Next-Generation KRAS Inhibitors and Practice Change

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 next-generation KRAS inhibitors in non-small cell lung cancer (NSCLC). Dr. Veluswamy expresses excitement about daraxonrasib, whose recent New England Journal of Medicine paper showed roughly 90% of patients experiencing some toxicity, though not all grade 3 or 4, and about divarasib's ongoing phase 3 head-to-head trial against sotorasib and adagrasib, with only press-release results so far. He also highlights zoldonrasib, a KRAS G12D-directed molecular glue showing a benefit signal in nearly every patient with a rapid time to response, alongside other G12D-directed agents topping 60% response rates and new G12V-specific drugs in development. Dr. Jani notes his institution is separately studying efficacy after progression on prior KRAS inhibitors, while Dr. Veluswamy states that retiring docetaxel from the second line will require a new agent with a substantial, not marginal, progression-free survival benefit plus a demonstrated overall survival benefit.