Comparative safety of immune checkpoint inhibitor combined with chemotherapy as first-line treatment for solid tumors: a systematic review and network meta–analysis

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Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become standard first-line treatment for multiple solid tumors, yet their safety profiles vary across therapeutic agents and tumor types. This systematic review and network meta-analysis (NMA) compared the safety of ICI plus chemotherapy regimens across multiple solid tumor types. We systematically searched PubMed, Embase, and Web of Science for eligible phase III randomized controlled trials (RCTs) published between January 1, 2015, and August 5, 2026, that evaluated first-line ICI plus chemotherapy regimens in advanced solid tumors. The primary outcome was the grade ≥ 3 immune-related adverse events (irAEs). The risk of bias was assessed using the Cochrane Risk of Bias 2 tool. An NMA was performed estimating odds ratios (ORs) with 95% credibility intervals (CrI) and ranking regimens using Bayesian ranking probabilities. A total of 58 phase III RCTs were included, comprising 36,664 patients and regimens combining chemotherapy with 20 distinct ICIs across multiple tumor types. For grade ≥ 3 irAEs, 17 ICI–chemotherapy regimens were analyzed, with adebrelimab plus chemotherapy ranking the most favorably based on cumulative ranking probabilities and achieving the highest the surface under the cumulative ranking curve value (76.27%); pooled OR versus placebo plus chemotherapy of 1.62 (95% CrI 0.28–9.83). Avelumab plus chemotherapy ranked highest for all-grade irAEs and all-grade treatment-related adverse events (TRAEs). Durvalumab- and penpulimab-based regimens showed favorable safety profiles for grade ≥ 3 TRAEs. This study identifies clinically meaningful differences in safety profiles among ICI plus chemotherapy regimens across multiple solid tumors, providing comparative evidence that may aid in optimizing regimen selection from a safety perspective.

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