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

<b><i>Background:</i></b> The aim of the study was 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. <b><i>Summary:</i></b> 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. The literature search identified 2,464 records. Twenty studies (4,146 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, <i>p</i> &#x3c; 0.001; grade ≥3 OR = 9.35, 95% CI: 4.53–19.29, <i>p</i> &#x3c; 0.001) and ICIs plus intravenous targeted agents (all-grade OR = 4.91, 95% CI: 1.80–13.42, <i>p</i> = 0.003; grade ≥3 OR = 4.21, 95% CI: 1.42–12.48, <i>p</i> = 0.012) were associated with increased trAEs compared with monotherapy. The all-grade trAEs with the highest pooled incidences were reactive capillary endothelial proliferation (49.2%, 95% CI: 26.3–72.3), neutropenia (34.6%, 95% CI: 17.1–57.5), and proteinuria (32.8%, 95% CI: 19.8–49.2). The grade ≥3 trAEs with the highest pooled incidences were hypertension (11.1%, 95% CI: 4.0–29.0), neutropenia (10.5%, 95% CI: 7.0–15.4), and increased aspartate aminotransferase (7.7%, 95% CI: 6.3–9.4). The pooled incidence of trAEs leading to treatment discontinuation was 8.0% (95% CI: 6.0–10.5), and the overall incidence of treatment-related mortalities was 1.1%. <b><i>Key Messages:</i></b> This study comprehensively summarized the incidence and spectrum of trAEs in unresectable HCC patients receiving ICIs or ICI-based combinations in clinical trials. The results from this study will provide a useful reference to guide clinical practice.