Association between immune-related adverse events and prognosis after immune checkpoint inhibitor in hepatocellular carcinoma: A meta-analysis and systematic review.

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Background: Immune checkpoint inhibitors (ICIs) have become the preferred treatment for unresectable hepatocellular carcinoma (HCC). Conflicting data exist regarding the prognostic value of immune-related adverse events (irAEs) in these patients. We aimed to explore potential the association between irAEs and prognosis in HCC patients treated with ICIs. Methods: We searched PubMed, Scopus, Web of Science, and CENTRAL databases for articles published from inception to June 2024 using keywords including ICI, HCC, and irAEs. Two reviewers independently screened studies for eligibility and relevant data. A random effects model was used for statistical analysis, and subgroup analysis was performed by the grade of irAEs. Results: Of 3,028 studies, 25 (n=4,116 patients) met criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n=10 studies). About half (49.5%) of patients experienced irAEs. irAEs were associated with increased objective response rate (ORR) (pooled OR: 1.72; 95% CI: 1.36 – 2.19, I ² =39%), higher complete response rate (pooled OR: 1.45; 95% CI: 1.21-1.74, I ² =74%), and longer progression-free survival (PFS) (pooled HR: 0.66; 95% CI: 0.52-0.84, I ² =71%). Although irAEs were associated with longer overall survival, this difference was not statistically significant (pooled HR: 0.83; 95% CI: 0.62 – 1.11, I ² =73%). Subgroup analysis showed a survival benefit for patients with grade 1-2 irAEs (pooled HR: 0.50; 95% CI: 0.36-0.67, I ² =0%) but not for those with grade 3-4 irAEs (pooled HR: 0.95; 95% CI: 0.24-3.72, I ² =84%). Conclusions: The development of irAEs is associated with a favorable prognosis in HCC, including improved PFS and higher ORR. A survival benefit was noted in patients with mild irAEs, but not in those with severe irAEs. Future studies are needed to determine if a differential survival benefit relates to the continuation vs. discontinuation of ICI therapy.