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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.