Jingyi Li Bowen Yang Zang Teng Yunpeng Liu Danni Li ^* Xiujuan Qu ^*

• The First Hospital of China Medical University, Department of Medical Oncology, China

The first-line treatment for advanced hepatocellular carcinoma has evolved significantly. This study aimed to identify the most beneficial regimen.A systematic search was conducted from July 2012 to August 2024 across the following four databases: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. This search focused on phase III prospective randomized controlled trials that compared first-line treatment for advanced hepatocellular carcinoma.Seventeen studies involving 10322 patients were included in this network meta-analysis. Of the studies we included, twelve studies were global multicenter clinical studies, four were initiated in China, and one was initiated in Korea. The results of our statistical analysis suggest that Hepatic artery infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) demonstrated significant overall survival (OS) benefits compared with most treatments, including various immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). In terms of OS, HAIC had shown similar efficacy with sorafenib plus FOLFOX (HR, 0.88; 95% CI: 0.37-2.09) and transcatheter arterial chemoembolization (TACE) combined with lenvatinib (HR, 0.69; 95% CI: 0.30-1.56). Notably, immune-related treatments, such as ICIs combined with anti-VEGF therapies, also showed improved OS compared with anti-VEGF-TKIs alone. In terms of progressionfree survival (PFS), HAIC-FO outperformed anti-VEGF-TKI monotherapy, ICI monotherapy, and several ICI combinations. However, it was not superior to lenvatinib plus TACE or lenvatinib plus pembrolizumab. Based on the Surface Under the Cumulative Ranking Curve (SUCRA) values, HAIC-FO was ranked the most effective in terms of OS (SUCRA = 0.961) and objective response rate (ORR) (SUCRA = 0.971). The results of the subgroup analysis suggested that HAIC-FO achieved the best OS benefit in the macrovascular invasion (MVI) and extrahepatic spread (EHS) subgroup (SUCRA = 0.99) and that tremelimumab combined with durvalumab achieved the best OS benefit in the Asian subgroup (SUCRA = 0.88).This systematic review and network meta-analysis suggest that HAIC-based therapies may become a potential first-line treatment option for advanced HCC, especially for patients in Mainland China with MVI and EHS. Additionally, immune-related treatments may be more suitable for Asian populations.