KRAS-Targeted Therapy in Non–Small Cell Lung Cancer: Current Standards, Resistance Mechanisms, and Emerging Therapeutic Strategies
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in non–small cell lung cancer (NSCLC), particularly in lung adenocarcinoma, and for decades were regarded as therapeutically intractable. The development of covalent KRAS G12C inhibitors has changed this paradigm, establishing direct KRAS inhibition as a clinically actionable strategy. Sotorasib and adagrasib have demonstrated antitumor activity in previously treated KRAS G12C–mutated advanced NSCLC and are now important targeted options following prior systemic therapy. However, the clinical benefit of current monotherapy remains limited. Randomized trials have shown improved progression-free survival compared with docetaxel, but a definitive overall survival advantage has not been established. Acquired resistance is common and biologically heterogeneous, involving secondary KRAS alterations, KRAS amplification, receptor tyrosine kinase activation, downstream Mitogen-Activated Protein Kinase (MAPK) or Phosphoinositide 3-Kinase (PI3K) pathway reactivation, histologic transformation, and adaptive feedback signaling. Outcomes are further influenced by central nervous system involvement, treatment-related toxicity, prior immunotherapy exposure, and co-occurring genomic alterations such as TP53, STK11, and KEAP1. Emerging strategies include more potent KRAS G12C inhibitors, active-state RAS inhibitors, pan-RAS approaches, KRAS G12D inhibitors and degraders, rational combination regimens, and KRAS-directed immunotherapies. Direct KRAS inhibition has thus transformed KRAS G12C–mutated NSCLC from a previously undruggable subtype into a targetable disease, but durable disease control remains an unmet need. Future progress will require comprehensive molecular profiling, broader targeting of non–G12C KRAS variants, improved intracranial efficacy, resistance-informed combinations, equitable access to molecular diagnostics, and randomized evidence demonstrating meaningful survival and quality-of-life benefits.