{"entity":{"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","aka":[],"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.","summary":"Open-label phase 3 trial of 345 patients with KRAS G12C-mutated advanced NSCLC previously treated with platinum chemotherapy and a PD-1 inhibitor, randomised to sotorasib 960 mg daily or docetaxel. Primary endpoint was PFS by blinded review.\n\nMedian PFS was 5.6 vs 4.5 months (HR 0.66) with a higher response rate (28.1% vs 13.2%) and less high-grade toxicity, but overall survival was not different (HR about 1.0), partly because a third of docetaxel patients crossed over. It confirmed that KRAS G12C is druggable, and also that first-generation inhibitors give short-lived benefit; the FDA's concerns about the trial's design and a later dose-comparison requirement shaped how KRAS inhibitors were subsequently developed.","asOf":"2026-09-08","links":[{"label":"PubMed search: CodeBreaK 200 Lancet 2023","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CodeBreaK+200+sotorasib+docetaxel+de+Langen+Lancet"},{"label":"ClinicalTrials.gov NCT04303780","url":"https://clinicaltrials.gov/study/NCT04303780"},{"label":"Lancet 2023","url":"https://doi.org/10.1016/S0140-6736(23)00221-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36764316/"}],"tags":[],"related":["paper-ostrem-kras-g12c-nature-2013","paper-kras-nsclc-n-engl-j-med-2021","kras-roadmap"],"cancers":["nsclc","lung-cancer","kras-g12c-nsclc"],"sections":["targeted-therapy","drug-discovery"],"technologies":["kras-inhibitors","kinase-inhibitors"],"targets":["kras"],"drugs":["sotorasib","adagrasib","docetaxel"],"companies":["amgen"],"institutions":["nki"],"pathways":["ras-mapk"],"terms":["pfs","os","orr","resistance","accelerated-approval","driver-mutation"],"trials":["codebreak-300","codebreak-200","codebreak-100"],"people":["luis-paz-ares","solange-peters"],"bottlenecks":["b-undruggable-targets","b-resistance","b-trial-design","b-dose-optimisation","b-combination-space"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2023,"doi":"10.1016/S0140-6736(23)00221-0","pmid":"36764316","authors":"de Langen AJ, Johnson ML, Mazieres J, et al.","paperType":"rct","findings":["Median PFS 5.6 vs 4.5 months; HR 0.66 (95% CI 0.51-0.86); 12-month PFS 24.8% vs 10.1%.","Objective response 28.1% vs 13.2%; disease control 82.5% vs 60.3%.","Grade 3 or higher treatment-related adverse events 33% vs 40%; diarrhoea and liver enzyme elevation were the main sotorasib toxicities.","Overall survival not significantly different; the trial was not powered for OS and 34% of docetaxel patients crossed over to sotorasib.","The KRYSTAL-12 trial of adagrasib versus docetaxel later reported a similar PFS result (5.5 vs 3.8 months, HR 0.58)."],"whatItMeans":"Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.","caveats":["Open-label with a modest absolute PFS gain of about one month and no OS benefit.","Crossover and the sample size reduction made during the trial (from 650 to 345) drew criticism from regulators.","Resistance develops through multiple mechanisms (secondary KRAS mutations, bypass pathways), limiting durability.","Response rates in KRAS G12C lung cancer (around 30-40%) are far lower than for EGFR or ALK inhibitors, reflecting KRAS biology."],"changedPractice":true,"participants":345},"route":"/key-papers/paper-codebreak-200-lancet-2023/","neighbours":{"paper":[{"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/"},{"id":"paper-kras-nsclc-n-engl-j-med-2021","kind":"paper","name":"Sotorasib for Lung Cancers with KRAS p.G12C Mutation","route":"/key-papers/paper-kras-nsclc-n-engl-j-med-2021/"}],"roadmap":[{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/"},{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"}],"cancer":[{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","route":"/cancers/kras-g12c-pdac/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"company":[{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/"}],"institution":[{"id":"nki","kind":"institution","name":"Netherlands Cancer Institute (NKI-AvL)","route":"/institutions/nki/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"orr","kind":"term","name":"Objective response rate (ORR)","route":"/terms/orr/"},{"id":"os","kind":"term","name":"Overall survival (OS)","route":"/terms/os/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"}],"trial":[{"id":"codebreak-100","kind":"trial","name":"CodeBreaK 100 (pancreatic cancer cohort)","route":"/trials/codebreak-100/"},{"id":"codebreak-200","kind":"trial","name":"CodeBreaK 200","route":"/trials/codebreak-200/"},{"id":"codebreak-300","kind":"trial","name":"CodeBreaK 300","route":"/trials/codebreak-300/"}],"person":[{"id":"ferdinandos-skoulidis","kind":"person","name":"Ferdinandos Skoulidis","route":"/people/ferdinandos-skoulidis/"},{"id":"luis-paz-ares","kind":"person","name":"Luis Paz-Ares","route":"/people/luis-paz-ares/"},{"id":"solange-peters","kind":"person","name":"Solange Peters","route":"/people/solange-peters/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"journal":[{"id":"lancet","kind":"journal","name":"The Lancet","route":"/journals/lancet/"}]}}