TROP-2-targeted antibody-drug conjugate SHR-A1921 for advanced or metastatic solid tumors: A first-in-human phase 1 study

Jia Zhong; Lin Wu; Zhengbo Song; Nianzeng Xing; Jiujie Cui; Xingya Li; Kailun Fei; Dihong Tang; Qi Dang; Liang Chen; Tianshu Liu; Caigang Liu; Yong Li; Shichuan Zhang; Xinghua Han; Juxiang Xiao; Feng Guo; Min Yan; Huiting Xu; Chunxiu Yuan; Jincai Zhong; Rongrui Liu; Xiujuan Qu; Shikai Wu; Shusuan Jiang; Yan Yang; Panpan Zhang; Hongqian Guo; Ce Wang; Qiushi Xie; Zhifei Lin; Shuni Wang; Jie Wang

doi:10.1016/j.ccell.2025.09.012

TROP-2-targeted antibody-drug conjugate SHR-A1921 for advanced or metastatic solid tumors: A first-in-human phase 1 study

Cancer Cell. 2025 Oct 23:S1535-6108(25)00404-0. doi: 10.1016/j.ccell.2025.09.012. Online ahead of print.

Authors

Jia Zhong¹, Lin Wu², Zhengbo Song³, Nianzeng Xing⁴, Jiujie Cui⁵, Xingya Li⁶, Kailun Fei¹, Dihong Tang⁷, Qi Dang⁸, Liang Chen⁹, Tianshu Liu¹⁰, Caigang Liu¹¹, Yong Li¹², Shichuan Zhang¹³, Xinghua Han¹⁴, Juxiang Xiao¹⁵, Feng Guo¹⁶, Min Yan¹⁷, Huiting Xu¹⁸, Chunxiu Yuan¹⁹, Jincai Zhong²⁰, Rongrui Liu²¹, Xiujuan Qu²², Shikai Wu²³, Shusuan Jiang²⁴, Yan Yang²⁵, Panpan Zhang²⁶, Hongqian Guo²⁷, Ce Wang²⁸, Qiushi Xie²⁸, Zhifei Lin²⁸, Shuni Wang²⁸, Jie Wang²⁹

Affiliations

¹ State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
² Thoracic Medical Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine/Hunan Cancer Hospital, Central South University, Changsha 410000, China.
³ Phase І Clinical Trial Ward, Zhejiang Cancer Hospital, Hangzhou 310022, China.
⁴ Department of Urology, Shanxi Provincial Cancer Hospital, Taiyuan 030013, China.
⁵ Oncology Department, Shanghai Jiaotong University School of Medicine Renji Hospital, Shanghai 200127, China.
⁶ Medical Oncology, The Second Ward of Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁷ Gynecologic Oncology Ward IV, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410000, China.
⁸ Phase I Clinical Research Center, Shandong First Medical University Affiliated Tumor Hospital, Jinan 250000, China.
⁹ Gynecological Tumor Ward 1, Shandong First Medical University Affiliated Tumor Hospital, Jinan 250000, China.
¹⁰ Oncology Department, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
¹¹ Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110000, China.
¹² Internal Medicine, Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
¹³ Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610000, China.
¹⁴ Department of Chemotherapy Oncology, Anhui Provincial Hospital, Hefei 230000, China.
¹⁵ Internal Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
¹⁶ Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215000, China.
¹⁷ Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
¹⁸ Department of Abdominal Oncology 1, Hubei Cancer Hospital, Wuhan 430000, China.
¹⁹ Department of Medical Oncology, General Hospital of Ningxia Medical University, Ningxia 750001, China.
²⁰ Department of Medical Oncology, Ward 1, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, China.
²¹ Oncology Department, The First Medical Center of the General Hospital of the People's Liberation Army of China, Beijing 100039, China.
²² Medical Oncology, The First Hospital of China Medical University, Shenyang 110000, China.
²³ Department of Medical Oncology, Peking University First Hospital, Beijing 100034, China.
²⁴ Urology Surgery Department, Hunan Cancer Hospital, Changsha 410006, China.
²⁵ Department of Gastroenterology, Gansu Provincial Cancer Hospital, Lanzhou 730050, China.
²⁶ Department of Early Drug Development Centre, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing 100142, China.
²⁷ Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing 210008, China.
²⁸ Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai 201210, China.
²⁹ State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China. Electronic address: zlhuxi@163.com.

PMID: 41135519
DOI: 10.1016/j.ccell.2025.09.012

Abstract

This study is a first-in-human, three-stage, phase 1 trial (NCT05154604) designed to evaluate the trophoblast cell-surface antigen 2 (TROP-2)-targeted antibody-drug conjugate SHR-A1921 (1.5-6.0 mg/kg every 3 weeks) in 391 patients with pretreated advanced/metastatic solid tumors. Grade ≥3 treatment-related adverse events occurred in 132 patients (33.8%), with the most common being stomatitis, affecting 57 patients (14.6%). SHR-A1921 showed a low incidence of hematologic toxicities, with only 3.1% of patients experiencing grade ≥3 decreases in neutrophil count. The overall objective response rate was 24.8% (95% confidence interval [CI], 20.6-29.4), ranging from 18.2% to 43.1% across cohorts with platinum-resistant ovarian cancer, triple-negative breast cancer, small-cell lung cancer, non-small cell lung cancer, hormone receptor-positive breast cancer, cervical cancer, and biliary tract cancer. No significant correlation was found between TROP-2 expression and treatment efficacy. In summary, SHR-A1921 exhibited promising antitumor activity and a manageable safety profile, with 3.0 mg/kg every 3 weeks selected for further clinical development.

Keywords: SHR-A1921; TROP-2; advanced/metastatic solid tumor; antibody-drug conjugate.