KRAS-Targeted Therapies in NSCLC: Resistance, Combination Strategies, and Emerging Clinical Paradigms

KRAS mutations represent the most common oncogenic driver in Western NSCLC and a major therapeutic challenge historically deemed "undruggable." The approval of allele-specific KRAS G12C inhibitors has transformed management, yet overall survival gains remain modest and resistance is inevitable. Rapid advances in next-generation KRAS inhibitors, rational combinations, and mutant-specific strategies (G12D, G12V) necessitate an updated synthesis of evolving evidence. To critically review the therapeutic landscape of KRAS-mutant NSCLC, covering biological underpinnings, clinical efficacy of approved and investigational inhibitors, mechanisms of resistance, combination strategies, and emerging paradigms likely to redefine future standards of care. A comprehensive narrative review of published clinical trials, translational studies, resistance-mechanism analyses, and real-world datasets focusing on KRAS-mutant NSCLC. Key sources include phase I-III trials of sotorasib, adagrasib, next-generation G12C inhibitors, mutant-specific G12D inhibitors, and ongoing combination studies integrating KRAS blockade with immunotherapy, MAPK-axis inhibitors, SHP2/SOS1 inhibitors, EGFR/MET inhibitors, and chemotherapy. Sotorasib and adagrasib achieve ORRs of 37-43% and median PFS ~ 6-7 months in previously treated KRAS G12C NSCLC, with improved tolerability over docetaxel. Next-generation inhibitors (olomorasib, divarasib, glecirasib, D-1553, IBI351) demonstrate ORRs 45-55% and, in some studies, PFS exceeding first-generation agents, while emerging KRAS G12D inhibitors show early proof-of-concept activity. Resistance arises through on-target KRAS alterations, RTK-RAS bypass signaling, MAPK/PI3K pathway reactivation, and co-mutation-driven phenotypic remodeling. Combination strategies-particularly KRAS inhibitor + PD-1 blockade, SHP2/SOS1 inhibition, EGFR/MET inhibition, or platinum doublets-are yielding higher response rates and deeper, more durable suppression in early trials. KRAS-mutant NSCLC is transitioning from historically untargetable disease to a therapeutically actionable subset. Future progress hinges on resistance-directed combinations, biomarker-guided personalization, expansion to non-G12C mutants, and evaluation in earlier disease settings.