Efficacy and safety of first-line immune checkpoint inhibitors combinations for extensive-stage small-cell lung cancer: A systematic review and network meta-analysis

Abstract

Background: Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a major clinical research focus. Patients with extensive-stage small-cell lung cancer (ES-SCLC) have been treated with different first-line ICI combinations in randomized controlled trials (RCTs), but the optimal combination strategy has not yet been determined. Our aim was to evaluate this strategy through a systematic review and meta-analysis. Methods: Articles published from inception to October 20, 2024 were systematically searched in PubMed, Cochrane CENTRAL, Embase, and MEDLINE. Candidates were RCTs using ICI treatments as first-line treatment for ES-SCLC. According to PRISMA guidelines, 3 independent investigators extracted data. Hazard/odds ratios (HRs/ORs) with their 95% confidence intervals (CIs) and adverse event (AEs) were extracted. ICI combinations were compared for overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and AEs. A random-effects model and Bayesian network meta-analysis were used. PROSPERO: CRD42023388838. Results: The meta-analysis included 8 RCTs with 3910 patients. Overall, ICI-chemotherapy provided superior OS (HR, 0.78; 95% CI, 0.72 to 0.86), PFS (HR, 0.73; 95% CI, 0.64 to 0.82), ORR (OR, 1.20; 95% CI, 1.01 to 1.42) and DCR (OR, 2.64; 95% CI, 1.32 to 5.24) compared with chemotherapy alone. A higher risk of any grade irAEs (OR, 3.88; 95% CI, 2.09 to 7.18) and grade ≥ 3 irAEs (OR, 5.54; 95% CI, 2.38 to 12.88) was associated with ICI addition. ICI-chemotherapy combinations did not differ significantly in OS, PFS, ORR, DCR, or safety. In the Bayesian ranking analysis, the PD-1 inhibitor–based regimens Serplu-EP and Nivo-EP achieved the highest efficacy rankings; Serplu-EP ranked first for both OS and PFS, followed by Nivo-EP. Efficacy and safety were effectively balanced in Serplu-EP and Adebre-EP. Similar results were shown in subgroup analyses. Conclusion: First-line ICI-chemotherapy combinations improved survival outcomes but increased the risk of irAEs, with no significant differences in efficacy or safety among ICI-chemotherapy combinations. Among the evaluated regimens, the PD-1 inhibitor–based Serplu-EP and Nivo-EP achieved the highest efficacy rankings, whereas Serplu-EP and Adebre-EP appeared to provide the most favorable efficacy-safety balance. Further head-to-head trials are warranted to confirm the optimal first-line ICI strategy for ES-SCLC.