AUTHOR=Jaime-Casas Salvador , Barragan-Carrillo Regina , Zugman Miguel , Shah Koral , Ebrahimi Hedyeh , Mercier Benjamin , Castro Daniela V. , Zang Peter D. , LeVee Alexis , Yip Wesley , Li Xiaochen , Dizman Nazli , Salgia Nicholas J. , Zengin Zeynep , Meza Luis , Hsu JoAnn , Nguyen Charles B. , Chehrazi-Raffle Alexander , Pal Sumanta K. , Tripathi Abhishek 

TITLE=Efficacy and safety of antibody-drug conjugate combination therapy in advanced urothelial carcinoma

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1669526

DOI=10.3389/fonc.2025.1669526

ISSN=2234-943X

ABSTRACT=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.