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

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收录情况： ◇ SCIE

作者：
Dan Liu[1] * ; Jun Zhou[2] * ; Yongsheng Wang[3] ; Mingjun Li[4] ; Haiping Jiang[5] ; Yunpeng Liu[6] ; Xianli Yin[7] ; Minghua Ge[8] ; Xiaojun Xiang[9] ; Jieer Ying[10] ; Jian Huang[11] ; Yan‑qiao Zhang[12] ; Ying Cheng[13] ; Zhigang Huang[14] ; Xianglin Yuan[15] ; Weiqing Han[16] ; Dong Yan[17] ; Xinshuai Wang[18] ; Pan Liu[19] ; Linna Wang[19] ; Xiaojing Zhang[19] ; Suxia Luo[20] ; Tianshu Liu[21] ; Lin Shen[2] ;
机构： [1]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Edu‑cation), Early Drug Development Center, Peking University Cancer Hospital & Institute, Beijing, China [2]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu‑Cheng Road 52, Hai‑Dian District, Beijing 100142, China [3]Oncology, West China Hospital, Sichuan University, Chengdu, China [4]Oncology Department, The First Afliated Hospital of Zhengzhou University, Zhengzhou, China [5]Department of Medical Oncology, First Afliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China [6]Medical Oncology, The First Hospital of China Medical University, Shenyang, China [7]Department of Gastroenterology, Hunan Cancer Hospital, Changsha, China [8]Head and Neck Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China [9]Oncology Department, The First Afli‑ated Hospital of Nanchang University, Nanchang, China [10]Hepatobiliary Pancreatic Gastroenterology, Zhejiang Cancer Hospital, Hangzhou, China [11]Urinary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China [12]Ward 2, Department of Gastroenterology, Harbin Medi‑cal University Cancer Hospital, Harbin, China [13]Oncology Department, Jilin Cancer Hospital, Changchun, China [14]Otolaryngology Head and Neck Surgery Center, Beijing Tongren Hospital, Beijing, China [15]Oncology Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [16]Urology Surgery, Hunan Cancer Hospital (The Afliated Cancer Hospital of Xiangya School of Medicine, Central South University), Changsha, China [17]Oncology Department, Beijing Luhe Hospital, Capital Medical University, Beijing, China [18]Oncology Department, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Afliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China [19]Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co。, Ltd, Shanghai, China [20]Department of Gas‑troenterology, Henan Tumor Hospital, Dongming Road 127, Jinshui District, Zhengzhou 450003, China [21]Medical Oncology, Zhongshan Hospital Fudan University, Fenglin Road 180, Xuhui District, Shanghai 200032, China
出处：
DOI： 10.1186/s12916-022-02605-9
ISSN：

摘要：
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.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).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, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR.SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration.ClinicalTrials.gov , NCT03710265.© 2022. The Author(s).

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外文
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出版当年[2021]版：
大类 | 1 区 医学
小类 | 1 区 医学：内科
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 医学：内科
JCR分区：
出版当年[2020]版：
Q1 MEDICINE, GENERAL & INTERNAL
最新[2023]版：
Q1 MEDICINE, GENERAL & INTERNAL

影响因子： 最新[2023版] 最新五年平均 出版当年[2020版] 出版当年五年平均 出版前一年[2019版] 出版后一年[2021版]

第一作者：
第一作者机构： [1]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Edu‑cation), Early Drug Development Center, Peking University Cancer Hospital & Institute, Beijing, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Dan Liu,Jun Zhou,Yongsheng Wang,et al.Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial[J].BMC MEDICINE.2022,20(1):doi:10.1186/s12916-022-02605-9.
APA：
Dan Liu,Jun Zhou,Yongsheng Wang,Mingjun Li,Haiping Jiang...&Lin Shen.(2022).Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.BMC MEDICINE,20,(1)
MLA：
Dan Liu,et al."Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial".BMC MEDICINE 20..1(2022)

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