Neoadjuvant radiotherapy combined with lenvatinib and sintilimab in patients with resectable hepatocellular carcinoma with portal vein tumor thrombus: An open-label, single-arm, multicenter, prospective phase I clinical trial.

4113 Background: Surgical resection remains the potentially curative treatment for resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) in selected patients, but recurrence remains a major challenge. Neoadjuvant therapies have been proposed to reduce tumor burden and the risk of recurrence. This trial aimed to evaluate the safety and efficacy of neoadjuvant RT combined with lenvatinib and sintilimab followed by resection in resectable HCC patients with PVTT. Methods: This open-label, single-arm, multicenter, prospective phase I trial enrolled patients with resectable hepatocellular carcinoma classified as Barcelona Clinic Liver Cancer stage C without extrahepatic metastasis at 2 hospitals in China. Patients received RT (300cGy ×10 fractions) targeting intrahepatic lesions and PVTT, concurrent with two cycles of lenvatinib and sintilimab, followed by surgery 8 weeks post-RT and postoperative adjuvant therapy with lenvatinib and sintilimab for 1 year. Safety, pathological response, and feasibility were assessed. This trial is registered with ClinicalTrials.gov (NCT05225116). Results: From October 2022 to January 2026, 17 patients (VP2:5, VP3:11, VP4:1) were enrolled, 14 patients had completed neoadjuvant therapy, 12 patients had received surgeries (R0 rate: 100%, 10/10), while 1 patient had disease progression, 1 patient postponed surgery due to abnormal liver function. Preoperative imaging (mRECIST criteria) showed stable disease (SD), partial response (PR), and complete response (CR) rates of 16.7%, 75.0%, and 8.3.0% for primary lesions, and 0%, 58.3%, and 41.7% for PVTT. Postoperative pathological complete response (pCR) rates were 25.0% for primary lesions and 75.0% for PVTT. Concordance between imaging and pathology was 66.7% for primary lesions and 50.0% for PVTT. The median recurrence-free survival (mRFS) was 17 months and median overall survival (mOS) was 27 months. No Grade 3 or worse treatment-related adverse events occurred. Conclusions: Neoadjuvant radiotherapy combined with lenvatinib and sintilimab can bring a high tumor response rate in patients with resectable hepatocellular carcinoma with portal vein tumor thrombus with a favorable safety profiles. PVTT demonstrates higher response rate than primary HCC lesions. Discrepancies between imaging and pathological responses highlight the need for improved predictive biomarkers. These interim results support further investigation of this approach in larger cohorts. Clinical trial information: NCT05225116 .