Immunotherapy and targeted therapy plus hepatic arterial infusion chemotherapy for HCC with portal vein tumor thrombosis (CHANCE2504): a nationwide target trial emulation study

Background: The treatment strategy for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) remains controversial because of its the dismal prognosis. This study aimed to evaluate the safety and efficacy of immune checkpoint inhibitors (ICIs) plus molecular-targeted agents (MTA) with or without hepatic arterial infusion chemotherapy (HAIC) as a first-line treatment for HCC with PVTT. Methods: This nationwide retrospective cohort study utilized a target trial emulation framework with a clone-censor-weighting (CCW) approach and was conducted in 36 centers across China. The study population comprised patients diagnosed with HCC and PVTT who received HAIC in combination with ICIs and MTA (HAIC-ICIs-MTA) or ICIs plus MTA (ICIs-MTA) from June 2018 to December 2024. The primary endpoint was overall survival (OS), which was evaluated through restricted mean survival time (RMST) with bootstrapping. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety profiles. Results: This study included a total of 1649 HCC patients (614 in the HAIC-ICIs-MTA group and 1035 in the ICIs-MTA group). After CCW, the median OS of the HAIC-ICIs-MTA group was 23.3 months, whereas that of the ICIs-MTA group was 16.4 months. The difference in RMST for OS was 7.4 months (95% confidence interval [CI]: 3.5-11.7, bootstrapped P<0.001). The HAIC-ICIs-MTA group also had a significantly longer median PFS (8.7 months vs. 6.2 months, bootstrapped P=0.002) with an RMST of 2.6 months (95% CI: 0.9-4.5), and a higher ORR (38.9% vs. 22.7%, P<0.001) as per the Response Evaluation Criteria in Solid Tumors Version 1.1. Grade ≥3 treatment-related adverse events occurred in 243 patients in the HAIC-ICIs-MTA group (39.6%) and 335 patients in the ICIs-MTA group (32.4%). Conclusions: HAIC in combination with ICIs and MTA is associated with improved survival and an acceptable safety profile compared to ICIs plus MTA alone, supporting this regimen as a promising treatment strategy for HCC patients with PVTT that warrants further prospective validation.