Not significant"},{"name":"Fulvestrant","n":311,"value":3.6}],"hr":0.83,"ci":[0.68,1.02],"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA1000"}],"setting":"ER+/HER2- advanced breast cancer after CDK4/6 and endocrine therapy: vepdegestrant vs fulvestrant","enrolled":624,"enrolledBasis":"registry"},{"id":"mariposa","name":"MARIPOSA","route":"/trials/mariposa/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Amivantamab + lazertinib","n":429,"value":23.7},{"name":"Osimertinib","n":429,"value":16.6}],"hr":0.7,"ci":[0.58,0.85],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2403614"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Amivantamab + lazertinib","note":"Median not reached"},{"name":"Osimertinib","value":36.7}],"hr":0.75,"ci":[0.61,0.92],"p":"0.005","source":"https://clinicaltrials.gov/study/NCT04487080"}],"setting":"First-line EGFR-mutant NSCLC: amivantamab + lazertinib vs osimertinib","enrolled":1074,"enrolledBasis":"registry"},{"id":"flaura2","name":"FLAURA2","route":"/trials/flaura2/","outcomes":[{"endpoint":"Progression-free survival (investigator)","primary":true,"unit":"months","arms":[{"name":"Osimertinib + chemotherapy","n":279,"value":25.5},{"name":"Osimertinib","n":278,"value":16.7}],"hr":0.62,"ci":[0.49,0.79],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2306434"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Osimertinib + chemotherapy","value":47.5},{"name":"Osimertinib","value":37.6}],"hr":0.77,"ci":[0.61,0.96],"p":"0.02","source":"https://clinicaltrials.gov/study/NCT04035486"}],"setting":"First-line EGFR-mutant NSCLC: osimertinib + chemotherapy vs osimertinib","enrolled":587,"enrolledBasis":"registry"}],"papers":[]},{"era":"2026-2030","title":"Fourth generations, degraders and switching on a blood test","description":"Neladalkib is designed to work after lorlatinib (ALKOVE-1); pirtobrutinib works after other BTK inhibitors and a BTK degrader is in phase 3 (CaDAnCe-304); the first MET-directed ADC is in its confirmatory trial. SERENA-6 changed endocrine therapy on a blood test before the scan changed, and INSIGHT is matching GIST drugs to the resistance mutation found in blood. The next trial designs assign treatment by how the tumour escaped rather than where it started.","status":"emerging","refs":[{"id":"neladalkib","kind":"drug","name":"Neladalkib","route":"/drugs/neladalkib/","status":"phase-3","tldr":"A fourth-generation ALK pill that works after lorlatinib and avoids the TRK-related brain side effects; under FDA priority review with a decision due 27 November 2026."},{"id":"alkove-1","kind":"trial","name":"ALKOVE-1","route":"/trials/alkove-1/","status":"positive","tldr":"The registrational study of a fourth-generation ALK pill designed to work after lorlatinib and to spare the brain-related side effects."},{"id":"nuvalent","kind":"company","name":"Nuvalent","route":"/companies/nuvalent/","tldr":"Designer of cleaner kinase inhibitors; zidesamtinib (ROS1) approved July 2026, neladalkib (ALK) next."},{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/","status":"approved","tldr":"A BTK blocker that works after the older ones stop, because it grips a different part of the enzyme. Fully approved for CLL in December 2025."},{"id":"bruin-cll-321","kind":"trial","name":"BRUIN CLL-321","route":"/trials/bruin-cll-321/","status":"positive","tldr":"The randomised trial that confirmed pirtobrutinib works after other BTK inhibitors fail, leading to full approval in December 2025."},{"id":"cadance-304","kind":"trial","name":"CaDAnCe-304","route":"/trials/cadance-304/","status":"recruiting","tldr":"CaDAnCe-304 is the first phase 3 of a protein degrader in leukaemia, pitting BTK destruction against the best available BTK inhibitor."},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/","tldr":"The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill."},{"id":"telimet-nsclc-01","kind":"trial","name":"TeliMET NSCLC-01","route":"/trials/telimet-nsclc-01/","status":"recruiting","tldr":"The confirmatory trial for the first c-MET ADC, which was approved early on response rate alone."},{"id":"serena-6","kind":"trial","name":"SERENA-6","route":"/trials/serena-6/","status":"positive","tldr":"The first trial to change treatment because of a blood test rather than a scan: switching to camizestrant when an ESR1 mutation appeared in the blood delayed progression by seven months."},{"id":"insight-gist","kind":"trial","name":"INSIGHT","route":"/trials/insight-gist/","status":"active","tldr":"A blood-test-selected trial testing whether matching the drug to the specific resistance mutation beats the standard second-line drug."},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/","status":"standard-of-care","tldr":"A blood test that reads fragments of DNA shed by the tumour, so you can genotype or monitor cancer without a needle in the tumour."},{"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/","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."