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.

BACKGROUND

First-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.

OBJECTIVES

To 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.

DESIGN

The BITS-TO-HCC study is a prospective, single-center, single-arm, phase II trial.

METHODS AND ANALYSIS: Patients 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.

ETHICS: The final protocol was approved by the Ethics Committee of the Affiliated Cancer Hospital of Shandong First Medical University.

DISCUSSION: This 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).