Overall survival with immune checkpoint inhibitors across treatment settings and clinical and PD-L1-defined subgroups in advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis of randomized trials.

Introduction: To quantify overall-survival effects of immune-checkpoint-inhibitor (ICI)-containing regimens by treatment line and to evaluate whether clinical characteristics or PD-L1 definitions modify relative treatment benefit in advanced esophageal squamous cell carcinoma (ESCC). Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception through 1 August 2026. Two reviewers independently screened records, assessed full texts, extracted data, and evaluated risk of bias. Reports were linked to their parent randomized trial family. First-line single-checkpoint blockade plus chemotherapy and later-line checkpoint monotherapy were synthesized separately using REML random-effects models and modified Hartung-Knapp inference. Treatment-effect modification was quantified using within-trial ratios of hazard ratios (RHRs). Twenty-one interactions with at least two independent trial families entered Holm correction; Bonferroni correction was used as a sensitivity analysis. Results: We identified 14 independent randomized trial families represented by 31 reports. The primary overall-survival analysis included 7 first-line trials ( Discussion: ICI-containing regimens improved overall survival in both first- and later-line settings, but aggregate within-trial interaction analyses did not identify a reliable clinical or PD-L1-defined treatment-effect modifier. Sparse subgroup reporting and the predominantly Asian evidence base limit the precision and generalizability of these findings. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551725.