Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study

Amanda Nizam¹, Charles B Nguyen², Jinju Li³, Emily C Zabor⁴, Pavlos Msaouel⁵, Cindy Y Jiang⁶, Omar Alhalabi⁵, Eugene Oh⁷, Matthew P Davidsohn⁸, Ilana B Epstein⁸, Dimitra Rafailia Bakaloudi⁹, Rafee Talukder¹⁰, Tanya Jindal¹¹, Amy K Taylor¹², Michael J Glover¹³, Ali Raza Khaki¹³, Emily Lemke¹⁴, Hannah Mabey¹⁵, Bashar Abuqayas¹⁶, Albert Jang^{17

18}, Jason R Brown¹⁸, Sean T Evans¹⁹, Cameron Pywell²⁰, Arnab Basu²⁰, Mehmet A Bilen¹⁹, Pedro C Barata^{17

18}, Yousef Zakharia¹⁶, Matthew I Milowsky¹⁵, Deepak Kilari¹⁴, Christopher J Hoimes²¹, Sumit A Shah¹³, Hamid Emamekhoo¹², Nancy B Davis²², Shilpa Gupta¹, Petros Grivas^{9

23}, Joaquim Bellmunt⁸, Matthew T Campbell⁵, Ajjai S Alva², Vadim S Koshkin¹¹

Affiliations

¹ Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
² Department of Hematology and Oncology, University of Michigan Rogel Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
³ Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁴ Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
⁵ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁶ Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁸ Genitourinary Oncology Program, Dana-Farber Cancer Institute-IMIM Research Lab, Boston, Massachusetts, USA.
⁹ Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁰ Division of Hematology/Oncology, Baylor College of Medicine, Houston, Texas, USA.
¹¹ Department of Hematology/Oncology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
¹² Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
¹³ Division of Oncology, Stanford University, Stanford, California, USA.
¹⁴ Division of Hematology and Oncology, Froedtert and the Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁵ Department of Medicine, Division of Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
¹⁶ Department of Medicine, University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USA.
¹⁷ Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
¹⁸ Department of Medicine, Case Western Reserve University/University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.
¹⁹ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
²⁰ Department of Medicine, University of Alabama at Birmingham O'neal Comprehensive Cancer Center, Birmingham, Alabama, USA.
²¹ Department of Medicine, Duke Cancer Institute, Durham, North Carolina, USA.
²² Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²³ Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.

PMID: 41031719
PMCID: PMC12486332
DOI: 10.1002/cam4.71284

Multicenter Study

Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study

Amanda Nizam et al. Cancer Med. 2025 Oct.

. 2025 Oct;14(19):e71284.

doi: 10.1002/cam4.71284.

Authors

Affiliations

¹ Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
² Department of Hematology and Oncology, University of Michigan Rogel Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
³ Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁴ Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.
⁵ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁶ Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁸ Genitourinary Oncology Program, Dana-Farber Cancer Institute-IMIM Research Lab, Boston, Massachusetts, USA.
⁹ Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁰ Division of Hematology/Oncology, Baylor College of Medicine, Houston, Texas, USA.
¹¹ Department of Hematology/Oncology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
¹² Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
¹³ Division of Oncology, Stanford University, Stanford, California, USA.
¹⁴ Division of Hematology and Oncology, Froedtert and the Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁵ Department of Medicine, Division of Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
¹⁶ Department of Medicine, University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USA.
¹⁷ Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
¹⁸ Department of Medicine, Case Western Reserve University/University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA.
¹⁹ Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
²⁰ Department of Medicine, University of Alabama at Birmingham O'neal Comprehensive Cancer Center, Birmingham, Alabama, USA.
²¹ Department of Medicine, Duke Cancer Institute, Durham, North Carolina, USA.
²² Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²³ Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.

PMID: 41031719
PMCID: PMC12486332
DOI: 10.1002/cam4.71284

Abstract

Introduction: Enfortumab vedotin-ejfv (EV), an antibody-drug conjugate approved for advanced urothelial carcinoma (aUC), has limited real-world safety data and no validated predictive biomarkers. Retrospective studies suggest higher objective response rates (ORR) among patients developing EV-related dermatologic toxicities, but survival implications remain unclear. This analysis assessed the safety of EV monotherapy and the impact of dermatologic and neurologic toxicities on efficacy outcomes in a multi-institutional cohort.

