Sotorasib in KRAS(G12C) mutated lung cancer: Can we rule out cracking KRAS led to worse overall survival?

The KRAS oncogene is present in up to 25% of solid tumors and for decades had been undruggable. Sotorasib was the first-in-class KRAS inhibitor to reach the US and European market, and its pharmacological inhibition is restricted to the KRAS p.G12C mutation. Sotorasib showed activity (tumor shrinkage) in patients with non-small cell lung cancer harboring this specific mutation, and efficacy was tested in the CodeBreaK 200, open-label, phase 3 trial (NCT04303780). The results were presented in the ESMO 2022 meeting. CodeBreaK 200 found an improvement in the primary endpoint of progression-free survival (PFS), but overall survival, a key secondary endpoint, was not improved. However, critical questions about the trial's design may limit inferences regarding the reported results. The control arm treatment was inferior to the best standard of care. A late protocol modification (which lowered the sample size and allowed a problematic crossover) prohibited the trial from making a determination regarding overall survival. Imbalance in censoring rates, with potential informative censoring, makes PFS estimates unreliable. Quality-of-life data were also limited. Ultimately, CodeBreaK 200 does not clarify how this therapy should be used in practice, and while we maintain cautious enthusiasm for this and other Ras inhibitors, we await more informative trials