FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non–small cell lung cancer

KRAS G12C (Gly ¹² →Cys) inhibitors (G12Cis) have improved outcomes for patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), but their clinical benefit is limited by the emergence of resistance mechanisms. Here, we demonstrate that combining the RAF/MEK clamp avutometinib and the focal adhesion kinase (FAK) inhibitor defactinib with a G12Ci enhanced antitumor activity by deepening mitogen-activated protein kinase (MAPK) pathway suppression and simultaneously inhibiting adaptive resistance pathways induced by G12Ci and avutometinib treatment, including FAK and PI3K signaling. In KRAS G12C NSCLC mouse models, the triplet combination produced greater tumor growth inhibition than either sotorasib alone or the sotorasib plus avutometinib doublet. Moreover, in KRAS G12C NSCLC mouse models resistant to sotorasib, the addition of avutometinib and FAK inhibition restored sensitivity to sotorasib and increased both the depth and durability of antitumor responses. Collectively, these findings demonstrate that concurrent targeting of KRAS G12C, RAF/MEK, and FAK signaling can overcome multiple resistance mechanisms and provide a strong rationale for the clinical evaluation of sotorasib, avutometinib, and defactinib in patients with KRAS G12C–mutated NSCLC (RAMP 203; NCT05074810).