Materials and methods: UNITE is a multicenter, retrospective study across 16 US sites of patients with aUC treated with targeted agents, including EV. Primary endpoints were the incidence of EV treatment-related adverse events (TRAEs, any grade) and TRAE-related treatment modifications. Secondary endpoints included a comparison of ORR, progression-free survival (PFS), and overall survival (OS) between patients with and without dermatologic toxicities and neuropathy. To reduce immortal time bias, Cox regression models incorporated TRAEs as time-dependent covariates to adjust for EV treatment duration as well as Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, and liver metastases.

Results: Between 2018 and 2023, 485 patients with aUC received > 1 dose of EV monotherapy. Most (67%) received > 2 prior therapy lines. Any grade TRAEs occurred in 77%, most frequently neuropathy (36%) and dermatologic toxicities (27%); 57% required treatment modification and 21% discontinued EV, primarily due to neuropathy (9%) and fatigue (3%). Patients with dermatologic toxicities and neuropathy had higher ORR (56% vs. 42%; p = 0.007 and 64% vs. 35%; p < 0.0001, respectively). Neuropathy was independently associated with improved OS (HR 0.66; 95% CI 0.50-0.87; p = 0.002); dermatologic TRAEs were not associated with PFS or OS benefit.

Conclusions: EV safety outside clinical trials was consistent with prior reports, with no new signals. Treatment modifications were most often due to neuropathy, dermatologic toxicities, and fatigue. Both dermatologic toxicities and neuropathy correlated with higher ORR, but only neuropathy was independently associated with improved OS.

Keywords: adverse events; antibody–drug conjugates; enfortumab vedotin; treatment‐related toxicity; urothelial carcinoma.

