Human epidermal growth factor receptor 2 (HER2)–directed antibody–drug conjugate monotherapy has shown preliminary clinical efficacy in patients with chemotherapy-refractory HER2-positive locally advanced or metastatic urothelial cancer. Previous data showed promising antitumor activity and safety of HER2-specific disitamab vedotin as monotherapy and when combined with programmed cell death protein 1 (PD-1)–directed immunotherapy in this cancer.
Methods
In this phase 3, multicenter, open-label, randomized trial, we assigned patients with previously untreated HER2-expressing (immunohistochemical score of 1+, 2+, or 3+) locally advanced or metastatic urothelial cancer in a 1:1 ratio to receive either disitamab vedotin plus PD-1–specific toripalimab every 2 weeks or chemotherapy (gemcitabine plus cisplatin or carboplatin) every 3 weeks. The dual primary end points were progression-free survival (assessed by blinded independent review) and overall survival. Secondary end points included objective response and safety. Here we report the prespecified progression-free survival analysis and interim overall survival analysis.
Results
A total of 484 patients underwent randomization. The median follow-up was 18.2 months. Progression-free survival was significantly longer in the disitamab vedotin–toripalimab group than in the chemotherapy group (median, 13.1 vs. 6.5 months; hazard ratio for progression or death, 0.36; 95% confidence interval [CI], 0.28 to 0.46; P<0.001). Overall survival was also significantly longer in the disitamab vedotin–toripalimab group than in the chemotherapy group (median, 31.5 vs. 16.9 months; hazard ratio for death, 0.54; 95% CI, 0.41 to 0.73; P<0.001). The percentage of patients with an objective response was 76.1% (95% CI, 70.3 to 81.3) in the disitamab vedotin–toripalimab group and 50.2% (95% CI, 43.7 to 56.7) in the chemotherapy group. The safety profile of disitamab vedotin plus toripalimab was more favorable than that of chemotherapy; grade 3 or higher treatment-related adverse events occurred in 55.1% of patients who received disitamab vedotin plus toripalimab and 86.9% of those who received chemotherapy.
Conclusions
Disitamab vedotin–toripalimab led to a significantly greater improvement in outcomes than chemotherapy among patients with untreated HER2-expressing locally advanced or metastatic urothelial cancer. (Funded by RemeGen and others; RC48-C016 ClinicalTrials.gov number, NCT05302284; ChinaDrugTrials.org.cn number, CTR20220348.)
- Xinan Sheng, MD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Genitourinary Oncology, Peking University Cancer Hospital and Institute, Beijing
- Gongqian Zeng, MD, Hunan Cancer Hospital, Changsha, China
- Cuijian Zhang, MD, Peking University First Hospital, Beijing
- Qingyun Zhang, MD, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China
- Jiasheng Bian, MD, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Haitao Niu, MD, Affiliated Hospital of Qingdao University, Qingdao, China
- Jun Li, MD, Chongqing University Cancer Hospital, Chongqing, China
- Yanxia Shi, MD, Sun Yat-sen University Cancer Center, Guangzhou, China
- Kai Yao, MD, Sun Yat-sen University Cancer Center, Guangzhou, China
- Bin Hu, MD, Liaoning Cancer Hospital and Institute, Shenyang, China
- Ziling Liu, MD, First Hospital of Jilin University, Changchun, China
- Hong Liao, MD, Sichuan Cancer Hospital, Chengdu, China
- Zhixian Yu, MD, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Baiye Jin, MD, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Peng Zhao, MD, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Tiejun Yang, MD, Affiliated Cancer Hospital of Zhengzhou University–Henan Cancer Hospital, Zhengzhou, China
- Xianling Liu, MD, Second Xiangya Hospital of Central South University, Changsha, China
- Yang Qin, MD, Yunnan Cancer Hospital, Kunming, China
- Xueyi Xue, MD, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Xin Gou, MD, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Jian Huang, MD, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Jiang Gu, MD, Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Xiaolong Qi, MD, Zhejiang Provincial People’s Hospital, Hangzhou, China
- Lu Zhang, MD, RemeGen, Yantai, China
- Guoxian Ma, MD, RemeGen, Yantai, China
- Beisong Liu, BSc, RemeGen, Yantai, China
- Jianmin Fang, PhD, School of Life Science and Technology, Tongji University, Shanghai
- Shusuan Jiang, MD, Hunan Cancer Hospital, Changsha, China
- Zhisong He, MD, Peking University First Hospital, Beijing
- Aiping Zhou, MD, National Cancer Center, National Clinical Research Center for Cancer, and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
- Jun Guo, MD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Genitourinary Oncology, Peking University Cancer Hospital and Institute, Beijing
- for the RC48-C016 Trial Investigators
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