Local Consolidation After Sintilimab Plus Lenvatinib for Metastatic Liver Cancer

Overview

This study evaluates whether comprehensive local consolidative therapy added to continued sintilimab plus lenvatinib improves survival compared with continued sintilimab plus lenvatinib alone in patients with oligo-extrahepatic metastatic hepatocellular carcinoma. All enrolled participants receive induction treatment with sintilimab plus lenvatinib for 4 cycles. Participants who achieve disease control and are confirmed by central multidisciplinary review to be feasible for complete consolidation are randomized in a 1:1 ratio to receive either comprehensive local consolidative therapy followed by continued systemic therapy or continued systemic therapy alone. The primary outcome is overall survival.

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.