Abstract

KRAS G12C inhibitors have transformed treatment options for a subset of NSCLC and colorectal cancers, but acquired resistance emerges within a median of 6.5 months. This paper characterises resistance mechanisms observed across 214 post-progression biopsies, identifying convergent activation of RTK signalling, secondary KRAS mutations, and epithelial-mesenchymal transition programmes. We propose a three-tier surveillance framework for early resistance detection and outline combination strategies now entering Phase Ib evaluation.