Therapeutic advances with KRASG12C inhibitors and combination strategies in non-small cell lung cancer brain metastases

Abstract Non-small cell lung cancer (NSCLC) frequently metastasizes to the brain in approximately 20–40% of cases. Mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) are common in NSCLC, with the KRAS G12C variant accounting for approximately 40% of KRAS-mutant cases. Up to 40% of NSCLC patients harboring the KRAS G12C mutation develop brain metastases during follow-up, and a substantial proportion present with brain metastases at diagnosis. While KRAS G12C inhibitors such as sotorasib and adagrasib are approved therapies, most patients with KRAS G12C mutant NSCLC experience disease progression within 5 to 6 months. Emerging KRAS G12C inhibitors, such as adagrasib, RMC-6236, and olomorasib, show intracranial activity in KRAS G12C mutant NSCLC brain metastases, but adaptive resistance limits their effectiveness as monotherapies. This article examines the clinical and translational application of specific next-generation blood-brain barrier penetrant KRAS G12C inhibitors, such as sotorasib, adagrasib, olomorasib, RMC-6236, and D3S-001, and their rational integration with radiation therapy, targeted therapies, and immunotherapies to overcome therapeutic resistance in patients with NSCLC brain metastases. This review summarizes recent advances aimed at enhancing intracranial tumor control and overall survival in patients with NSCLC brain metastases through the use of next-generation KRAS G12C inhibitors and multimodal therapies.