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KRAS G12C inhibition in non-small cell lung cancer: clinical evidence, resistance mechanisms, and combination strategies

KRAS mutations occur in approximately 25–30% of NSCLC cases, with the G12C substitution accounting for ~40% of KRAS-mutant NSCLC. Covalent KRAS G12C inhibitors have established a new targeted therapy era in thoracic oncology, following decades without approved KRAS-directed agents.

Approved KRAS G12C inhibitors demonstrated objective response rates of 37–43% in previously treated KRAS G12C-mutant NSCLC; one agent showed notable intracranial activity. Primary and acquired resistance limit durability. Mechanisms include secondary KRAS mutations, co-occurring STK11/KEAP1 alterations (associated with reduced response), and bypass signaling through EGFR, MET, and RET. Rational combination strategies pairing KRAS G12C inhibitors with EGFR antibodies, SHP2 inhibitors, or SOS1 inhibitors are under active investigation. Next-generation pan-KRAS and multi-KRAS inhibitors are in early-phase evaluation, aiming to overcome limitations of G12C-selective covalent approaches.

Thoracic oncologists, pulmonologists, and medical oncologists managing KRAS G12C-mutant NSCLC will benefit from peer discussion on approved KRAS inhibitor evidence, rational combination strategies, resistance profiling, and emerging next-generation approaches.

How do you incorporate STK11, KEAP1, and co-mutation status into KRAS G12C inhibitor candidacy assessment, and does co-mutation burden influence your treatment sequencing decisions? What is your approach to molecular profiling at progression on a KRAS G12C inhibitor, and how does resistance mechanism characterization guide subsequent therapy selection?

  • 1w
    I would consider STK11 and KEAP1 co-mutations important prognostic factors. In the frontline setting, for an appropriate patient, I would generally favor platinum-based chemotherapy with PD-1/PD-L1 immunotherapy, with CTLA-4 inhibition in selected patients, rather than using KRAS G12C inhibition upfront. At progression, I would repeat molecular profiling when feasible and use the resistance profile to guide second-line KRAS G12C–targeted therapy with subsequent sequencing individualized according to prior therapy, resistance mechanisms, performance status, and remaining treatment options.
  • 2w
    IF a KRAS is co mutation with STK 11 or KEAP1, the OS is worse. Adagrasib has shown efficacy though. Single agent immunotherapy tends not to work well in these cold tumors. Typically, first line is chemotherapy and 2nd line I would use adagrasib