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Author: Admin | 2025-04-28
Not benefit all patients equally. Instead, immunotherapy for these patients should be individualized according to the presence of major co-mutations. For instance, single-agent anti–PD-1/PD-L1 therapy is an effective therapy and might be sufficient to obtain tumor regression in at least a subset of patients with KRAS/TP53 co-mutant tumors. Conversely, patients with KRAS/STK11 co-mutated NSCLC may benefit more from a regimen incorporating a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody to the chemotherapy and PD-1/PD-L1 inhibitor backbone. In POSEIDON, a phase 3 trial of first-line treatment in patients with metastatic NSCLC, those who received a combination of the anti–CTLA-4 agent tremelimumab, the anti–PD-L1 agent durvalumab (Imfinzi, AstraZeneca), and chemotherapy reported a survival benefit compared with those who received chemotherapy alone, irrespective of KRAS, STK11, or KEAP1 mutational status.20The combination of sotorasib and PD-1 inhibition increases the infiltration of CD8+ T cells into the tumor microenvironment and confers a complete and durable response to the combined treatment in most models.21 In KRAS G12C–mutated mouse models, adagrasib reduces intratumor myeloid-derived suppressor cells and increases M1 macrophages, dendritic cells, and CD4+/CD8+ T cells, positively modulating the tumor microenvironment immune composition.22 These observations provided a strong biological rationale for combining KRAS G12C inhibitors and immune checkpoint inhibitors. The first data on the safety and efficacy of this combined approach came from the phase 1b CodeBreak 100/101 study.23 Overall, 58 NSCLC patients with KRAS G12C mutations received sotorasib in combination with either atezolizumab (Tecentriq, Genentech) or pembrolizumab (Keytruda, Merck). At a median follow-up of 12.8 months, confirmed responses were 29%, with a median duration of 17.9 months and a median OS of 15.7 months (95% CI, 9.8-17.8). Combination therapy resulted in a high rate of grade 3/4 toxicities, which were reported in 60% to 80% of patients and led to treatment discontinuation in approximately 50% of them. The incidence of hepatotoxicity was similar in checkpoint inhibitor–naive and –pretreated patients. Lowering the dose of sotorasib as well as making use of lead-in administration of sotorasib followed by combination treatment with pembrolizumab may be strategies to address this.23 Clinical trials combining either sotorasib or adagrasib with anti–PD-1/PD-L1 inhibitors are
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