OBJECTIVES: This research aimed to compare the first-line systemic therapies for advanced hepatocellular carcinoma (HCC).

METHODS: We conducted a systematic literature review of randomized controlled trials assessing first-line systemic therapies for treating adults with locally advanced or metastatic unresectable HCC. The data sources included biomedical databases (Embase, MEDLINE, and CENTRAL), relevant conferences, and grey literature searches. Clinical and statistical heterogeneity was evaluated using trial, patient, and outcome-level covariates. Network meta-analysis (NMA) used generalized linear models with random effects within a Bayesian framework (using informative priors). The risk of bias was assessed using the funnel plot and Egger's regression test. The proportional hazards (PH) assumption was also tested for the appropriateness of conventional HR-based NMA.

RESULTS: A total of 12 RCTs assessing first-line chemotherapy, molecular targeted therapy, or immunotherapy, as mono or combination therapies, were included in the NMA. Most studies were conducted in a Global (n=8) setting, followed by Asia (n=3) and non-Asian (n=1) settings. Compared with placebo, sintilimab + bevacizumab [HR, 95% CI: 0.39, 0.2-0.77], camrelizumab + rivoceranib [0.43, 0.22-0.81], and atezolizumab + bevacizumab [0.43, 0.22-0.81] were associated with significantly better survival. Compared with sorafenib, all treatments showed numerically better but statistically non-significant results. SUCRA rankings were generally better for combination therapies (sintilimab + bevacizumab, camrelizumab + rivoceranib, atezolizumab + bevacizumab, lenvatinib + pembrolizumab, tremelimumab + durvalumab) followed by monotherapies (donafenib, nivolumab,tislelizumab, durvalumab, lenvatinib, sorafenib) and placebo.

CONCLUSIONS: Atezolizumab plus bevacizumab was confirmed to be an effective first-line treatment to improve survival in patients with advanced HCC. The promising results of immunotherapy combinations with TKIs and other agents indicate the availability of more first-line options in the near future for advanced HCC patients.