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

"Conflict of Interest Statement The authors have no conflicts of interest to declare."

"This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS,2021-I2M-1-066, 2017-I2M 4-002, 2021-I2M-1-019), the National Natural Science Foundation of China (81972311, 82141127, 31970794), the State Key Project on Infection Diseases of China (2017ZX10201021-007-003), the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2019PT310026), the Sanming Project of Medicine in Shenzhen (SZSM202011010), and the State Key Laboratory Special fund from the Ministry of Science (2060204). The funding sources did not participate in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript."

"This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement []. The study protocol was registered prospectively on PROSPERO (CRD42022319255). Two authors (Y. Z. and M. W.) independently performed the study selection and data extraction. All discrepancies were resolved by discussion with a third author (H. Z.) to reach a consensus. Summary: 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, p < 0.001; grade ≥3 OR = 9.35, 95% CI: 4.53–19.29, p < 0.001) and ICIs plus intravenous targeted agents (all-grade OR = 4.91, 95% CI: 1.80–13.42, p = 0.003; grade ≥3 OR = 4.21, 95% CI: 1.42–12.48, p = 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%."