KRAS G12C mutant NSCLC is the subtype with a glycine-to-cysteine substitution at codon 12 (G12C) of the KRAS (Kirsten rat sarcoma viral oncogene homolog) gene and is the most common driver mutation in NSCLC. Total KRAS mutations account for 25-30% of NSCLC, with KRAS G12C specifically present in 13%. KRAS mutations were historically deemed 'undruggable' because the protein surface lacked a binding pocket. The 2013 discovery by the Shokat group that the cysteine in KRAS G12C could be targeted covalently led to the development of selective KRAS G12C inhibitors such as sotorasib and adagrasib. Typical patient profile: current or former smoker (more than 95% of KRAS G12C cases are smoking-related), older age, adenocarcinoma histology, often with co-mutations in CDKN2A, STK11, or KEAP1.
KRAS is a small GTPase oncoprotein that plays a key role in cellular signaling. Normally KRAS cycles between an active GTP-bound and inactive GDP-bound state. The G12C mutation impairs GAP-mediated GTP hydrolysis and locks KRAS in the active state. Active KRAS engages the RAF/MEK/ERK (MAPK) and PI3K/AKT pathways, driving tumor growth and survival. KRAS G12C inhibitors covalently bind the GDP-bound form (in the switch II pocket), block nucleotide exchange and conversion to GTP, and trap KRAS in the inactive state. Patients with STK11 (LKB1) and KEAP1 co-mutations respond poorly to immunotherapy and have a worse prognosis.
Approved KRAS G12C inhibitors: (1) Sotorasib (Lumakras, AMG 510) — the first FDA-approved KRAS inhibitor (2021); CodeBreaK 100 monotherapy showed a response rate of 37%, median PFS of 6.8 months, and median OS of 12.5 months; CodeBreaK 200 versus docetaxel demonstrated a PFS advantage that was less dramatic than expected. (2) Adagrasib (Krazati, MRTX849) — second approval (2022); KRYSTAL-1 reported a 43% response rate, PFS 6.9 months, and CNS activity. Both agents are approved for the second line and beyond (after prior systemic therapy), with first-line trials ongoing. Resistance mechanisms include secondary KRAS mutations (H95D, Y96D), bypass activation (RAS-GEF activation, RAF dimerization, MET amplification), and histologic transformation (adeno → squamous). Combination strategies under study include KRAS G12C inhibitors plus SHP2 inhibitors, MEK inhibitors, EGFR inhibitors, PD-1 inhibitors, and CDK4/6 inhibitors. Immunotherapy is generally effective in KRAS G12C+ NSCLC (especially without STK11/KEAP1 co-mutation), and the first-line standard remains chemotherapy plus pembrolizumab.