},{"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/","tldr":"Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer."},{"id":"idea-bio1-resistance-platform-trial","kind":"idea","name":"A standing platform trial that assigns treatment by how the tumour escaped","route":"/ideas/idea-bio1-resistance-platform-trial/","tldr":"Instead of a new trial for each resistance mechanism, one continuous trial could sort patients into arms based on the reason their last treatment failed."}],"trials":[{"id":"alkove-1","name":"ALKOVE-1","route":"/trials/alkove-1/","outcomes":[{"endpoint":"Objective response rate, TKI-pretreated ALK+ NSCLC (pivotal cohort)","primary":true,"unit":"%","arms":[{"name":"Neladalkib, lorlatinib-pretreated","value":51}],"source":"https://clinicaltrials.gov/study/NCT05384626"}],"setting":"ALK-positive NSCLC after prior ALK TKIs (including lorlatinib): neladalkib single arm","enrolled":840,"enrolledBasis":"registry"},{"id":"bruin-cll-321","name":"BRUIN CLL-321","route":"/trials/bruin-cll-321/","outcomes":[{"endpoint":"Progression-free survival (median)","primary":true,"unit":"months","arms":[{"name":"Pirtobrutinib","n":119,"value":11.2},{"name":"Idelalisib-rituximab or bendamustine-rituximab","n":119,"value":8.7}],"hr":0.58,"source":"https://www.ajmc.com/view/fda-grants-full-approval-to-pirtobrutinib-for-cll-sll"}],"setting":"Relapsed/refractory CLL/SLL after a covalent BTK inhibitor: pirtobrutinib vs investigator's choice (idelalisib-rituximab or bendamustine-rituximab)","enrolled":238,"enrolledBasis":"registry"},{"id":"serena-6","name":"SERENA-6","route":"/trials/serena-6/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Switch to camizestrant + CDK4/6","n":157,"value":16},{"name":"Continue AI + CDK4/6","n":158,"value":9.2}],"hr":0.44,"ci":[0.31,0.6],"p":"<0.0001","source":"https://www.onclive.com/view/fda-approves-camizestrant-plus-a-cdk4-6-inhibitor-for-emergent-esr1-mutated-hr-her2-advanced-breast-cancer"}],"setting":"First-line HR+/HER2- advanced breast cancer on AI + CDK4/6 with an ESR1 mutation detected in ctDNA before radiographic progression: switch to camizestrant + CDK4/6 vs continue AI + CDK4/6","enrolled":315,"enrolledBasis":"registry"}],"papers":[]},{"era":"2026-2032","title":"New modalities for the old targets","description":"Molecular glues and degraders reach proteins without a druggable pocket; degrader-antibody conjugates deliver them into the tumour; antisense and siRNA silence the gene rather than the protein; designed proteins grip surfaces no small molecule can. Synthetic lethality finds a second gene a cancer needs only because its first is broken: PRMT5 inhibitors for MTAP-deleted tumours and WRN inhibitors for mismatch-repair-deficient ones are the leading examples. Chemoproteomics is finding covalent handles on KRAS and beyond.","status":"emerging","refs":[{"id":"molecular-glue-platforms","kind":"technology","name":"Molecular glue discovery platforms","route":"/technologies/molecular-glue-platforms/","status":"phase-1","tldr":"Molecular glues are small molecules that stick two proteins together so the cell destroys one of them. They are smaller and more drug-like than bifunctional degraders."},{"id":"degrader-antibody-conjugate","kind":"technology","name":"Degrader-antibody conjugate (DAC)","route":"/technologies/degrader-antibody-conjugate/","status":"phase-1","tldr":"An ADC that delivers a protein-destroying molecule instead of chemotherapy, hitting targets inside the cell that were previously unreachable."},{"id":"antisense-sirna","kind":"technology","name":"Oligonucleotide therapeutics","route":"/technologies/antisense-sirna/","status":"phase-2","tldr":"Oligonucleotide therapeutics are short synthetic strands of genetic code that silence a specific cancer gene."},{"id":"de-novo-protein-design","kind":"technology","name":"De novo designed protein binders","route":"/technologies/de-novo-protein-design/","status":"phase-1","tldr":"Designing a protein from scratch on a computer to grip a chosen target, instead of finding one in an animal or a library."},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/","status":"approved","tldr":"Finding a second gene that a cancer needs only because its first gene is broken, then hitting the second one."},{"id":"prmt5-mtap","kind":"target","name":"PRMT5 (MTAP-deleted cancers)","route":"/targets/prmt5-mtap/","tldr":"An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials."},{"id":"frontier-medicines","kind":"company","name":"Frontier Medicines","route":"/companies/frontier-medicines/","tldr":"Chemoproteomics company with FMC-376, a KRAS G12C inhibitor that hits both the ON and OFF states of the protein, in phase 1/2."},{"id":"black-diamond-therapeutics","kind":"company","name":"Black Diamond Therapeutics","route":"/companies/black-diamond-therapeutics/","tldr":"Black Diamond Therapeutics designs cancer pills that hit whole families of mutations in a growth protein at once. Its lead drug, silevertinib, targets mutated EGFR in lung cancer and brain tumours."