Background <p>In the randomized phase 3 ASTRUM-005 trial, adding serplulimab to chemotherapy improved survival in extensive-stage small cell lung cancer (ES-SCLC), but whether these results generalize to routine practice remains uncertain. To evaluate the real-world effectiveness and safety of first-line serplulimab plus chemotherapy in China and to benchmark outcomes against the pivotal trial using a matching-adjusted indirect comparison (MAIC).</p> Methods <p>This nationwide, observational study enrolled ES-SCLC patients treated with serplulimab and investigator-selected chemotherapy across 14 sites in China. For subsequent analyses, patients were grouped by alignment with the ASTRUM-005 trial regimen: an RCT-regimen cohort and a real-world regimen cohort. The primary endpoints were overall survival (OS) and real-world progression-free survival (rwPFS); secondary endpoints included objective response rate (ORR) and safety. The MAIC weighted eligible real-world patients to the aggregate baseline profile of the pivotal trial.</p> Results <p>Among 635 patients, the median OS was 17.20 months (95% CI, 15.43–19.77) and the median rwPFS was 8.17 months (95% CI, 7.40–9.20). The ORR was 69.05%, with comparable efficacy observed between RCT-regimen and real-world cohorts. Poor performance status and liver metastases independently predicted higher mortality. In the MAIC, OS in the RCT-regimen cohort was comparable to the serplulimab arm of the pivotal ASTRUM-005 trial (weighted log-rank <i>P</i> = 0.784). Safety was manageable and consistent with known profiles.</p> Conclusions <p>This large-scale real-world study confirms the efficacy of serplulimab plus chemotherapy and tolerability in diverse ES-SCLC population, supporting the external validity and generalizability of the pivotal ASTRUM-005 trial results.</p> Clinical trial registration <p>ClinicalTrials.gov (NCT06748495).</p>