First-Line Dual Immune Checkpoint Inhibition with PD-1/PD-L1 and CTLA-4 Blockade for Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Although immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), the optimal first-line combination strategy remains uncertain. This systematic review and meta-analysis evaluated the efficacy and safety of first-line PD-1/PD-L1 inhibitors in combination with CTLA-4 inhibitors for the treatment of advanced NSCLC. Five databases were searched up to September 2025, identifying ten randomized controlled trials involving 6,565 patients, which were deemed to have an overall low risk of bias. Dual immune checkpoint blockade (ICB) was found to significantly improve overall survival (OS; hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.76–0.93) compared with chemotherapy, but showed no significant benefit in progression-free survival (PFS; HR 0.96, 95% CI 0.87–1.06) or objective response rate (ORR; odds ratio [OR] 1.15, 95% CI 0.95–1.40). However, when combined with chemotherapy, CP significantly improved OS (HR 0.73, 95% CI 0.67–0.80), PFS (HR 0.70, 95% CI 0.63–0.77) and ORR (OR 1.85, 95% CI 1.53–2.23). There was a greater PFS benefit in patients with PD-L1 expression of at least 50% (HR 0.63, 95% CI 0.49–0.81). CP showed no overall differences in OS, PFS or ORR compared with PD-1/PD-L1 inhibitor monotherapy, but provided superior OS benefits in the PD-L1 <1% subgroup. Overall, there was low to moderate heterogeneity, which supports the robustness of the findings and suggests that first-line CP, particularly when combined with chemotherapy, is a feasible and promising treatment option for selected patients with advanced NSCLC.