Efficacy of PD-1/PD-L1 plus CTLA-4 inhibitors in advanced/metastatic NSCLC: a meta-analysis based on RCTs

Background: Dual immune checkpoint inhibitor (ICI) therapy (PD-1/PD-L1+CTLA-4 inhibitors) has emerged as a promising strategy, but its efficacy and optimal patient selection remain uncertain. This meta-analysis aimed to evaluate the efficacy of dual ICI therapy in advanced/metastatic non-small cell lung cancer (NSCLC) based on randomized controlled trials (RCTs). Methods: We systematically searched Cochrane Library, Embase, Web of Science, and PubMed from inception to August 2025 for RCTs comparing dual ICI therapy (PD-1/PD-L1+CTLA-4 inhibitors) versus control treatments in advanced/metastatic NSCLC. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Results: Ten RCTs comprising 6,369 patients were included. The OS (HR = 0.84, 95%CI 0.76-0.92, p=0.003) and PFS (HR = 0.78, 95%CI 0.68-0.89, p=0.002) of patients who received dual ICI treatment were significantly better than those in the control group. Subgroup analyses of the OS revealed significant benefits, including: squamous, non-squamous, PD-1 inhibitor, PD-L1 inhibitor, bone metastases, without bone metastases, male, age<65, ECOG = 0, Asian, PD-L1 TPS<1%, PD-L1 TPS≥50%, with high TMB (TMB≥10 or TMB≥20), smokers, brain metastases, without liver metastases, and when the control group received chemotherapy, placebo, first-line (1L) or non 1L (all p<0.05). Conversely, no significant benefit was observed in patients aged≥65, low TMB (TMB<10 or TMB<20), non-smokers, without brain metastases, or when the control group received monotherapy immunotherapy (all p>0.05 and P_interaction <0.05). Conclusion: Dual ICI therapy with PD-1/PD-L1 plus CTLA-4 inhibitors improves prognosis in advanced/metastatic NSCLC, with efficacy difference across subgroups. TMB may serve as a complementary predictive biomarker for dual immunotherapy. Systematic review registration: PROSPERO, identifier: CRD420251147483.