Comparative efficacy of immune checkpoint inhibitor backbones in <i>STK11/KEAP1</i> -mutant advanced non–small cell lung cancer: A systematic review and meta-analysis.

Abstract

e20640 Background: Immunotherapy is a cornerstone of treatment for advanced non–small cell lung cancer (NSCLC), though efficacy varies by genomic context. Mutations in STK11 and KEAP1 are associated with immune resistance and poor outcomes, while co-occurring KRAS G12C mutations or higher tumor mutational burden (TMB) may influence response. Multiple immune checkpoint inhibitor (ICI) backbones are used, but their comparative efficacy in STK11/KEAP1-mutant NSCLC remains unclear. We performed a systematic review and meta-analysis to compare outcomes across ICI strategies and molecular subgroups. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science for randomized trials and comparative observational studies evaluating ICI-based regimens in advanced NSCLC with STK11 and/or KEAP1 mutations. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included response rates and toxicity. Random-effects meta-analyses pooled log-transformed hazard ratios (HRs) using an inverse-variance DerSimonian-Laird model, with heterogeneity assessed by I². Prespecified subgroup analyses examined the treatment backbone, mutation profile, and TMB (as available). Analyses were performed in R. Results: Twenty-five studies encompassing 13,065 patients were identified; seven studies (n = 7,467) contributed to the meta-analysis. Most studies showed male predominance. Patients predominantly had non-squamous NSCLC (largely adenocarcinoma), were treated primarily in the first-line setting, and had reported genomic alterations, with primary emphasis on STK11 and KEAP1 mutations. Compared to chemotherapy alone, chemoimmunotherapy improved OS (pooled HR 0.79; 95% CI, 0.70–0.89; I² = 9.8%) and PFS (HR 0.71; 95% CI, 0.63–0.80; I² = 0%). Dual ICI plus chemotherapy yielded similar benefits (OS HR 0.75; 95% CI, 0.67–0.84; PFS HR 0.71; 95% CI, 0.63–0.80). Mutation-specific analyses revealed inferior outcomes in STK11-mutant versus wild-type tumors (pooled PFS HR 1.46; OS HR 1.57). Median OS and PFS varied substantially across regimens. PD-L1 expression and TMB were inconsistently reported and could not be pooled. Toxicities were primarily hematologic and constitutional; serious immune-mediated events and treatment-related mortality remained uncommon. Conclusions: In advanced NSCLC harboring STK11 and/or KEAP1 mutations, intensified ICI backbones, particularly chemoimmunotherapy and dual ICI plus chemotherapy, provide survival benefits over chemotherapy alone, mitigating the adverse prognostic impact of STK11 mutations. These results support prioritizing combination ICI strategies in this high-risk subgroup and highlight the need for prospective, genomically stratified trials with standardized TMB assessment to refine treatment selection.