BackgroundDespite numerous immunotherapy and chemotherapy regimens available for patients with extensive-stage small cell lung cancer (ES-SCLC), it remains unclear which regimen is the most effective and safest; relative studies comparing such regimens are scarce.ObjectiveThe aim of this study was to investigate the efficacy and safety of first-line immunotherapy combinations with chemotherapy for patients with extensive-stage small cell lung cancer. In addition, for the first time, comparisons among the first-line systemic regimens on OS and PFS in ES-SCLC by each time node were made.MethodsDatabases including PubMed, Embase, Cochrane Library, Scopus, Google Scholars, and ClinicalTrials.gov, and major international conferences were searched for randomized controlled trials (RCTs) regarding comparing immunotherapy combinations with chemotherapy as first-line treatments for patients with advanced ES-SCLC from inception to 1 November. Hazard ratios (HRs) and odds ratios (ORs) were generated for dichotomous variants by RStudio 4.2.1. The outcomes comprised overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (Grade ≥ 3 AEs).ResultsEventually, a total of nine RCTs reporting 4,352 individuals with nine regimens were enrolled. The regimens were ipilimumabnu (Ipi), atezolizumab (Atez), durvalumab plus tremelimumab (Durv-Trem), durvalumab (Durv), pembrolizumab (Pemb), adebrelimab (Adeb), serplulimab (Serp), atezolizumab plus tiragolumab (Atez-Tira), and nivolumab (Nivo). With regard to OS, serplulimab (HR = 0.63, 95% CI: 0.49 to 0.81) was found to yield the best OS benefit when compared with chemotherapy. Meanwhile, serplulimab had the highest probability (46.11%) for better OS. Furthermore, compared with chemotherapy, serplulimab significantly increased the OS rate from the 6th to the 21st month. With regard to PFS, serplulimab (HR = 0.47, 95% CI: 0.38 to 0.59) was found to yield the best PFS benefit when compared with chemotherapy. Simultaneously, serplulimab had the highest probability (94.48%) for better PFS. Serplulimab was also a long-lasting first-line regimen in both OS and PFS from a longitudinal perspective. In addition, there was no significant difference among the various treatment options for ORR and grade ≥3 AEs.ConclusionConsidering OS, PFS, ORR, and safety profiles, serplulimab with chemotherapy should be recommended as the best therapy for patients with ES-SCLC. Certainly, more head-to-head studies are needed to confirm these findings.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022373291.