The efficacy and safety of immune checkpoint inhibitor combinations for hepatocellular carcinoma: a systematic review and network meta-analysis

The management of hepatocellular carcinoma (HCC) faces ongoing challenges despite therapeutic advances. Although combination regimens incorporating immune checkpoint inhibitors (ICIs) have demonstrated improved clinical outcomes, direct comparisons between different ICI-based combination therapies are limited. To bridge this knowledge gap, we conducted a comprehensive network meta-analysis to quantitatively assess and rank the efficacy and safety of available ICI-based combination systemic treatments for HCC. A systematic literature search was conducted in PubMed, Cochrane Library, and Web of Science to identify randomized controlled trials comparing ICI-based combination systemic therapies to tyrosine kinase inhibitor (TKI) monotherapies in patients with HCC. A random-effects network meta-analysis was then employed to compare outcomes, including overall survival (OS), progression-free survival (PFS), disease control rate, objective response rate (ORR), and the incidence of grade 3 or higher adverse events. The quality of evidence for these comparisons was systematically assessed using the GRADE framework. Eight randomized controlled trials, comprising a total of 4637 patients, were included in the meta-analysis. Compared to the control group, ICI-based combination systemic therapy was associated with significant improvements in overall survival (OS: HR 0.75, 95% CI 0.67–0.84; moderate certainty), progression-free survival (PFS: HR 0.71, 95% CI 0.62–0.83; moderate certainty), and objective response rate (ORR: OR 3.91, 95% CI 2.63–5.81; moderate certainty). Subgroup analyses indicated consistent survival benefits across most predefined subgroups ( P < 0.05), except among patients with hepatitis C virus (HCV) infection or non-viral etiology. In the network meta-analysis, ICI plus anti-VEGF therapy demonstrated superior OS (HR 0.74, 95% CI 0.55–0.98) and PFS (HR 0.75, 95% CI 0.63–0.89) compared to ICI plus TKIs. Although both dual ICI therapy and ICI plus anti-VEGF significantly improved ORR versus control ( P < 0.05), there was no significant difference between these two regimens (OR 0.79, 95% CI 0.42–1.48). Notably, ICI plus TKIs did not show a statistically significant OS benefit in any predefined subgroup. For patients with HCC, ICI-based combination systemic therapy—with the notable exception of those with HCV or non-viral etiology—should be considered as a preferred strategy over TKI monotherapy to enhance treatment efficacy. Among the evaluated regimens, ICI plus anti-VEGF therapy demonstrated superior OS and PFS compared with ICI plus TKI therapy. No statistically significant differences in OS or PFS were observed between dual ICI and ICI plus TKI therapies. Although all regimens significantly improved the objective response rate, no statistically significant difference was observed in disease control rate compared to single-agent TKIs. This network meta-analysis offers high-quality evidence to inform the selection of optimal ICI-based combination therapies for advanced HCC. Further large-scale, high-quality randomized trials are warranted to validate these findings and refine patient stratification.