BACKGROUND/OBJECTIVE: The treatment strategy for hepatocellular carcinoma (HCC) with Vp4 (main trunk) portal vein tumor thrombosis (PVTT) remains controversial due to the dismal prognosis. We aimed to investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus lenvatinib and tislelizumab in these patients. METHODS: This multicenter retrospective study included treatment-naive HCC patients with Vp4 PVTT from 2017 to 2022. They were treated with HAIC plus lenvatinib and tislelizumab (HLP group) or HAIC alone (HAIC group). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) were assessed. Propensity score matching (PSM) was performed to reduce bias. RESULTS: In this study, 155 HCC patients with Vp4 PVTT were included, with 38 in the HLP group and 117 in the HAIC group, with 35 per group matched by PSM. The HLP group showed longer median OS (23.2 vs. 6.9 months
HR 0.333, p <
0.001) and PFS (6.6 vs. 2.4 months
HR 0.403, p = 0.002) than the HAIC group. Higher ORR for tumor (77.1% vs. 42.9%, p = 0.003) and PVTT (51.4% vs. 22.9%, p = 0.025) was observed in the HLP group. More patients underwent hepatectomy post-conversion therapy (15.8% vs. 0.9%). Grade 3/4 AEs were higher in the HLP group (47.4% vs. 35.0%), but there was no significant difference, and no grade 5 AEs occurred in either group. CONCLUSIONS: HAIC combined with lenvatinib and tislelizumab may be a promising treatment in patients with HCC and Vp4 PVTT because of the improved prognosis and acceptable safety profile.