Efficacy and safety of first-line immunotherapy-based regimens for patients with extensive-stage small cell lung cancer: a systematic review and network meta-analysis.

Background: Combination regimens of immunotherapy plus chemotherapy have been approved as the first-line and standard of care for extensive-stage small cell lung cancer (ES-SCLC). Novel regimens are continuously being explored, with the ETER701 study being the representative randomized controlled trial (RCT). ETER701 study has assessed the efficacy and safety of chemotherapy with or without anlotinib (multi-target angiogenesis inhibitor) + benmelstobart (programmed cell death ligand 1 inhibitor) (Anl/Ben/CT). There is no evidence-based medicine available proving that Anl/Ben/CT is the optimal regimen due to the lack of direct or indirect comparisons among varying immunotherapy-based regimens. In this study, we aimed to identify the optimal regimen to assist in clinical decision-making. Methods: The eligible RCTs were identified by searching PubMed, Embase, Cochrane Library databases, and major international conferences. Then, the network meta-analysis was analyzed to compare the efficacy and safety among 15 first-line regimens in ES-SCLC. The Cochrane Risk of Bias Tool was used to assess the risk of bias in included studies. Results: A total of 12 immunotherapy-related RCTs covering 15 interventions and 6,178 patients with ES-SCLC were included. Overall, most RCTs exhibited a low risk of bias across multiple domains. The results indicated that most immunotherapy-based regimens could significantly prolong progression-free survival (PFS) compared with chemotherapy alone, especially Anl/Ben/CT [hazard ratio (HR) 0.32, 95% confidence interval (CI): 0.25-0.40]. Similar results were observed regarding overall survival (OS), that is, most immunotherapy-related regimens dramatically reduced the risk of death in ES-SCLC, with Anl/Ben/CT being the most prominent (HR 0.61, 95% CI: 0.47-0.80). The Bayesian ranking probabilities showed that Anl/Ben/CT ranked first and serplulimab plus chemotherapy ranked second in both PFS and OS among 15 regimens. Regarding safety, Anl/Ben/CT ranked 3rd, and serplulimab plus chemotherapy ranked 7th. Conclusions: Adding anlotinib and benmelstobart to chemotherapy significantly improved PFS and OS compared with chemotherapy alone or chemotherapy plus immunotherapy, with an acceptable safety profile in patients with ES-SCLC. In conclusion, Anl/Ben/CT could be a new, preferable first-line treatment option but further clinical studies are needed to validate its efficacy and safety.