The efficacy of immune checkpoint inhibitors in advanced hepatocellular carcinoma: a meta-analysis based on 40 cohorts incorporating 3697 individuals

Background: This study was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC).

Methods: Electronic databases were scanned to identify relevant trials. The primary endpoints were overall survival (OS), progression-free survival (PFS), and their prognostic factors. Stratified analyses were accomplished on ICIs agent and evaluation criteria.

Results: Totally, 3697 individuals from 40 cohorts were recruited. For patients treated with ICIs, the pooled median time to progression (TTP) was 8.0 months, median PFS 4.9 months, and median OS 12.0 months; the pooled median PFS and OS of ICIs plus anti-vascular endothelial growth factor (VEGF) agents (PFS: 6.3 months, OS: 16.4 months) were longer than those of ICIs alone. Furthermore, Child-Pugh stage (HR = 1.37, P = 0.0123) and Eastern Cooperative Oncology Group (ECOG) (HR = 1.40, P = 0.0016) were prognostic factors for PFS. Hepatitis C virus (HCV) (HR = 0.71, P = 0.0356), Alpha-fetoprotein (AFP) (HR = 1.17, P < 0.0001), Child-Pugh stage (HR = 1.58, P < 0.0001), Barcelona Clinic Liver Cancer (BCLC) stage (HR = 1.23, P = 0.0005), ECOG (HR = 1.50, P = 0.0012), portal vein invasion (HR = 1.32, P = 0.0053), extrahepatic metastasis (HR = 0.84, P = 0.0047), best response (HR = 0.58, P < 0.0001), and neutrophil-to-lymphocyte ratio (NLR) (HR = 1.23, P = 0.0451) were the prognostic factors for OS. According to both RECIST 1.1 and mRECIST, the objective response rate (ORR) and disease control rate (DCR) rate of ICIs plus anti-VEGF agents were better than those of ICIs alone. The overall rate of any grade adverse events (AEs) was 0.76 (95% CI 0.61-0.89), grade 3 or higher AEs was 0.28 (95% CI 0.15-0.42), and the rate of AEs leading to treatment discontinuation was 0.09 (95% CI 0.06-0.12).

Conclusions: The ICIs was promising in HCC with good efficacy and tolerated toxicity. Compared with ICIs monotherapy, the joint application of ICIs and anti-VEGF agents can contribute a lot more benefits to the survival of patients according to clinical practices.