Targeting KRAS G12C in non-small cell lung cancer: Breakthrough inhibitors and combination approaches

KRAS mutations occur in approximately 25-30% of NSCLC cases, with the KRAS G12C substitution present in 10-13% of advanced non-squamous tumors. Historically, KRAS was considered an undruggable oncogene, associated with limited therapeutic options and poor outcomes. The clinical development of KRAS G12C inhibitors has changed this landscape, demonstrating that KRAS can be effectively targeted. Several inhibitors are in clinical development, showing heterogeneous efficacy and safety profiles. Despite clinically meaningful antitumor activity, the durability of benefit achieved with currently available agents remains limited. The therapeutic benefit of currently available KRAS inhibitors is constrained by the emergence of resistance mechanisms, including secondary RAS alterations, activation of bypass signaling pathways, metabolic adaptations, and phenotypic plasticity, leading to early disease progression in a substantial proportion of patients. To address these limitations, next-generation strategies are under active development. ON-state and pan-RAS inhibitors aim to improve suppression of oncogenic signaling and to retain activity in the context of resistance to first-generation compounds. In parallel, multiple combination approaches are being evaluated, including associations with chemotherapy, immune checkpoint inhibitors, and novel pharmacological classes designed to counteract pathway reactivation, enhance response depth and improve clinical benefit. This review provides a comprehensive and updated overview of KRAS G12C inhibition in NSCLC, summarizing biological mechanisms underlying KRAS oncogenesis, clinical evidence supporting currently approved therapies, emerging drug development strategies, mechanisms of therapeutic resistance, and evolving combination approaches. Collectively, these advances are transforming KRAS G12C-mutant NSCLC from a refractory molecular subtype into a disease increasingly amenable to precision oncology strategies.