Authors
Akhil Kapoor, Bipinesh Sansar, Anuj Gupta, Bal Krishna Mishra, Archi Rungta, Ankita Pal, Shreya Srivastava, Minit Shah, Nandini Menon, Trupti Pai, Omshree Shetty, Pratik Chandrani, Anuradha Choughule, Vanita Noronha, Kumar Prabhash
Published in
Medical oncology (Northwood, London, England). Volume 43. Issue 9. Aug 20, 2026. Epub Aug 20, 2026.
Abstract
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.
PMID:
42622884
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.
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