Supplementary Material for: Adverse Events of Immune Checkpoint Inhibitor-Based Therapies for Unresectable Hepatocellular Carcinoma in Prospective Clinical Trials: A Systematic Review and Meta-analysis

Introduction: To investigate the incidence and spectrum of adverse events in unresectable hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs) or ICI-based combinations. Methods: The study protocol was prospectively registered on PROSPERO (CRD42022319255). We searched PubMed, EMBASE, and the Cochrane Library for published clinical trials from database inception to April 22, 2022. Studies that included at least one group of unresectable HCC patients treated with ICIs or ICI-based combinations and reported the incidence or spectrum of treatment-related adverse events (trAEs) or immune-related adverse events (irAEs) were eligible. The incidence and spectra of all-grade and grade ≥3 trAEs were the primary outcomes. The profiles of irAEs, the incidence of trAEs leading to treatment discontinuation, and treatment-related mortalities were additional outcomes. We applied random-effects models to pool the incidence and spectra of adverse events. Subgroup analyses and meta-regression were performed. Results: The literature search identified 2464 records. Twenty studies (4146 participants with HCC) met the eligibility criteria. The pooled incidences of all-grade trAEs, grade ≥3 trAEs, all-grade irAEs, and grade≥3 irAEs were 80.1% (95% CI 73.8-85.2), 35.4% (95% CI 27.2-44.6), 31.1% (95% CI 21.0-43.5), and 6.6% (95% CI 3.6-11.8), respectively. ICIs plus oral targeted agents (all-grade OR=17.07, 95% CI 6.05-48.16, P<0.001; grade ≥3 OR=9.35, 95% CI 4.53-19.29, P