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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.
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.
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