Systematic review and meta-analysis of phase 3 RCTs of first-line chemoimmunotherapy versus PD-(L)1 inhibitor monotherapy for advanced NSCLC with high PD-L1 expression

For patients with advanced non-small cell lung cancer (aNSCLC) and PD-L1 expression of 50% or higher, PD-(L)1 inhibitor monotherapy is commonly used as first-line therapy. Systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) published before August 3, 2025 evaluated addition of chemotherapy in this population. Among 24 trials including 5546 patients with untreated aNSCLC, 16 evaluated chemoimmunotherapy and 8 evaluated PD-(L)1 inhibitor monotherapy. Compared with chemotherapy alone, survival was improved by both chemoimmunotherapy (OS: HR 0.63; 95% CI 0.56-0.72; PFS: 0.44; 0.39-0.49) and PD-(L)1 inhibitor monotherapy (OS: 0.74; 0.69-0.80; PFS: 0.70; 0.65-0.76). Tests for subgroup differences suggested improved benefit with chemoimmunotherapy compared to PD-(L)1 inhibitor monotherapy, consistent with meta-regression analysis (OS: HR 0.85; 95% CI 0.72-1.00; PFS: 0.61; 0.50-0.75) and network meta-analyses (OS: 0.85; 0.73-0.99; PFS: 0.61; 0.50-0.75). In a reconstructed individual patient data analysis, median OS and PFS were longer with chemoimmunotherapy (29.2 months and 11.3 months, respectively) than with PD-(L)1 inhibitor monotherapy (19.8 months and 6.8 months, respectively). The authors conclude that first-line chemoimmunotherapy was associated with significantly improved OS and PFS compared with PD-(L)1 inhbitor monotherapy in patients with aNSCLC and high PD-L1 expression.