Sacituzumab tirumotecan in participants with advanced or metastatic urothelial carcinoma and disease progression after chemotherapy and immune checkpoint inhibitors

Y Zhu; S Jiang; Y Shi; S Wang; F Yuan; F Zhou; K Jiang; X Zhang; L Seneviratne; G Yu; M Zhang; T Liu; X Li; X Chen; X Wang; S Zhang; Y Liu; Y Ge; M Chen; G Blumenthal; O Akala; Y Li; X Li; J Ge; D Ye

doi:10.1016/j.annonc.2025.11.013

Sacituzumab tirumotecan in participants with advanced or metastatic urothelial carcinoma and disease progression after chemotherapy and immune checkpoint inhibitors

Ann Oncol. 2025 Nov 21:S0923-7534(25)06272-6. doi: 10.1016/j.annonc.2025.11.013. Online ahead of print.

Authors

Y Zhu¹, S Jiang², Y Shi³, S Wang¹, F Yuan⁴, F Zhou³, K Jiang⁵, X Zhang⁶, L Seneviratne⁷, G Yu⁸, M Zhang⁹, T Liu¹⁰, X Li¹¹, X Chen¹², X Wang¹³, S Zhang¹⁴, Y Liu¹⁵, Y Ge¹⁶, M Chen¹⁷, G Blumenthal¹⁷, O Akala¹⁷, Y Li¹⁸, X Li¹⁸, J Ge¹⁸, D Ye¹⁹

Affiliations

¹ Fudan University Shanghai Cancer Center, Shanghai, China.
² The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China.
³ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
⁴ Chongqing University Cancer Hospital (Chongqing Cancer Institute and Chongqing Cancer Hospital) Chongqing, China.
⁵ The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
⁶ Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁷ Los Angeles Hematology Oncology Medical Group, Los Angeles, USA.
⁸ Weifang People's Hospital, Weifang, China.
⁹ The Second Hospital of Anhui Medical University, Hefei, China.
¹⁰ Zhongshan Hospital, Fudan University, Shanghai, China.
¹¹ The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹² Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
¹³ Sir Run Run Shaw Hospital, Affiliated with Zhejiang University School of Medicine, Hangzhou, China.
¹⁴ West China Hospital of Sichuan University, Chengdu, China.
¹⁵ The First Hospital of China Medical University, Shenyang, China.
¹⁶ Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
¹⁷ Merck & Co., Inc., Rahway, USA.
¹⁸ Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., Chengdu, China.
¹⁹ Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Shanghai, China. Electronic address: dwyeli@163.com.

PMID: 41276258
DOI: 10.1016/j.annonc.2025.11.013

Abstract

Background: Trophoblast cell-surface antigen 2 (TROP2) is overexpressed in advanced or metastatic urothelial cancer (UC), representing a promising therapeutic target. Sacituzumab tirumotecan (sac-TMT) is a TROP2-directed antibody-drug conjugate with a unique, bifunctional linker that maximizes payload delivery to tumor cells. We present preliminary results for sac-TMT monotherapy from cohort 9 of the phase 1/2 2870-001/KL264-01 study in participants with advanced or metastatic UC.

Participants and methods: Eligible participants with locally advanced or metastatic UC and disease progression on one or more prior line of platinum-based chemotherapy and anti-programmed cell death-(ligand) protein 1 therapy received sac-TMT 5 mg/kg intravenously every 2 weeks until disease progression, unacceptable toxicity, or participant/physician decision. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Results: By data cut-off (17 February 2025), 49 participants were treated with sac-TMT; 37 (76%) had received two or more prior lines of therapy. Median follow-up for this analysis was 18.8 months. The confirmed ORR was 31% [95% confidence interval (CI), 18% to 45%] and the disease control rate was 71% (95% CI 57% to 83%). Median DOR was not reached [range 2.1-22.2+ (+ indicates censored data for the longest DOR, suggesting that patients may have achieved longer remission duration) months], and the 12-month probability of sustained response was 53%. Median PFS and OS were 5.5 months (95% CI 3.6-7.2 months) and 12.1 months (95% CI, 9.9-15.3 months), with 18-month rates of 26% and 33%, respectively. Grade 3/4 treatment-related adverse events (AEs) occurred in 31 participants (63%), and the most common (≥5%) were anemia (41%), decreased neutrophil count (35%), decreased white blood cell count (20%), stomatitis (12%), and decreased platelet count (8%). There were no grade 5 treatment-related AEs or febrile neutropenia events.

Conclusions: Sac-TMT 5 mg/kg monotherapy every 2 weeks demonstrated promising antitumor activity in participants with heavily pretreated advanced or metastatic UC, with a manageable safety profile, warranting further evaluation of sac-TMT in this population.

Keywords: antibody-drug conjugate; metastatic urothelial carcinoma; sacituzumab tirumotecan; urothelial cancer.