Updated Network Meta-Analysis of First-Line Systemic Treatments for Advanced HCC: Consistent Role of TACE

Abstract

Background and Aims: We conducted an updated network meta-analysis to evaluate and identify the optimal first-line treatment for advanced hepatocellular carcinoma (HCC) among all relevant interventional and targeted therapies. Methods: We analyzed 16 phase 2 or 3 randomized controlled trials involving 9,482 patients with metastatic or unresectable HCC published between 2018 and 2024. The trials evaluated 11 systemic agents and 5 interventional treatments in combination with systemic therapy, using either sorafenib or lenvatinib as the control. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS) and grade 3-4 adverse events. Subgroup analyses were conducted to assess individual treatment efficacies in specific clinical settings. Results: Transarterial chemoembolization (TACE) combined with lenvatinib provided the greatest improvement in OS over sorafenib, with a hazard ratio of 0.41 (95% confidence interval, 0.30-0.58), followed by sintilimab + IBI305 (0.57; 0.43-0.75), camrelizumab + rivoceranib (0.62; 0.48-0.80), atezolizumab + bevacizumab (0.66; 0.51-0.85), lenvatinib + pembrolizumab (0.77; 0.62-0.97), and tremelimumab + durvalumab (0.78; 0.64-0.95). These combinations, except for tremelimumab + durvalumab, also showed significantly superior PFS to sorafenib. TACE + lenvatinib was ranked first in OS analyses with the other current standard-of-care regimens (lenvatinib, atezolizumab + bevacizumab, and tremelimumab + durvalumab) as controls. TACE + lenvatinib, sintilimab + IBI305, and atezolizumab + bevacizumab demonstrated consistently significant extension of OS over sorafenib in subsets with portal invasion, extrahepatic metastasis, and hepatitis B. All immunotherapy-based combinations were significantly associated with a higher risk of adverse events than sorafenib. Conclusions: For advanced HCC, our first-line analysis consistently scored TACE + lenvatinib the best for survival outcomes, followed by various immunotherapy-based combinations. However, the superior efficacy of TACE + lenvatinib should be interpreted with consideration of its derivation from a region with high hepatitis B virus prevalence.