PubMed Disclaimer

Conflict of interest statement

Amanda Nizam reports the following disclosures—consulting or advisory role: AVEO Oncology, Astellas Pharma, Seagen, Pfizer, EMD Serono/Merck KGaA, Mashup Media, IDEOlogy Health; Honoraria: Cleveland Clinic, Aptitude Health, Targeted Oncology, IntegrityCE, MECC Global Meetings, ASCO, Doximity; Travel and accommodation expenses: ASCO, MECC Global Meetings, Mashup Media; Section editor (bladder cancer): GU Oncology Now (Mashup Media). Charles B. Nguyen reports no conflicts of interest. Jinju Li reports no conflicts of interest. Emily C. Zabor reports no conflicts of interest. Pavlos Msaouel reports the following disclosures—Consulting or advisory role: Mirati Therapeutics, Bristol Myers Squibb, Exelixis, Axiom Healthcare, KCCure; Honoraria: Exelixis, Pfizer; Steering committee member: Kidney Cancer Association; Research funding: Takeda, Bristol Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research; Institutional research funding: National Cancer Institute (Grant P30 CA0166672). Cindy Y. Jiang reports no conflicts of interest. Omar Alhalabi reports the following disclosures—Consulting or advisory role: Seagen, Silverback Therapeutics, Cardinal Health; Institutional research funding: AstraZeneca, Ikena Oncology, Roche/Genentech, Arcus Biosciences. Eugene Oh reports no conflicts of interest. Matthew P. Davidsohn reports no conflicts of interest. Ilana B. Epstein reports no conflicts of interest. Dimitra Rafailia Bakaloudi reports the following disclosures—Research funding: KureIt Cancer Research Award. Rafee Talukder reports no conflicts of interest. Tanya Jindal reports no conflicts of interest. Amy K. Taylor reports no conflicts of interest. Michael J. Glover reports no conflicts of interest. Ali Raza Khaki reports the following disclosures—Consulting or advisory role (all uncompensated): Janssen, Pfizer, Astellas Pharma; Institutional research funding: Janssen, 23andMe. Emily Lemke reports the following disclosures—Consulting or advisory role: AXDEV; Honoraria: AXDEV. Hannah Mabey reports no conflicts of interest. Bashar Abuqayas reports no conflicts of interest. Albert Jang reports no conflicts of interest. Jason R. Brown reports the following disclosures—Consulting or advisory role: Pfizer, AstraZeneca, EMD Serono; Speaker's Bureau: EMD Serono; Institutional research funding: Bicycle Therapeutics, Roche, Pfizer. Sean T. Evans reports no conflicts of interest. Cameron Pywell reports no conflicts of interest. Arnab Basu reports the following disclosures—Consulting or advisory role: Sanofi Aventis, EMD Serono, Bristol Myers Squibb, Pfizer, Dendreon, Astellas Pharma, Eisai, Seagen; Speaker's Bureau: Eisai; Honoraria: Eisai, Natera, Gilead Sciences, Cardinal Health; Institutional research funding: Merck, EMD Serono, Natera, Astellas Pharma, Bristol Myers Squibb, Celgene, Roche/Genentech, AVEO Oncology. Mehmet A. Bilen reports the following disclosures—Consulting or advisory role: Exelixis, Sanofi, Nektar, EMD Serono, Eisai, Janssen, Genomic Health, Pfizer, Bristol Myers Squibb, Bayer, Exelixis, Calithera Biosciences, AstraZeneca, Seagen; Institutional research funding: Bayer, Bristol Myers Squibb, Roche/Genentech, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Pfizer, Seagen, Xencor, Exelixis, Advanced Accelerator Applications, Genome and Company, Peloton Therapeutics, Merck, NiKang Therapeutics. Pedro C. Barata reports the following disclosures—Consulting or advisory role: Astellas Pharma, AstraZeneca, Bayer, Eisai, Caris Life Sciences, Exelixis, Janssen, EMD Serono, Dendreon, Pfizer, Seagen, Bristol Myers Squibb, Bayer, Guardant Health, Myovant; Honoraria: UroToday, OncLive, Targeted Oncology; Research funding: AstraZeneca, Merck, Caris Life Sciences, ESSA Pharma, Myovant, Merck, Exelixis, Merus. Yousef Zakharia reports the following disclosures—Consulting or advisory role: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, AstraZeneca, Array, Bayer, Pfizer, Clovis, EMD Serono, Myovant; Data safety monitoring committee: Janssen Research and Development; Institutional research funding: NewLinkGenetics, Pfizer, Exelixis, Eisai. Matthew I. Milowsky reports the following disclosures—Consulting or advisory role: Loxo/Lilly, G1 Therapeutics; Honoraria: Elsevier, Medscape, Research to Practice; Stock and other ownership interests: Pfizer, Merck, Gilead Sciences; Institutional research funding: Merck, Roche/Genentech, Bristol Myers Squibb, Mirati Therapeutics, Incyte, Seagen, G1 Therapeutics, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Clovis Oncology, Arvinas, ALX Oncology, Loxo, Hoosier Cancer Research Network, AstraZeneca/MedImmune, Novartis, Acrivon