Local Consolidation After Sintilimab Plus Lenvatinib for Metastatic Liver Cancer

This is a multicenter, prospective, open-label, randomized, event-driven phase 3 strategy trial in patients with oligo-extrahepatic metastatic hepatocellular carcinoma (HCC). All enrolled participants receive induction therapy with sintilimab 200 mg intravenously every 3 weeks plus lenvatinib orally once daily for 4 cycles. The recommended lenvatinib dose is 12 mg once daily for participants with body weight greater than or equal to 60 kg and 8 mg once daily for participants with body weight less than 60 kg. Approximately 620 participants are expected to enter induction, and approximately 400 participants are expected to undergo 1:1 randomization after induction.

After 4 induction cycles, participants undergo imaging reassessment and central multidisciplinary team review. Only participants with disease control by blinded independent central review and central confirmation that all residual active lesions can be safely covered by comprehensive local consolidative therapy are eligible for randomization. Randomized participants are assigned to either comprehensive local consolidative therapy plus continued sintilimab and lenvatinib or continued sintilimab and lenvatinib alone.

Comprehensive local consolidative therapy is intended to treat all residual active lesions, including intrahepatic and extrahepatic disease, using protocol-specified stereotactic body radiotherapy, thermal ablation, surgery, or a combination thereof. Consolidative treatment should begin within 4 to 8 weeks after randomization. In the control arm, planned full-lesion consolidative local treatment is not permitted before RECIST-defined progression, although urgent palliative local treatment may be allowed when medically necessary and will be recorded.

The primary endpoint is overall survival from randomization. Key secondary endpoints include progression-free survival, time to strategy failure, time to widespread progression, no-evidence-of-disease rate at 12 weeks after randomization, local control rate, time to next-line systemic therapy, quality of life, and safety. Imaging is performed during induction at Week 6 and Week 12, then every 6 weeks through Week 54 after randomization and every 9 weeks thereafter until progression, treatment discontinuation, death, or study end. Safety monitoring includes treatment-related adverse events, immune-related adverse events, anti-VEGF-related adverse events, and local treatment-related complications.

Inclusion criteria

• Age 18 to 75 years
• Hepatocellular carcinoma confirmed by imaging and/or histology according to institutional diagnostic standards
• Advanced or unresectable disease with extrahepatic metastases meeting protocol-defined oligo-extrahepatic metastatic disease criteria: 1 to 5 extrahepatic metastatic lesions and no more than 2 involved extrahepatic organs
• At least 1 measurable lesion according to RECIST version 1.1
• No prior systemic therapy for advanced or metastatic hepatocellular carcinoma
• ECOG performance status 0 to 1
• Child-Pugh class A or stable Child-Pugh B7
• Adequate hematologic, hepatic, renal, and coagulation function according to protocol
• Baseline center multidisciplinary team assessment indicating potential feasibility for complete consolidative intent if disease control is achieved after induction
• Written informed consent and willingness to comply with treatment, follow-up, and protocol-required assessments

Exclusion criteria

• More than 5 extrahepatic metastatic lesions or more than 2 involved extrahepatic organs
• Diffuse peritoneal seeding, leptomeningeal disease, or uncontrolled brain metastases
• Main portal vein trunk invasion, extensive inferior vena cava or right atrial tumor thrombus, or disease considered unlikely to become fully consolidable after induction
• Diffuse intrahepatic disease or liver tumor burden considered unlikely to be controllable with protocol-specified local treatment
• Prior PD-1, PD-L1, CTLA-4, anti-VEGF monoclonal antibody, tyrosine kinase inhibitor, or other systemic antitumor therapy for advanced HCC
• Active autoimmune disease requiring systemic immunosuppression
• Active severe infection, including uncontrolled bacterial or fungal infection, active tuberculosis, or uncontrolled hepatitis B without appropriate antiviral therapy
• Gastrointestinal bleeding within the previous 6 months, or untreated or uncontrolled high-risk gastroesophageal varices
• Uncontrolled hypertension, recent major thrombotic event, myocardial infarction, unstable angina, or stroke
• Active interstitial lung disease or noninfectious pneumonitis requiring systemic treatment
• Severe proteinuria or renal dysfunction considered unsuitable for lenvatinib treatment
• Pregnancy or breastfeeding
• Any condition that, in the investigator's judgment, would make participation unsafe or compromise protocol compliance