Adverse events of immune checkpoint inhibitors in hepatocellular carcinoma: a systemic review and meta-analysis

The introduction of immune checkpoint inhibitors (ICIs) has reshaped the therapy of hepatocellular carcinoma (HCC). ICIs are a novel therapy with frequent adverse events (AEs), including treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). However, no comprehensive overview of the toxicity spectrum of ICIs in HCC patients has been provided. Electronic databases were searched to identify eligible studies. A meta-analysis of the incidence rate of AEs in HCC patients treated with ICIs was performed. Lastly, the prognostic value of irAEs in HCC patients treated with ICIs was verified. Forty-seven studies with 6472 participations met the inclusion criteria. The pooled all-grade trAEs incidence rate was 83.4% (95% confidence interval [95% CI] 77.0–89.1%), ≥ grade 3 trAEs incidence rate was 33.0% (95% CI 26.9–39.5%), all-grade irAEs incidence rate was 34% (95% CI 22–47%), and ≥ grade 3 irAEs incidence rate was 9% (95% CI 5–14%). Aspartate aminotransferase (AST) increase (38%, 95% CI 35–40%) is the most common trAEs. Fatigue (14%, 95% CI 7–23%) is the most common irAEs. The pooled results also showed that 18.8% (95% CI 13.2–25.2%) of patients required systemic steroid therapy due to AEs, while 6.6% (95% CI 4.6–9.0%) of patients withdrew from treatment due to AEs. Additionally, patients experiencing irAEs may have a better progression-free survival (PFS) (multivariate analysis: hazard ratio [HR] = 0.41, 95% CI 0.27–0.61, I 2 = 36.3%) but not overall survival (OS) (multivariate analysis: HR = 0.54, 95% CI 0.22–1.36, I 2 = 83.2%) than those with no irAEs. Our study presents a systemic assessment of the AEs profile in HCC patients receiving ICIs, providing important reference for clinicians on toxicity profile. Besides, patients with irAEs may have a better PFS. More large-scale and prospective studies are needed to confirm our conclusions.