Immune-Related Adverse Events Are Associated With Improved Outcomes After Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the first-line treatment of unresectable hepatocellular carcinoma (HCC). The prognostic value of immune-related adverse events (irAEs) in these patients remains controversial. We aimed to investigate the association between irAEs and clinical outcomes in patients with HCC treated with ICIs. METHODS: We searched the PubMed, Scopus, Web of Science, and Central Register of Controlled Trials databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was performed with a random effects model. RESULTS: Of 3,028 studies, 24 (4,127 patients) met the criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n = 10 studies). IrAEs were associated with an increased objective response rate (pooled relative ratio: 1.73; 95% confidence interval [CI]: 1.36–2.21, I 2 = 41%), a higher disease control rate (pooled relative ratio: 1.45; 95% CI: 1.21–1.74, I 2 = 74%), and longer progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52–0.84, I 2 = 71%). There was a trend toward longer overall survival for patients with irAEs compared with those without (pooled HR: 0.84; 95% CI: 0.63–1.12, I 2 = 73%). Subgroup analysis indicated a survival benefit for patients with grade 1–2 irAEs (pooled HR: 0.50; 95% CI: 0.36–0.67, I 2 = 0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48–0.83, I 2 = 12%). DISCUSSION: The development of irAEs is associated with favorable clinical outcomes in HCC, including improved progression-free survival and higher objective response rate. Overall survival benefit was noted in patients with mild irAEs but not those with severe irAEs.