Ranking of Transarterial and Targeted Therapies for Advanced Hepatocellular Carcinoma in the Era of Immuno-Oncology: A Network Meta-Analysis

Background: We aimed to compare and rank all relevant transarterial and targeted treatments competing with atezolizumab plus bevacizumab in the first-line setting for advanced hepatocellular carcinoma (HCC) based on direct and indirect evidence. Methods: This network meta-analysis was conducted in the context of a systematic review of phase 2 and 3 randomized sorafenib-controlled trials investigating systemic treatment strategies for advanced HCC as first-line option published between 2008 and 2021. We ranked the treatments based on overall survival (OS) as the primary outcome, together with progression-free survival (PFS) and grade 3-4 adverse events. Subgroup analyses were also implemented to estimate the efficacies of the interventions in particular groups. Findings: We identified 3,451 publications, and 15 trials comprising 7,158 patients were finally included in the analysis: they involved 14 different therapies including combinations of sorafenib with transarterial chemoembolization (TACE), hepatic arterial chemoinfusion, and radioembolization. Regarding OS, atezolizumab+bevacizumab was the only regimen significantly superior to sorafenib (hazard ratio 0.42; 95% confidence interval [CI] 0.25-0.70), and it ranked first. This combination was also the best in the PFS analysis (0.59; 0.47-0.74), followed by lenvatinib (0.66; 0.57-0.76) and TACE+sorafenib (0.73; 0.59-0.91), which all had significantly better outcomes than sorafenib alone. TACE+sorafenib (0.52; 0.27-1.00) was ranked first based on OS in a subset with portal invasion, but not in the metastatic series, with atezolizumab+bevacizumab second (0.58; 0.38-0.89). Lenvatinib (odds ratio 1.76; 95% CI 1.35-2.30) and TACE+sorafenib (2.02; 1.23-3.32), but not atezolizumab+bevacizumab (1.38; 0.93-2.05), were significantly less safe than sorafenib monotherapy. Interpretation: Our results indicate that atezolizumab+bevacizumab is the best first-line clinically relevant modality in patients with advanced HCC. TACE+sorafenib may also be considered for the disease with portal invasion. Funding Information: National Research Foundation of Korea, Hanyang University. Declaration of Interests: The authors declare no competing interests.