Abstract
BACKGROUND: Donafenib demonstrates superior survival benefits and safety compared to sorafenib. Hepatic arterial infusion chemotherapy (HAIC) proves effective for large unresectable hepatocellular carcinoma (uHCC) over transarterial chemoembolization. This study aims to investigate the safety and efficacy of combining HAIC with donafenib and sintilimab in patients with uHCC. METHODS: This prospective single-arm study enrolled patients with histologically confirmed uHCC and no prior systemic treatment from December 2021 to May 2023 in Tianjin Medical University Cancer Institute and Hospital, China. Participants received donafenib, sintilimab and HAIC until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included overall survival (OS), event-free survival (EFS), disease control rate (DCR) and safety. The study was registered at ClinicalTrials.gov, NCT05166772. FINDINGS: A total of 36 patients were enrolled, and the median follow-up was 16 months. ORR were 58.3% and 80.6% per RECIST 1.1 and mRECIST respectively, and DCR were all 94.4%. 24-month OS rate was 59.6%. Median EFS was 15.3 months. The conversion success rate was 50.0%, 18 patients underwent hepatectomy, seven (38.9%) achieved pathological complete response, and nine (50.0%) achieved major pathological responses. Median OS was not achieved (NA) in the surgical group vs. 14.3 months (95% CI 12.1-NA) in the non-surgical group (p = 0.035). Adverse reactions were manageable. INTERPRETATION: Combining HAIC with donafenib and sintilimab demonstrates promising clinical outcomes while maintaining acceptable toxicity, making it a potential strategy for conversion therapy. FUNDING: Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A) and Precision Treatment Project of Surgical Oncology of Tianjin Medical University Cancer Institute and Hospital (No. ZLWKJZZL14).