Bevacizumab plus iparomlimab/tuvonralimab with hepatic artery infusion chemotherapy followed by stereotactic body radiotherapy in patients with BCLC stage C hepatocellular carcinoma with thrombus and/or extrahepatic oligometastases (BITS-TO-HCC): study protocol of a prospective, single-center, single-arm, phase II study.

Abstract

BackgroundFirst-line immunotherapy-based combinations have improved outcomes in advanced hepatocellular carcinoma (HCC), but many patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC with portal vein tumor thrombus (PVTT) and/or extrahepatic oligometastases remain difficult to treat and often unresectable.ObjectivesTo characterize the safety, feasibility, and efficacy of a sequential strategy combining hepatic artery infusion chemotherapy with infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO), iparomlimab/tuvonralimab plus bevacizumab, followed by stereotactic body radiotherapy (SBRT), in patients with BCLC stage C HCC with PVTT and/or extrahepatic oligometastases.DesignThe BITS-TO-HCC study is a prospective, single-center, single-arm, phase II trial.Methods and analysisPatients with BCLC stage C HCC complicated by PVTT and/or extrahepatic oligometastases and Child-Pugh class A liver function will be enrolled. On day 1 of each cycle, patients will receive HAIC-FO followed by bevacizumab plus iparomlimab/tuvonralimab after protocol-defined laboratory reassessment. HAIC-FO will be delivered for up to four cycles. After cycle 4, patients without progressive disease will receive protocol-specified SBRT (25-40 Gy in 5 fractions). Patients with radiographic complete response or no residual SBRT-amenable lesion will continue systemic therapy and follow-up. The primary endpoint is progression-free survival. Secondary endpoints include objective response rate, disease control rate, overall survival, local control rate, safety, and quality of life.EthicsThe final protocol was approved by the Ethics Committee of the Affiliated Cancer Hospital of Shandong First Medical University.DiscussionThis trial will prospectively evaluate whether a sequential strategy combining HAIC with bevacizumab plus iparomlimab/tuvonralimab followed by SBRT can provide a surgery-sparing, ablative locoregional-systemic pathway for this high-risk population, potentially enhancing efficacy while maintaining an acceptable safety profile. Trial registration: This study is registered on ClinicalTrials.gov Identifier: NCT07062055 (July 14, 2025).