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.