Literature review of advances and challenges in KRAS G12C mutant non-small cell lung cancer.

Abstract

Background and objective: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are one of the most common oncogenic driver mutations in non-small cell lung cancer (NSCLC), with the KRAS G12C mutation being the most common prevalent subvariant. The review aims to explore optimal diagnostic and therapeutic strategies for KRAS G12C mutant NSCLC, and to provide guidance for the development of precise treatment approaches for affected.

Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, MEDLINE, the Cochrane Library, and major international conferences proceedings for all English-language publications available up to December 31, 2024. Relevant studies were systematically reviewed, analyzed, and synthesized to inform this review.

Key content and findings: In this review, we explore the KRAS G12C mutation and its associated signaling pathways, detection techniques, recent advancements in drug development and mechanisms of therapeutic resistance. The KRAS G12C mutation was once considered "undruggable" until the breakthrough approval of two targeted inhibitors: AMG510 (sotorasib) and MRTX849 (adagrasib). In China, IBI351 and D-1553 have also been approved for the treatment of adult patients with advanced NSCLC harboring the KRAS G12C mutation. Although currently approved only as second-line therapies for metastatic disease, these inhibitors-along with ongoing development of additional KRAS-targeted agents-are significantly advancing our understanding of KRAS-driven tumor biology. Notably, recent findings indicate that combining dual immune checkpoint inhibitors (ICIs; durvalumab and tremelimumab) with chemotherapy (CT) in patients with advanced NSCLC, including those with KRAS mutations, can result in durable survival benefits. This approach is emerging as a promising first-line treatment strategy.

Conclusions: The landscape of KRAS-mutant NSCLC has undergone substantial progress, marked by the successive approval of multiple KRAS G12C inhibitors and the development of novel targeted therapies. Moreover, the POSEIDON trial has highlighted the potential of dual ICI therapy combined with CT to achieve sustained clinical benefits. Despite these advances, the heterogeneity of tumor responses underscores the need for further investigation into intrinsic resistance mechanisms and the strategic optimization of combination therapies to enhance treatment outcomes.