Efficacy and tolerability of first-line treatment regimens for extensive-stage small cell lung cancer – a grade-assessed network meta-analysis of randomized controlled trials

The treatment landscape for extensive-stage small-cell lung cancer (ES-SCLC) has advanced with the introduction of immunotherapy, targeted therapy, and novel chemotherapy combinations. A comprehensive evaluation of safety and efficacy across these treatments remains essential. This study aimed to compare the outcomes of all first-line treatment regimens for ES-SCLC. A systematic literature search of PubMed, Scopus, and Web of Science databases was conducted from inception to June 2025 to identify randomized controlled trials evaluating first-line treatments for ES-SCLC (CRD42024543408). Etoposide plus platinum (EP), the standard regimen, was used as the reference treatment. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR) and adverse events (AEs). Hazard ratios (HR) were used for survival outcomes, and risk ratios (RR) for efficacy outcomes. A frequentist network meta-analysis was performed using the Netmeta R package (v2.9-0). Risk of bias was assessed using the Cochrane risk of bias tool v2, and certainty of evidence was evaluated according to GRADE guidelines. This analysis included 34 studies with 10,658 participants and 22 treatment regimes. For OS, immunotherapy-based regimens such as Serplulimab + EP (HR = 0.63, 95% CI: 0.44–0.90, p = 0.01), Atezolizumab + EP (HR = 0.70, 95% CI: 0.49–1.00, p = 0.05), and Durvalumab + EP (HR = 0.71, 95% CI: 0.53–0.96, p = 0.02) showed significant improvements compared to EP. For PFS, Serplulimab + EP provided the greatest benefit (HR = 0.48, 95% CI: 0.31–0.75, p = 0.0012). Irinotecan + platinum was the only regimen to significantly improve the complete response rate (CRR) (RR = 1.91, 95% CI: 1.06–3.46, p = 0.03). Safety outcomes varied: Atezolizumab + EP and Tiragolumab + Atezolizumab + EP demonstrated lower risks of treatment discontinuation, while regimens such as Ipilimumab + EP and Tislelizumab + EP were associated with increased risks of serious AEs. Heterogeneity was generally low, with moderate variability observed for PFS and AEs leading to discontinuation. Immunotherapy-based combinations, particularly Serplulimab + EP, demonstrated improved survival outcomes while maintaining an acceptable safety profile in most cases. However, some regimens showed increased AE risks. Future research should prioritize long-term outcomes and focus on balancing efficacy and tolerability to optimize therapeutic strategies.