Ranking of transarterial and targeted therapies for advanced hepatocellular carcinoma in the era of immuno-oncology: A network meta-analysis of randomized sorafenib-controlled trials

Abstract

To date, no studies have compared the new first-line atezolizumab+bevacizumab with transarterial therapies combined with the prior standard-of-care, sorafenib, in patients with advanced hepatocellular carcinoma (HCC). We compared and ranked all relevant transarterial and targeted treatments competing with atezolizumab+bevacizumab for such disease, based on direct and indirect evidence. This network meta-analysis was conducted as a systematic review of phase 2 and 3 randomized sorafenib-controlled trials investigating systemic treatment strategies for HCCs unsuitable for or that progressed after surgery or locoregional treatments 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 intervention efficacies in particular groups. We identified 3451 publications, 15 trials consisting of 7158 patients, using 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); 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. Conclusion: Our results indicate that atezolizumab+bevacizumab is the best first-line clinically relevant systemic modality in advanced HCC. TACE+sorafenib may also be considered for the disease with portal invasion. (PROSPERO No. CRD42021250701).