Phase III meta-analysis of first-line chemo-immunotherapy in ES-SCLC: Survival benefit without detectable class-level...

PD-1/PD-L1 inhibitors plus platinum-etoposide are standard first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC), but the consistency of benefit across trials and potential PD-1 versus PD-L1 class differences remain debated. We conducted an updated systematic review and meta-analysis of phase III trials in untreated ES-SCLC.

MEDLINE, Scopus, and Cochrane CENTRAL were searched through 11 February 2026 for phase III randomized trials comparing platinum-etoposide plus a PD-1/PD-L1 inhibitor versus platinum-etoposide alone. OS and PFS hazard ratios (HRs) were pooled using random-effects (REML). A pre-specified meta-regression tested PD-1 versus PD-L1 class effect (ratio of HRs). Safety endpoints were synthesized using risk ratios (RRs). RoB 2 and GRADE were applied.

Six trials (n = 2,897) were included. Chemo-immunotherapy improved OS (HR 0.74, 95% CI 0.67-0.81; I² = 0%) and PFS (HR 0.68, 95% CI 0.58-0.78; I² = 65.6%). No statistically detectable difference between PD-1 and PD-L1 inhibitor classes was identified for OS (ratio of HRs 1.01, 95% CI 0.85-1.21; p = 0.89) or PFS (0.83, 0.64-1.09; p = 0.18). Grade ≥ 3 treatment-related adverse events were not increased (RR 1.01, 0.96-1.06), while immune-mediated adverse events were more frequent (RR 2.39, 1.61-3.54) with substantial heterogeneity. Certainty was high for OS, low for PFS, and moderate-to-very low for safety.

Adding a PD-1/PD-L1 inhibitor to platinum-etoposide in first-line ES-SCLC provides a consistent overall survival benefit, with no statistically detectable differences between PD-1 and PD-L1 inhibitor classes. This finding should be interpreted as absence of detectable class-level divergence rather than pharmacologic equivalence.