CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug
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.
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.
- 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).
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.
- 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.
Pages like this
not linked directly; found by shared links- Key paperCodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer
Shares CodeBreaK 300, Amgen, Sotorasib, KRAS & RAS inhibitors.
- Key paperOstrem and Shokat: the hidden pocket that made KRAS G12C druggable
Shares Adagrasib, Sotorasib, KRAS & RAS inhibitors, KRAS.
- PersonKevan M. Shokat
Shares Adagrasib, Sotorasib, KRAS & RAS inhibitors, KRAS.
- PairingKRAS G12C inhibitor + anti-EGFR antibody (colorectal)
Shares CodeBreaK 300, Adagrasib, Sotorasib, KRAS & RAS inhibitors.
- RoadmapKRAS roadmap: undruggable → G12C → pan-RAS
Shares Adagrasib, Sotorasib, KRAS & RAS inhibitors, KRAS.
- TrialKRYSTAL-12
Shares Adagrasib, KRAS, The undruggable drivers, Non-small-cell lung cancer.
- IdeaCovalent chemistry for the RAS mutations that still have no drug
Shares Adagrasib, Sotorasib, KRAS & RAS inhibitors, KRAS.
- TrialKrascendo 1
Shares Adagrasib, Sotorasib, KRAS, Non-small-cell lung cancer.