Stereotactic Body Radiation Therapy Combined with Cadonilimab and Lenvatinib in the Treatment of Hepatocellular Carcinoma with Vp3 or Vp4 Portal Vein Tumor Thrombus: A Prospective, Multicenter, Single-Arm, Phase II Clinical Trial

Ning Mo¹Kai Hu²Zhiming Zeng¹Lihua Yang¹Yeying Fang²Jie Zeng¹Ye Li¹Zhendong Yang²Jing Tang¹Tingting Zhang²Fuchao Ma¹Cuizhen Liu¹Haiping Zheng¹Jinfeng Qiu¹Yanfeng Jiang¹Yufeng Lv³Li Liang⁴Xiaofang Huang^1,5xiwen Liao⁶Yan Wang⁷Xiuyuan Lu⁸Lijun Ning⁸Shixue Laoguo⁸Jie Ma¹Rensheng Wang^9*

• ¹Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
• ²Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
• ³Department of Oncology, Foresea Life Insurance Guangxi Hospital, Nanning, Guangxi, China
• ⁴Department of Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
• ⁵Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
• ⁶Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
• ⁷Medical Center, Akeso Biopharma, Inc, Zhongshan，guangdong, China
• ⁸Guangxi Medical University, Nanning, China
• ⁹First Affiliated Hospital, Guangxi Medical University, Nanning, China

Background: Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) exhibit a dismal prognosis, occurring in 44%–62.2% of cases at initial diagnosis. The optimal treatment for this population remains undefined. Methods: In this prospective, multicenter, single-arm phase II trial across three Chinese centers, eligible HCC patients with Vp3/4 PVTT received combined stereotactic body radiotherapy (SBRT), cadonilimab, and lenvatinib. Primary endpoint was objective response rate (ORR) in primary liver lesions (RECIST v1.1/mRECIST); secondary endpoints included ORR in PVTT, progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Results: Of 24 enrolled patients, 21 were evaluable for efficacy. ORR for primary lesions was 38.1% (RECIST v1.1) and 47.6% (mRECIST), with a disease control rate (DCR) of 100% by both criteria. For PVTT, ORR and DCR were 76.2% and 100%, respectively. At a median follow-up of 19.7 months, median PFS was 6.8 months (95% CI: 4.6–12.9), DOR was 10.4 months (95% CI: 2.9–NE), and OS was 13.4 months (95% CI: 6.8–NE). Early biomarker declines (≥75% AFP reduction or ≥50% PIVKA-II decline at 6 weeks) correlated with superior outcomes: AFP reduction predicted longer PFS (HR=0.22, p = 0.006) and OS (HR=0.25, p = 0.024); PIVKA-II reduction similarly predicted PFS (HR=0.28, p = 0.007) and OS (HR=0.18, p = 0.002). Common treatment-related adverse events (TRAEs) included hypertension (50%), thrombocytopenia (42%), and fatigue (38%). Conclusions: The combination of SBRT, cadonilimab, and lenvatinib showed promising efficacy and manageable toxicity in HCC patients with Vp3/4 PVTT. Early AFP or PIVKA-II response at 6 weeks may serve as a prognostic biomarker. Clinical trial registration: ClinicalTrials.gov, identifier NCT06040177.