First-line treatment of extensive-stage small cell lung cancer with immune checkpoint inhibitors acting on different targets: a systematic review and network meta-analysis.

Background: Incorporating immune checkpoint inhibitors (ICIs) into the platinum and etoposide regimen for extensive-stage small-cell lung cancer (ES-SCLC) has been established as the standard of care for first-line treatment. Currently, there is still no network meta-analysis (NMA) to evaluate the differences in efficacy and safety between ICIs targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death-ligand 1 (PD-L1). This Bayesian NMA aims to evaluate the differences in efficacy and safety among ICIs targeting CTLA-4, PD-1, and PD-L1 as first-line treatments for ES-SCLC. By providing an evidence-based framework, we seek to address existing clinical research gaps and guide the selection of optimal ICIs for future trials. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science to retrieve relevant randomized, controlled clinical trials (RCTs) published up to 16 February 2025. The key inclusion criteria are (I) histologically or cytologically confirmed ES-SCLC; (II) platinum-containing two-agent chemotherapy combined with only one ICI as first-line treatment for ES-SCLC; (III) phase II or III RCTs with results reporting hazard ratios (HR) and confidence intervals (CI) of at least one of progression-free survival (PFS) or overall survival (OS). The Markov Chain Monte Carlo method, implemented within the GEMTC and the JAGS package in R software, was used to conduct this NMA. Risk of bias assessment, heterogeneity testing, model reliability assessment, and sensitivity analyses were performed to ensure the robustness of the results. Results: Fifteen publications and 5,761 patients included in the final NMA are attributed to 13 clinical trials, of which 10 are phase III clinical trials, 3 are phase II clinical trials, 2 are clinical trials for CTLA-4 targets, 4 are clinical trials for PD-L1 targets, and 7 are clinical trials for PD-1 targets. Both the fixed effect modeling of the main and sensitivity analyses showed that CTLA-4 inhibitors (CTLA-4i) increased the risk of death compared with PD-1 inhibitors (PD-1i) [HR, 1.25 (95% CI: 1.06, 1.46)] and PD-L1 inhibitors (PD-L1i) [HR, 1.24 (95% CI: 1.05, 1.47)]. For PFS, objective response rate (ORR), and grade 3 or higher adverse events (≥grade 3 AEs), the main analyses and sensitivity analyses showed that no difference among CTLA-4i, PD-1i, and PD-L1i. Conclusions: CTLA-4i in combination with etoposide and platinum increased the risk of death compared to PD-1i/PD-L1i in combination with etoposide and platinum, which may be related to the timing of CTLA-4i application.