Molecular Mechanisms and Therapeutic Advances in KRAS G12C‐Mutant Non‐Small Cell Lung Cancer: Toward Mechanism‐Guided Longitudinal Management

KRAS G12C‐mutant non‐small cell lung cancer (NSCLC) has become a clinically actionable molecular subtype. Discovery of the switch‐Ⅱ pocket enabled the development of covalent KRAS G12C(OFF)‐state inhibitors, transforming a historically “undruggable” target into a therapeutic vulnerability. Drugging KRAS, however, proved to be a problem of chemistry, whereas sustaining its inhibition has proved to be a problem of biology. KRAS G12C‐mutant NSCLC is biologically heterogeneous, and the magnitude and durability of clinical benefit are shaped by co‐mutations, the tumor microenvironment, brain metastases status, pharmacologic differences between agents, and the dynamic evolution of resistance. Randomized trials have demonstrated that sotorasib and adagrasib improve progression‐free survival (PFS) and objective response rates (ORR) over docetaxel in previously treated disease, yet these gains have not translated consistently into a definitive overall survival (OS) advantage. This review synthesizes the epidemiology, molecular biology, diagnostic strategies, first‐ and later‐line treatment evidence, resistance mechanisms, and emerging KRAS/RAS‐directed approaches. We distinguish randomized or guideline‐supported practice from early‐phase and translational signals, and propose an implementable framework that combines PD‐L1, tumor mutational burden, STK11/KEAP1/TP53 status, TTF‐1 expression, brain metastases, and circulating tumor DNA (ctDNA) for risk stratification and mechanism‐guided management. At disease progression, oligoprogression should be distinguished from systemic progression, and tissue re‐biopsy together with plasma profiling should be considered when feasible. In China, several domestically developed KRAS G12C inhibitors have been approved, and reimbursement coverage is expanding; the cost of molecular testing, uneven institutional access, regional disparities and limited confirmatory and real‐world evidence nonetheless continue to constrain implementation. Future priorities include randomized first‐line comparisons, biomarker‐defined combination strategies, improved central nervous system activity and mechanism‐matched treatment after resistance.