Evaluating the efficacy of G12C inhibitors in conjunction with Gamma Knife radiosurgery for KRAS-mutant non-small cell lung cancer brain metastases

Purpose: KRAS G12C mutations occur in approximately 11% of non-small-cell lung cancer (NSCLC) patients and are associated with aggressive disease and poor prognosis. Although KRAS G12C-inhibitors are now approved, their impact on Gamma Knife radiosurgery (GKRS) outcomes remains unexplored. We assessed the safety and efficacy of KRAS G12C inhibitors with GKRS compared with conventional systemic therapies. Methods: Sixty-one NSCLC patients with KRAS mutations, thirty-three of which were G12C-mutated (G12C-mut), treated with GKRS from 2011 to 2024 were included. Sixteen received G12C inhibitors (adagrasib, sotorasib or divarasib). Data included demographics, treatment details, prior or concurrent systemic therapies (chemotherapy/IT), and mutational status. Kaplan-Meier analyses were performed to assess overall survival and distant brain failure (DBF) across treatment groups. Results: At 12 months, survival rates were highest in non-G12C-mut patients (74%), followed by G12C-mut patients not receiving inhibitors (56%), and lastly those receiving inhibitors (40%). By 36 months, survival rates decreased to 48%, 35%, and 8%, respectively. G12C-mut-on-KRAS inhibitor group exhibited a significantly shorter time to distant brain failure (median = 4 months) compared to those not receiving inhibitors (median = 6.5 months) and non-G12C-mut patients (median = 13 months, p = 0.0031). Local failure and adverse radiation effect rates did not differ significantly among the three cohorts (p > 0.9). Conclusion: Adding KRAS G12C-inhibitors to GKRS for G12C-mut NSCLC brain metastases did not improve survival and was linked to earlier DBF. Despite systemic activity, these agents may offer limited CNS-specific benefit versus EGFR/ALK therapies, warranting further investigation to optimize sequencing and patient selection.