Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial

作者：Dan Liu, Jun Zhou, Yongsheng Wang, Mingjun Li, Haiping Jiang, Yunpeng Liu, Xianli Yin, Minghua Ge, Xiaojun Xiang, Jieer Ying, Jian Huang, Yanqiao Zhang, Ying Cheng, Zhigang Huang, Xianglin Yuan, Weiqing Han, Dong Yan, Xinshuai Wang, Pan Liu, Linna Wang, Xiaojing Zhang, Suxia Luo, Tianshu Liu, Lin Shen · 发表于：BMC Medicine · 年份：2022 · DOI：10.1186/s12916-022-02605-9 · 被引用次数：84 · 研究领域：TGF-β signaling in diseases、Peptidase Inhibition and Analysis、Cancer Immunotherapy and Biomarkers

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined...