The anti-PD-L1/CTLA-4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: a phase II trial

Da Xu, Hongwei Wang, Quan Bao, Kemin Jin, Ming Liu, Wei Liu, Xiaoluan Yan, Lijun Wang, Yanqiao Zhang, Guangyu Wang, Yue Ma, Zhigang Ma, Chunhui Zhang, Jiebing Tang, Sha Wang, Jiaohui Pang, Ting Xu, Kun Wang () and Baocai Xing ()
Additional contact information
Da Xu: Peking University Cancer Hospital & Institute
Hongwei Wang: Peking University Cancer Hospital & Institute
Quan Bao: Peking University Cancer Hospital & Institute
Kemin Jin: Peking University Cancer Hospital & Institute
Ming Liu: Peking University Cancer Hospital & Institute
Wei Liu: Peking University Cancer Hospital & Institute
Xiaoluan Yan: Peking University Cancer Hospital & Institute
Lijun Wang: Peking University Cancer Hospital & Institute
Yanqiao Zhang: Harbin Medical University Cancer Hospital
Guangyu Wang: Harbin Medical University Cancer Hospital
Yue Ma: Harbin Medical University Cancer Hospital
Zhigang Ma: Harbin Medical University Cancer Hospital
Chunhui Zhang: Harbin Medical University Cancer Hospital
Jiebing Tang: Harbin Medical University Cancer Hospital
Sha Wang: Nanjing Geneseeq Technology Inc.
Jiaohui Pang: Nanjing Geneseeq Technology Inc.
Ting Xu: Jiangsu Alphamab Biopharmaceuticals Co. Ltd
Kun Wang: Peking University Cancer Hospital & Institute
Baocai Xing: Peking University Cancer Hospital & Institute

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract This open-label phase II trial (NCT04542837) aimed to evaluate the efficacy and safety of KN046 combined with lenvatinib in patients with advanced hepatocellular carcinoma (HCC), and explore the potential response biomarkers. Participants received KN046 5 mg/kg every 3 weeks and lenvatinib 12 or 8 mg once daily. The primary endpoints were safety, tolerability, dose-limiting toxicity (DLT), and objective response rate (ORR) according to RECIST v1.1. A total of fifty-five participants were enrolled. The results meet the pre-specified primary endpoints. No DLT was observed in the safety run-in period. The incidence of serious adverse events and grade ≥3 treatment-related adverse events (TRAEs) was 30.9% and 47.3%, respectively. Grade ≥3 immunotherapy-related adverse events occurred in 3 (5.5%) participants. Five (9.1%) participants discontinued treatment due to TRAEs, all of which were grade 1-2. The ORR was 45.5% (95% CI, 31.97-59.45). The median progression-free survival was 11.0 (95% CI, 8.21-15.24) months. The median overall survival (OS) was 16.4 (95% CI, 11.20-not estimable) months, and 12-month OS rate was 60.0% (95% CI, 45.87-71.55). Circulating tumor DNA status before the third cycle of treatment was associated with prognosis. In conclusion, First-line KN046 plus lenvatinib shows promising efficacy for advanced unresectable or metastatic HCC.

Date: 2025
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DOI: 10.1038/s41467-025-56537-y

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