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Author: Admin | 2025-04-28
KRAS G12C inhibitors have been developed that bind and block the KRAS G12C protein in its inactive GDP-bound state (off).11,12 Among these, both sotorasib (AMG-510) and adagrasib (MRTX849) are now US Food and Drug Administration (FDA) approved, and several other direct, covalent KRAS G12C inhibitors, such as GDC-6036, D-1553, JAB-21822, JDQ443, and LY3537982, are in the early phases of clinical development. Trials are also underway to test the efficacy of these KRAS G12C inhibitors in the adjuvant and neoadjuvant settings for the treatment of early-stage NSCLC.Role of PD-1/PD-L1 Inhibitors for Treating KRAS-Mutated NSCLCImmunotherapy represents a promising approach in KRAS-mutant NSCLC, as PD-L1 is upregulated by KRAS mutation through sustained phosphorylation of ERK activation. Furthermore, this upregulation induces CD3+ T-cell apoptosis, which can be reversed by anti–PD-1/PD-L1 antibody or ERK inhibitor treatment, suggesting that PD-1 blockade potentially restores the antitumor immunity of T cells in KRAS-mutated NSCLC.13,14 KRAS-mutant NSCLC, often linked to smoking, is frequently associated with high mutational burden.15,16 A meta-analysis of 6 studies showed that immunotherapy combined with chemotherapy significantly prolonged the overall survival (OS; hazard ratio [HR], 0.59; PP=.0003) in patients with KRAS-mutant NSCLC compared with chemotherapy alone, and the OS was significantly longer in patients with KRAS mutations than in the KRAS wild-type group (P=.001).17 KRAS co-occurring mutations are critical factors dictating distinct immune phenotypes within KRAS-mutant NSCLCs, with co-mutations in TP53 and STK11 profoundly influencing the tumor-immune contexture. In the Stand Up to Cancer cohort, PFS and OS were shorter in the KRAS/STK11 co-mutant lung adenocarcinoma group than in patients with KRAS/TP53 co-mutated tumors.8 Other reports have also demonstrated that KRAS/TP53 co-mutant lung tumors show remarkable benefits with single-agent PD-1 blockade.18 In a study investigating the impact of mutations in SWI/SNF genes, including SMARCA4, on immunotherapy outcomes in KRAS-mutant NSCLC, the worst OS and prognosis were associated with SMARCA4 mutations, indicating the unfortunate outcome of this gene alteration with KRAS.19 Notably, STK11 mutations are a major determinant of primary resistance to PD-1 blockade in PD-L1–positive NSCLC, regardless of KRAS mutational status.8 Therefore, despite PD-1/PD-L1 inhibitors being promising biological therapy for KRAS-mutant lung adenocarcinomas, these drugs do
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