Immune-related adverse events are associated with favorable clinical outcomes in esophageal cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis
TL;DR
In patients with EC receiving ICIs, the occurrence of irAEs may be a prognostic marker of favorable outcomes, however, wide PIs for PFS and ORR indicate that these associations may vary across future studies and immortal time bias may overestimate survival associations.
Abstract
Introduction Immune-related adverse events (irAEs) are distinctive toxicities associated with immune checkpoint inhibitors (ICIs) and have been reported to correlate with clinical outcomes in several cancers. However, whether this association also exists in patients with esophageal cancer (EC) receiving ICIs remains uncertain. This systematic review and meta-analysis aimed to evaluate the association between irAEs and clinical outcomes in this population. Methods This systematic review and meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to March 2, 2026. Eligible studies evaluated the association between irAEs and progression-free survival (PFS), overall survival (OS), objective response rate (ORR), or disease control rate (DCR). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled for PFS and OS, whereas odds ratios (ORs) with 95% CIs were pooled for ORR and DCR using random-effects models. Between-study heterogeneity, 95% prediction intervals (PIs), sensitivity analyses, publication bias, prespecified subgroup analyses, and immortal-time bias were also assessed. Results 14 studies involving 1, 546 patients were included. The occurrence of irAEs was associated with improved PFS (HR, 0.45; 95% CI, 0.31-0.63), OS (HR, 0.54; 95% CI, 0.46-0.64), ORR (OR, 4.00; 95% CI, 1.58-10.12), and DCR (OR, 3.85; 95% CI, 2.40-6.20). The 95% PIs were 0.16-1.24, 0.44-0.66, 0.19-82.57, and 1.42-10.44 for PFS, OS, ORR, and DCR, respectively, crossing the null value for PFS and ORR. Subgroup estimates were generally similar in direction but remained exploratory. No eligible survival estimates using landmark or time-varying approaches were available for the comparison between patients with and without irAEs. Conclusions In patients with EC receiving ICIs, the occurrence of irAEs may be a prognostic marker of favorable outcomes. However, wide PIs for PFS and ORR indicate that these associations may vary across future studies and immortal time bias may overestimate survival associations. This observational evidence derives mainly from East Asian patients with esophageal squamous cell carcinoma and is primarily applicable to these patients. Subgroup findings remain exploratory and require prospective validation. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD420261346294.