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Avutometinib + sotorasib is an investigational combination therapy for the treatment of KRAS G12C-mutant non–small cell lung cancer (NSCLC). Avutometinib is a small molecule RAF/MEK clamp that targets the RAS pathway, inhibiting downstream signaling and tumor growth. Sotorasib is a first-in-class, orally available small molecule that selectively and irreversibly inhibits KRAS G12C by covalently binding to the mutant cysteine residue, trapping it in its inactive GDP-bound state. The combination aims to provide a more complete vertical blockade of the MAPK pathway than either agent alone, resulting in deeper tumor regression and reduced relapse rates. This regimen has received FDA fast track designation for patients with locally advanced or metastatic KRAS G12C-mutant NSCLC who have received at least one prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor[1][2][4][5].
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