Iparomlimab and Tuvonralimab With Lenvatinib, Radiotherapy, and HAIC for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

This is a prospective, single-center, single-arm Phase II study designed to evaluate the efficacy and safety of a multimodal first-line treatment strategy consisting of iparomlimab and tuvonralimab (QL1706), lenvatinib, radiotherapy, and hepatic arterial infusion chemotherapy (HAIC) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). A total of 35 participants are planned to be enrolled.

Treatment will be administered according to the following sequence. Iparomlimab and tuvonralimab (QL1706) will be administered intravenously at a dose of 7.5 mg/kg on Day 1 of each 3-week cycle, with each infusion given over 30-60 minutes. Lenvatinib will be administered orally once daily at 8 mg for participants weighing <60 kg and 12 mg for those weighing ≥60 kg.

PVTT-directed external beam radiotherapy will be initiated within 7 days after the first administration of QL1706. The radiation target will include the PVTT. Gross tumor volume will be delineated based on the venous or delayed phase of contrast-enhanced imaging. A planning target volume margin of approximately 5-15 mm will be added according to the protocol. Stereotactic body radiotherapy will be delivered at a total dose of 18-40 Gy, with a dose of 3-6 Gy per fraction.

HAIC will be initiated in combination with the second cycle of QL1706. Lenvatinib will be withheld for 3 days before HAIC and for 7 days after HAIC. The interruption period may be extended at the investigator's discretion according to the participant's clinical condition and laboratory findings. HAIC will be performed using a FOLFOX-based regimen through a catheter selectively placed in the main tumor-feeding hepatic artery. Oxaliplatin will be administered at 85 mg/m² by hepatic arterial infusion over 3 hours, followed by leucovorin calcium at 200 mg/m² over 3-5 hours. Fluorouracil will then be administered at 400 mg/m² by hepatic arterial injection, followed by 2400 mg/m² as a continuous hepatic arterial infusion over 46 hours. HAIC will be repeated every 3 weeks for up to 4 cycles, with the number of cycles adjusted according to the participant's clinical condition.

QL1706 and lenvatinib will be continued for up to 2 years or until disease progression, unacceptable toxicity, or another protocol-defined reason for treatment discontinuation. Tumor response will be assessed every 2 treatment cycles, corresponding to approximately every 6 weeks, according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Participants who achieve sufficient tumor regression will be reviewed by a multidisciplinary team, and those considered suitable for curative resection may undergo conversion surgery.

The primary objective of the study is to evaluate progression-free survival. Secondary assessments include objective response rate, disease control rate, duration of response, overall survival, conversion-to-surgery rate, pathological complete response in participants undergoing surgery, and treatment safety.

Inclusion criteria

• Age ≥18 and ≤75 years at the time of signing informed consent.
• Histologically or clinically confirmed hepatocellular carcinoma (HCC) according to the 2024 Chinese Guidelines for the Diagnosis and Treatment of Primary Liver Cancer.
• Radiologically confirmed portal vein tumor thrombus (PVTT), classified as Cheng type I-IV.
• No prior systemic or local treatment directed at PVTT, including targeted therapy, immunotherapy, or systemic chemotherapy.
• Child-Pugh class A or B with a Child-Pugh score ≤7.
• Considered unsuitable for curative surgery or liver transplantation after multidisciplinary evaluation, but suitable for radiotherapy.
• Adequate organ function, including: WBC ≥3.0 × 10⁹/L; PLT ≥50 × 10⁹/L; hemoglobin ≥80 g/L; ALT ≤5 × ULN; AST ≤5 × ULN; total bilirubin ≤3 × ULN; albumin ≥28 g/L; and creatinine clearance ≥80 mL/min.
• At least one measurable lesion according to mRECIST.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy >3 months.
• No history of abdominal radiotherapy.
• Women of childbearing potential must use effective contraception beginning at least 1 month before screening and throughout the study until the protocol-specified period after study completion.
• Willing and able to comply with study follow-up until death, study completion, or study termination.

Exclusion criteria

• ECOG performance status ≥2.
• Child-Pugh score ≥8.
• Severe dysfunction of major organs, including the heart, liver, or kidneys.
• Prior targeted therapy, immunotherapy, radiotherapy, systemic chemotherapy, or other anticancer treatment.
• Known hypersensitivity or allergic reaction to any component of the study treatment.
• History of organ transplantation or autologous/allogeneic stem cell transplantation.
• Currently receiving chronic systemic immunotherapy or hormonal therapy other than physiologic replacement therapy.
• Any unstable systemic disease, including active infection; uncontrolled severe hypertension; unstable angina; new-onset angina within the previous 3 months; congestive heart failure of NYHA class II or higher; myocardial infarction within the previous 6 months; severe cardiac arrhythmia requiring medication; gastrointestinal bleeding within the previous 1 month; or active bleeding tendency.
• Concurrent other malignancy that has not been cured, except carcinoma in situ at another site.
• Any disease, metabolic disorder, physical examination finding, or laboratory abnormality that, in the investigator's judgment, suggests a contraindication to the study treatment or a high risk of treatment-related complications.
• Evidence of acute or active hepatitis B or hepatitis C infection, including HBV-DNA >2,000 IU/mL or HCV-RNA >1,000 copies/mL.
• Pregnancy or breastfeeding.
• Any other unfavorable medical or psychiatric condition that, in the investigator's judgment, may affect protocol compliance or evaluation of study endpoints and makes the participant unsuitable for the study.
• Lack of legal capacity or limited legal capacity.
• Other contraindications to radiotherapy or targeted/immunotherapy.
• Any participant considered unsuitable for enrollment by the investigator.