BRIEF RESEARCH REPORT article
Front. Oncol.
Sec. Genitourinary Oncology
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1669526
This article is part of the Research TopicUrothelial Neoplasms: An Integrated Approach to Prevention, Diagnostics, and Personalized TherapyView all 10 articles
Efficacy and safety of antibody-drug conjugate combination therapy in advanced urothelial carcinoma
Provisionally accepted
Salvador Jaime-Casas1*
Regina Barragan-Carrillo2Miguel Zugman1Koral Shah1Hedyeh Ebrahimi3Benjamin Mercier1Daniela V. Castro1Peter D. Zang1Alexis LeVee1Wesley Yip1Xiaochen Li1Nazli Dizman4Nicholas J. Salgia5JoAnn Hsu1Zeynep Zengin6Luis Meza6Charles Nguyen1
Alexander Chehrazi-Raffle1
Sumanta Kumar Pal1
Abhishek Tripathi1*- 1City of Hope, Duarte, United States
- 2Instituto Nacional de Cancerologia, Mexico City, Mexico
- 3Beth Israel Deaconess Medical Center Cancer Center, Boston, United States
- 4M.D. Anderson Cancer Center, Houston, TX, USA., Houston, United States
- 5Roswell Park Comprehensive Cancer Center, Buffalo, United States
- 6Yale School of Medicine, New Haven, United States
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Antibody-drug conjugates (ADCs) are revolutionizing the treatment landscape of advanced urothelial carcinoma (aUC). We systematically reviewed the PubMed and Embase databases for published clinical trials evaluating ADC-combination regimens in aUC. We extracted safety and efficacy outcomes, including objective-response rate (ORR), adverse events (AEs), and ≥ grade 3 AEs. We excluded narrative reviews, retrospective studies, and case reports. Two independent reviewers screened titles and abstracts for relevance, followed by a full-text review for eligibility. A total of 645 patients from 5 trials investigating anti-nectin-4 (enfortumab vedotin, EV), anti-TROP2 (sacituzumab govitecan, SG), and anti-HER2 (disitamab vedotin, DV) ADCs were identified. We recorded a pooled ORR of 65%. We recorded a pooled risk rate for all-grade toxicity of 57%. The most prevalent any-grade AEs were peripheral sensory neuropathy 52% (95% CI, 45%-59%), fatigue 45% (95% CI, 28%-64%), and diarrhea 42% (95% CI, 16%-74%). Peripheral sensory neuropathy, fatigue, and alopecia were more commonly observed in anti-nectin-4 regimens. Gastrointestinal (diarrhea and nausea) and hematologic (anemia and neutropenia) toxicities were more commonly observed in anti-TROP2 regimens. Hepatotoxicity was predominantly found in anti-HER2 regimens. While ADC-based combination regimens show promising responses, they also have high rates of AEs in patients with aUC.
Keywords: urothelial carcinoma, Antibody-drug conjugate, clinical trials, Immunotherapy, nectin-4, Trop-2, HER2
Received: 19 Jul 2025; Accepted: 18 Sep 2025.
Copyright: © 2025 Jaime-Casas, Barragan-Carrillo, Zugman, Shah, Ebrahimi, Mercier, Castro, Zang, LeVee, Yip, Li, Dizman, Salgia, Hsu, Zengin, Meza, Nguyen, Chehrazi-Raffle, Pal and Tripathi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Salvador Jaime-Casas, sjaimecasas@coh.org
Abhishek Tripathi, atripathi@coh.org
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