# CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug

Source: https://onco.cc/key-papers/paper-codebreak-200-lancet-2023/  
OnCo record `paper-codebreak-200-lancet-2023` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Median 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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: The Lancet
- Year: 2023
- DOI: 10.1016/S0140-6736(23)00221-0
- Authors: de Langen AJ, Johnson ML, Mazieres J, et al.
- 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).
- What it means: 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.

## Sources

- PubMed search: CodeBreaK 200 Lancet 2023: https://pubmed.ncbi.nlm.nih.gov/?term=CodeBreaK+200+sotorasib+docetaxel+de+Langen+Lancet
- ClinicalTrials.gov NCT04303780: https://clinicaltrials.gov/study/NCT04303780
- Lancet 2023: https://doi.org/10.1016/S0140-6736(23)00221-0
- PubMed: https://pubmed.ncbi.nlm.nih.gov/36764316/

## Connected records

- key papers: [Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable](https://onco.cc/key-papers/paper-ostrem-kras-g12c-nature-2013/), [Sotorasib for Lung Cancers with KRAS p.G12C Mutation](https://onco.cc/key-papers/paper-kras-nsclc-n-engl-j-med-2021/)
- roadmaps: [KRAS roadmap: undruggable → G12C → pan-RAS](https://onco.cc/roadmaps/kras-roadmap/), [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](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- cancers: [KRAS G12C-mutant non-small-cell lung cancer](https://onco.cc/cancers/kras-g12c-nsclc/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [KRAS](https://onco.cc/targets/kras/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Docetaxel](https://onco.cc/drugs/docetaxel/), [Sotorasib](https://onco.cc/drugs/sotorasib/)
- companies: [Amgen](https://onco.cc/companies/amgen/)
- institutions: [Netherlands Cancer Institute (NKI-AvL)](https://onco.cc/institutions/nki/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Objective response rate (ORR)](https://onco.cc/terms/orr/), [Overall survival (OS)](https://onco.cc/terms/os/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- trials: [CodeBreaK 100 (pancreatic cancer cohort)](https://onco.cc/trials/codebreak-100/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [CodeBreaK 300](https://onco.cc/trials/codebreak-300/)
- people: [Ferdinandos Skoulidis](https://onco.cc/people/ferdinandos-skoulidis/), [Luis Paz-Ares](https://onco.cc/people/luis-paz-ares/), [Solange Peters](https://onco.cc/people/solange-peters/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- journals: [The Lancet](https://onco.cc/journals/lancet/)

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