Safety Profiles of Immune Checkpoint Inhibitor Strategies in Gastrointestinal Cancers and Their Association With Clinical Outcomes: A Systematic Review and Meta‐Analysis
- 1Zhongshan Hospital, Fudan University
- 2School of Public Health, Fudan University
Abstract
Background Immune checkpoint inhibitors (ICIs) are increasingly used in patients with gastrointestinal cancer (GIC). However, ICI‐associated adverse event (AE) profiles in GIC remain poorly characterized, and whether AE incidence is associated with clinical outcomes is unclear. Methods Randomized controlled trials (RCTs) were identified through February 2025. Primary outcomes included treatment‐related AEs (TRAEs) and immune‐related AEs (irAEs) (any grade/Grade 3+). Single‐arm random‐effects meta‐analysis pooled AE incidences; risk ratios (RRs) compared toxicity across ICI regimens. Digitized Kaplan–Meier curves reconstructed survival data for pooled analysis and Cox models. Weighted Spearman's tests assessed correlations between AE incidences and median overall survival (OS)/progression‐free survival (PFS). Results Forty RCTs enrolling 10,233 patients investigated ICI monotherapy, dual‐ICI therapy, and ICI combination regimens. Pooled any‐grade TRAE incidences were 68.0% (monotherapy, 95% CI: 60%–76%, I2 = 97.4%, p < 0.001), 87.0% (dual therapy, 95% CI: 73%–100%, I2 = 98.0%, p < 0.001), and 90.0% (combination therapy, 95% CI: 83%–96%, I2 = 94.6%, p < 0.001). IrAE incidences reached 24.0% (monotherapy, 95% CI: 18%–29%, I2 = 67.2%, p < 0.05) and 37.0% (combination therapy, 95% CI: 25%–49%, I2 = 98.8%, p < 0.001). Relative to monotherapy, dual‐ICI therapy elevated any‐grade (RR = 1.28, 95% CI: 1.05–1.55) and grade ≥ 3 TRAEs (RR = 2.71, 95% CI: 1.84–3.99); ICI combination therapy increased any‐grade (RR = 1.32, 95% CI: 1.15–1.51) and grade ≥ 3 TRAEs (RR = 2.98, 95% CI: 2.30–3.87). Any‐grade TRAEs moderately correlated with median OS (R = 0.46, p < 0.001) and PFS (R = 0.50, p < 0.001). Any‐grade irAEs strongly correlated with median OS (R = 0.90, p < 0.001) and moderately with PFS (R = 0.57, p < 0.001). Conclusion While AE incidence is high among GIC patients receiving ICIs, most events are low‐grade. Dual‐ICI and ICI‐based combination therapies carry higher TRAE and irAE risks than monotherapy. At the trial level, higher non‐severe irAE incidence correlated with favorable survival outcomes; this exploratory ecological association does not apply to individual patients. Systematic Review Registration This study was registered on International Platform of Registered Systematic Review and Meta‐analysis Protocols (INPLASY202230144).
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BibTeX
@article{lei2026safety,
title = {{Safety Profiles of Immune Checkpoint Inhibitor Strategies in Gastrointestinal Cancers and Their Association With Clinical Outcomes: A Systematic Review and Meta‐Analysis}},
author = {Jing Lei and Yiyi Yu and Qing Liu and Ningping Zhang and Yi Wang and Yating Yang and Tianshu Liu and Minzhi Lv},
journal = {Cancer medicine},
year = {2026},
month = oct,
doi = {10.1002/cam4.72357},
url = {https://europepmc.org/article/PMC/PMC13673127},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Safety Profiles of Immune Checkpoint Inhibitor Strategies in Gastrointestinal Cancers and Their Association With Clinical Outcomes: A Systematic Review and Meta‐Analysis
AU - Jing Lei
AU - Yiyi Yu
AU - Qing Liu
AU - Ningping Zhang
AU - Yi Wang
AU - Yating Yang
AU - Tianshu Liu
AU - Minzhi Lv
PY - 2026
DA - 2026/10/01
JO - Cancer medicine
DO - 10.1002/cam4.72357
UR - https://europepmc.org/article/PMC/PMC13673127
AB - Background Immune checkpoint inhibitors (ICIs) are increasingly used in patients with gastrointestinal cancer (GIC). However, ICI‐associated adverse event (AE) profiles in GIC remain poorly characterized, and whether AE incidence is associated with clinical outcomes is unclear. Methods Randomized controlled trials (RCTs) were identified through February 2025. Primary outcomes included treatment‐related AEs (TRAEs) and immune‐related AEs (irAEs) (any grade/Grade 3+). Single‐arm random‐effects meta‐analysis pooled AE incidences; risk ratios (RRs) compared toxicity across ICI regimens. Digitized Kaplan–Meier curves reconstructed survival data for pooled analysis and Cox models. Weighted Spearman's tests assessed correlations between AE incidences and median overall survival (OS)/progression‐free survival (PFS). Results Forty RCTs enrolling 10,233 patients investigated ICI monotherapy, dual‐ICI therapy, and ICI combination regimens. Pooled any‐grade TRAE incidences were 68.0% (monotherapy, 95% CI: 60%–76%, I2 = 97.4%, p < 0.001), 87.0% (dual therapy, 95% CI: 73%–100%, I2 = 98.0%, p < 0.001), and 90.0% (combination therapy, 95% CI: 83%–96%, I2 = 94.6%, p < 0.001). IrAE incidences reached 24.0% (monotherapy, 95% CI: 18%–29%, I2 = 67.2%, p < 0.05) and 37.0% (combination therapy, 95% CI: 25%–49%, I2 = 98.8%, p < 0.001). Relative to monotherapy, dual‐ICI therapy elevated any‐grade (RR = 1.28, 95% CI: 1.05–1.55) and grade ≥ 3 TRAEs (RR = 2.71, 95% CI: 1.84–3.99); ICI combination therapy increased any‐grade (RR = 1.32, 95% CI: 1.15–1.51) and grade ≥ 3 TRAEs (RR = 2.98, 95% CI: 2.30–3.87). Any‐grade TRAEs moderately correlated with median OS (R = 0.46, p < 0.001) and PFS (R = 0.50, p < 0.001). Any‐grade irAEs strongly correlated with median OS (R = 0.90, p < 0.001) and moderately with PFS (R = 0.57, p < 0.001). Conclusion While AE incidence is high among GIC patients receiving ICIs, most events are low‐grade. Dual‐ICI and ICI‐based combination therapies carry higher TRAE and irAE risks than monotherapy. At the trial level, higher non‐severe irAE incidence correlated with favorable survival outcomes; this exploratory ecological association does not apply to individual patients. Systematic Review Registration This study was registered on International Platform of Registered Systematic Review and Meta‐analysis Protocols (INPLASY202230144).
SN - 2045-7634
ER -