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

Background & 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.