Dual immune checkpoint inhibitors or combined with anti-VEGF agents in advanced, unresectable hepatocellular carcinoma

Abstract

Background: Immune checkpoint inhibitor monotherapy did not show superiority of survival over standard therapy in advanced hepatocellular carcinoma. The combination immunotherapy including dual immune checkpoint inhibitors or combined with anti-VEGF agents have become a trend, but not fully evaluated. This study aimed to evaluate and compare distinct combination immunotherapy on efficacy in advanced hepatocellular carcinoma.

Methods: PubMed, Embase, Web of Science and Cochrane databases were systematically searched from inception to January 31, 2022. The primary endpoints were overall objective response rate (ORR), disease control rate (DCR), six-month progression-free survival rate (PFSR6m) and one-year overall survival rate (OSR1y).

Results: 11 studies with 16 independent cohorts and 3342 patients were included in the meta-analysis. Compared with first-line sorafenib, combination immunotherapy resulted in a significant improvement in ORR (RR, 2.74; 95%CI, 1.55-4.85; p = 0.0006), PFS (HR, 0.57; 95%CI, 0.49-0.65; p<0.0001) and OS (HR, 0.65; 95%CI, 0.52-0.82; p = 0.0002). Based on RECIST 1.1, the pooled ORR, PFSR6m and OSR1y for combination immunotherapy were 24.6% (95%CI: 20.3%-29.6%), 42.0% (95%CI: 34.2%-50.3%) and 61.8% (95%CI: 57.7%-65.7%), respectively. In distinct combination regimens, PD-1/L1 inhibitors plus anti-VEGF agents showed a significant superiority of clinical benefit than PD-1/L1 inhibitors plus CTLA-4 inhibitors (ORR: 25.2% vs 23.4%, p = 0.033; PFSR6m: 47.4% vs 23.2%, p<0.001; OSR1y: 65.1% vs 55.0%, p = 0.001).

Conclusions: This study was the first meta-analysis to demonstrate the better survival benefit and tolerable toxicity of combination immunotherapy than standard therapy in advanced hepatocellular carcinoma. Compared with PD-1/L1 inhibitors plus CTLA-4 inhibitors, the regimens of PD-1/L1 inhibitors plus anti-VEGF agents may be associated with a significantly better clinical benefit. The difference in long-term survival and response population between two distinct combination regimens required further exploration.

Keywords: Combination immunotherapy; Efficacy; Hepatocellular carcinoma; Immune checkpoint inhibitors; Meta-analysis.