Meta‐Analysis: Immune‐Related Adverse Events Are Associated With Improved Effectiveness of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

ABSTRACT Background While immune‐related adverse events (irAEs) have been linked to improved outcomes in melanoma and non‐small cell lung cancer (NSCLC), their prognostic role in hepatocellular carcinoma (HCC), a malignancy arising in a unique immune microenvironment shaped by chronic inflammation and cirrhosis, remains unexplored. This meta‐analysis investigated the relationship between irAEs and the effectiveness of immune checkpoint inhibitors (ICIs) in HCC. Methods Following PRISMA guidelines, we systematically reviewed studies from PubMed, Embase and the Cochrane Library (through December 2024) that evaluated the association between irAEs and ICIs' effectiveness in HCC. The primary outcomes were progression‐free survival (PFS) and overall survival (OS), and the secondary outcomes were objective response rate (ORR) and disease control rate (DCR). Subgroup analyses assessed irAEs' types, severity and corticosteroid impact. Results Among 24 retrospective studies (4798 patients), irAEs occurrence correlated with superior ORR (OR, 2.18; 95% CI, 1.64–2.89), DCR (OR, 3.09; 95% CI, 1.81–5.27), PFS (HR, 0.62; 95% CI, 0.51–0.75) and OS (HR, 0.76; 95% CI, 0.61–0.95). Dermatologic and endocrine irAEs were associated with improved survival (PFS: HR, 0.45 and 0.50; OS: HR, 0.51 and 0.59, respectively), while pulmonary, gastrointestinal and hepatobiliary irAEs did not show such relations. Low‐grade irAEs (Grades 1 and 2) were linked to better survival (PFS: HR, 0.47; OS: HR, 0.48), unlike high‐grade events. Corticosteroid use for irAEs management did not impair survival (PFS: HR, 0.97; OS: HR, 0.91). Conclusion irAEs, particularly dermatologic, endocrine and low‐grade events, were associated with improved ICIs' effectiveness in HCC. Early irAEs detection and corticosteroid management preserve survival benefits. However, more large‐scale prospective studies are needed to verify our findings.