Immune-related Adverse Events are Associated with Improved Outcomes after Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Abstract

INTRODUCTION Immune checkpoint inhibitors (ICIs) have become the first-line treatment for unresectable hepatocellular carcinoma (HCC). 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 HCC patients treated with ICIs. METHODS We searched the PubMed, Scopus, Web of Science, and CENTRAL databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was done 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 (ORR) (pooled relative ratio [RR]: 1.73; 95% confidence interval [CI]: 1.36-2.21, I2=41%), a higher disease control rate (DCR) (pooled RR: 1.45; 95% CI: 1.21-1.74, I2=74%), and longer progression-free survival (PFS) (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52-0.84, I2=71%). There was a trend toward longer overall survival (OS) for patients with irAEs compared to those without (pooled HR: 0.84; 95% CI: 0.63-1.12, I2=73%). Subgroup analysis indicated a survival benefit for patients with grade 1-2 irAEs (pooled HR: 0.50; 95% CI: 0.36-0.67, I2=0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48-0.83, I2=12%). DISCUSSION The development of irAEs is associated with favorable clinical outcomes in HCC, including improved PFS and higher ORR. OS benefit was noted in patients with mild irAEs but not those with severe irAEs.