}],"trials":[],"papers":[]},{"era":"2030+","title":"Forecasting resistance instead of waiting for it","description":"If the next resistance mutation can be predicted, as flu strains are, it could be blocked or vaccinated against before it takes over; adaptive dosing that keeps the sensitive clone dominant is in randomised phase 2. MYC and mutant p53, the drivers still without a drug, are the open frontier, and eprenetapopt's failure to refold p53 shows how hard it is. A ready-made KRAS vaccine after pancreatic surgery missed its primary goal, but the idea of vaccinating against a driver mutation remains live.","status":"speculative","refs":[{"id":"idea-bio1-evolution-forecasting","kind":"idea","name":"Forecast the next resistance mutation like the weather","route":"/ideas/idea-bio1-evolution-forecasting/","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."},{"id":"idea-bio1-resistance-mutation-vaccine","kind":"idea","name":"Vaccinate against the resistance mutation before it takes over","route":"/ideas/idea-bio1-resistance-mutation-vaccine/","tldr":"Resistance often arrives as the same few mutations. Teaching the immune system to recognise them in advance could remove the escaping cells while they are still rare."},{"id":"idea-bio1-adaptive-therapy-platform","kind":"idea","name":"A multi-cancer platform trial of adaptive (dose-holiday) therapy","route":"/ideas/idea-bio1-adaptive-therapy-platform/","tldr":"Instead of hitting a tumour with the maximum dose until it stops working, adjust the dose to keep the tumour small and let drug-sensitive cells suppress resistant ones. Test this properly across several cancers."},{"id":"idea-tr1-adaptive-therapy-randomised-phase-2","kind":"idea","name":"Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials","route":"/ideas/idea-tr1-adaptive-therapy-randomised-phase-2/","tldr":"Adaptive therapy uses just enough drug to keep a tumour in check, pausing when the burden falls and resuming when it rises, so drug-sensitive cells suppress resistant ones. A prostate cancer pilot with abiraterone lengthened time to progression against historical controls on half the drug; randomised phase 2 trials are the next step."},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/","tldr":"MYC is the most commonly amplified cancer gene, a master switch that turns on thousands of growth genes. It has no pocket for a conventional drug, so it remained 'undruggable' for 40 years; the first direct MYC drugs finally entered trials in the 2020s."},{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","route":"/drugs/eprenetapopt/","status":"negative","tldr":"Eprenetapopt (APR-246) was a drug meant to refold mutant p53, the most common broken protein in cancer. Its phase 3 in blood cancer failed in 2020."},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/","tldr":"The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug."},{"id":"eli-002-7p","kind":"drug","name":"ELI-002 7P","route":"/drugs/eli-002-7p/","status":"phase-2","tldr":"A ready-made vaccine against the seven commonest KRAS mutations, given after pancreatic cancer surgery. Its phase 2 missed the main goal in 2026 but showed signs of activity."}],"trials":[],"papers":[]},{"era":"What sets the pace","title":"Resistance, combinations, biomarkers and price","description":"Every targeted drug meets resistance; a tumour is many tumours, so the resistant clone is usually already there. There are thousands of possible combinations and sequences and trials can test a few dozen a year. A drug cannot be matched without a validated test, and tests lag drugs. And targeted therapy is priced per month for years, so the cost of a cure-like outcome compounds; the biosimilar and generic wave for the first generation is only now arriving.","status":"current","refs":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/","tldr":"Nearly every targeted therapy stops working within months to a few years as the tumour adapts."},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/","tldr":"Every tumour is a population of genetically distinct clones: in multi-region sequencing of kidney tumours, roughly two thirds of mutations were missing from at least one region. Treatment kills the dominant clones and leaves resistant minor clones to grow back, yet a single diagnostic biopsy is still treated as the whole disease."},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/","tldr":"There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year."},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/","tldr":"Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab."},{"id":"b-drug-pricing","kind":"bottleneck","name":"Prices and value","route":"/bottlenecks/b-drug-pricing/","tldr":"New cancer drugs routinely cost over $150,000 a year, often for months of benefit. Systems cannot afford them and patients go bankrupt."},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/","tldr":"The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug."}],"trials":[],"papers":[]}],"watch":[]}