Therapeutics, Astellas Pharma, Accuray, Boehringer Ingelheim, Amgen, Constellation Pharmaceuticals, Bayer, Prostate Cancer Clinical Trials Consortium. Deepak Kilari reports the following disclosures—Consulting or advisory role: Eisai, Exelixis, Sanofi, Merck Sharp & Dohme Inc., Myovant Sciences, Astellas Pharma, Pfizer; Speaker's Bureau: Janssen, AVEO Oncology, Seagen, Exelixis; Honoraria: MJH Life Sciences, Exelixis; Travel and accommodation expenses: Exelixis, Janssen, Astellas Pharma, AVEO Oncology; Institutional research funding: Exelixis, Genentech, Sobi, Astellas Pharma, Pfizer. Christopher J. Hoimes reports the following disclosures—Consulting or advisory role: Bristol Myers Squibb, Eisai, Prometheus, Seagen, Genentech/Roche, Merck Sharp & Dohme, 2bPrecise; Speaker's Bureau: Bristol Myers Squibb, Genentech/Roche, Astellas Pharma, Seagen, Eisai; Honoraria: Seagen; Institutional research funding: Merck Sharp & Dohme, Janssen Oncology, Novartis, Alkermes, Dynavax Technologies, Nektar, NanoCarrier, Seagen, Astellas Pharma, Bristol Myers Squibb Foundation, BioNTech SE, CRISPR Therapeutics, NeoImmuneTech, Mirati Therapeutics; Uncompensated Relationships: 2bPrecise (institutional). Sumit A. Shah reports no conflicts of interest. Hamid Emamekhoo reports the following disclosures—Consulting or advisory role: Seagen, Janssen Biotech, AVEO Oncology, Cardinal Health, Exelixis. Nancy B. Davis reports the following disclosures—Employment: Merck, Sharp & Dohme Inc.; Consulting or advisory role: Janssen Biotech; Institutional research funding: AstraZeneca, Roche, Pfizer, Merck, Incyte, Mirati Therapeutics, Seagen, Astellas Pharma, Calithera Biosciences, Immunomedics, Bristol Myers Squibb, Exelixis, Gilead Sciences. Shilpa Gupta reports the following disclosures—Consulting or advisory role: Gilead Sciences, EMD Serono, Pfizer, Merck, Foundation Medicine, Seagen, Bayer, Bristol Myers Squibb/Medarex; Speaker's Bureau: Bristol Myers Squibb, Janssen Oncology, Gilead Sciences, Seagen; Stock and other ownership interests: Moderna Therapeutics, BioNTech SE, Nektar; Institutional research funding: Bristol Myers Squibb Foundation, Merck, Roche/Genentech, EMD Serono, QED Therapeutics, Seagen, Moderna Therapeutics, Exelixis, Gilead Sciences, Novartis. Petros Grivas reports the following disclosures—Consulting or advisory role: MSD, Bristol Myers Squibb, AstraZeneca, EMD Serono, Seagen, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, Silverback Therapeutics, BostonGene, Fresenius Kabi, Lucence Health, PureTech, G1 Therapeutics, Aadi Biosciences, CG Oncology, Strata Oncology, ImmunityBio, Asieris Pharmaceuticals, AbbVie; Institutional research funding: Pfizer, Bristol Myers Squibb, MSD, QED Therapeutics, GlaxoSmithKline, Mirati Therapeutics, EMD Serono, G1 Therapeutics, Gilead Sciences, Acrivon Therapeutics, ALX Oncology, Genentech. Joaquim Bellmunt reports the following disclosures—Consulting or advisory role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers Squibb; Honoraria: UpToDate; Travel and accommodation expenses: Pfizer, MSD Oncology, Ipsen; Patents, royalties, other intellectual property: UpToDate Bladder Cancer (section editor); Stock and other ownership interests: Rainier Therapeutics; Steering Committee Member: Genentech; Data Safety Monitoring Board: Merck, Pfizer, MSD Oncology, Genentech, AstraZeneca; Institutional research funding: Millenium, Sanofi, Pfizer, EMD Serono. Matthew T. Campbell reports the following disclosures—Consulting or advisory role: Exelixis, Eisai, Seagen; Speaker's Bureau: Curio Science, Dava Oncology, MJH Life Sciences; Institutional research funding: ApricityHealth, AstraZeneca, Exelixis, Janssen, Pfizer, Seagen, United States Department of Defense. Ajjai S. Alva reports the following disclosures—Consulting or advisory role: AstraZeneca, Bristol Myers Squibb, Merck, Pfizer; Travel and accommodation expenses: Bristol Myers Squibb, Merck; Institutional research funding: Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Genentech, Merck Sharp & Dohme Inc., Janssen, Mirati Therapeutics, Progenics, Prometheus Laboratories, Roche. Vadim S. Koshkin reports the following disclosures—Consulting or advisory role: Janssen, Clovis Oncology, Astellas Pharma, Seagen, Pfizer, EMD Serono, Gerson Lehrman Group, ExpertConnect, Guidepoint Global; Steering Committee Member: Seagen; Institutional research funding: Clovis Oncology, Nektar, Endocyte, Taiho Oncology, Merck, Gilead Sciences, Lilly, Seagen, Novartis, Prostate Cancer Foundation.

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Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study

Affiliations

Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Medical