Emerging KRAS G12C Inhibitors in Development

Rajwanth R. Veluswamy, MD, MSCR, and Chinmay Jani, MD, of the Perlmutter Cancer Center at NYU Langone Health and the University of Miami Sylvester Comprehensive Cancer Center, discuss emerging KRAS G12C-directed agents in development for non-small cell lung cancer. Dr. Veluswamy highlights divarasib and olomorasib as more potent, direct off-state inhibitors showing improved response rates and durability compared with sotorasib and adagrasib, including a head-to-head trial of divarasib against sotorasib or adagrasib whose press release reported a positive result, with full data still pending. He also describes daraxonrasib, a multi-selective RAS inhibitor using a molecular-glue mechanism that targets KRAS in its active, on-state form rather than the off-state pocket earlier agents use, addressing resistance mutations that arise against those drugs. In a recent publication across all KRAS-mutated patients, daraxonrasib produced a response rate near 40%, a progression-free survival of 8.3 months, and a duration of response of 11.5 months, with an ongoing trial comparing it against docetaxel in the second line.