Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer
NCT ID: NCT04223856
Last Updated: 2025-06-13
Study Results
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View full resultsBasic Information
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ACTIVE_NOT_RECRUITING
PHASE3
886 participants
INTERVENTIONAL
2020-03-30
2028-03-01
Brief Summary
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Detailed Description
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This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + platinum-containing chemotherapy, in subjects with previously untreated locally advanced or metastatic urothelial cancer.
Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Pembrolizumab may be administered for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first. Cisplatin or carboplatin plus gemcitabine may be administered for a maximum of 6 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Arm A
Enfortumab vedotin + pembrolizumab
Enfortumab vedotin
Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle
Pembrolizumab
IV infusion on Day 1 of every 3-week cycle
Arm B
Gemcitabine + cisplatin or carboplatin
Cisplatin
administered as IV infusion on Day 1 of each 3-week cycle
Carboplatin
Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle
Gemcitabine
IV infusion on Days 1 and 8 of every 3 week cycle
Interventions
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Enfortumab vedotin
Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle
Pembrolizumab
IV infusion on Day 1 of every 3-week cycle
Cisplatin
administered as IV infusion on Day 1 of each 3-week cycle
Carboplatin
Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle
Gemcitabine
IV infusion on Days 1 and 8 of every 3 week cycle
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Measurable disease by investigator assessment according to RECIST v1.1
* Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy
* Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
* Participants that received neoadjuvant chemotherapy with recurrence \>12 months from completion of therapy are permitted
* Participants that received adjuvant chemotherapy following cystectomy with recurrence \>12 months from completion of therapy are permitted
* Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment
* Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization
* Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2
* Adequate hematologic and organ function
Exclusion Criteria
* Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor
* Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor
* Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment
* Uncontrolled diabetes
* Estimated life expectancy of less than 12 weeks
* Active central nervous system (CNS) metastases
* Ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline
* Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
* Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection.
* History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy
* Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization
* Receipt of radiotherapy within 2 weeks prior to randomization
* Received major surgery (defined as requiring general anesthesia and \>24 hour inpatient hospitalization) within 4 weeks prior to randomization
* Known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin
* Active keratitis or corneal ulcerations
* History of autoimmune disease that has required systemic treatment in the past 2 years
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
* Prior allogeneic stem cell or solid organ transplant
* Received a live attenuated vaccine within 30 days prior to randomization
18 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Seagen Inc.
INDUSTRY
Astellas Pharma Global Development, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Zejing Wang, MD, PhD
Role: STUDY_DIRECTOR
Seagen Inc.
John Lu, MD
Role: STUDY_DIRECTOR
Seagen Inc.
Locations
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Ironwood Cancer & Research Centers - Chandler
Chandler, Arizona, United States
Arizona Oncology Associates PD - HOPE
Tucson, Arizona, United States
Providence St Joseph Medical Center
Burbank, California, United States
City of Hope National Medical Center
Duarte, California, United States
University of California Los Angeles Medical Center
Los Angeles, California, United States
University of California Irvine - Newport
Orange, California, United States
Rocky Mountain Cancer Centers - Aurora
Aurora, Colorado, United States
University of Colorado Hospital / University of Colorado
Aurora, Colorado, United States
Cancer Centers of Colorado - Denver
Denver, Colorado, United States
Yale Cancer Center
New Haven, Connecticut, United States
Eastern CT Hematology and Oncology Associates
Norwich, Connecticut, United States
Lombardi Cancer Center / Georgetown University Medical Center
Washington D.C., District of Columbia, United States
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States
Winship Cancer Institute / Emory University School of Medicine
Atlanta, Georgia, United States
Georgia Cancer Specialists / Northside Hospital Cancer Institute
Marietta, Georgia, United States
Louisiana State University/ East Jefferson General Hospital
Metairie, Louisiana, United States
Maine Health Cancer Care
Biddeford, Maine, United States
Johns Hopkins Medical Center
Baltimore, Maryland, United States
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States
New Mexico Cancer Center
Albuquerque, New Mexico, United States
New York University (NYU) Cancer Institute
New York, New York, United States
Mount Sinai Medical Center
New York, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Vidant Medical Center
Greenville, North Carolina, United States
The Cleveland Clinic
Cleveland, Ohio, United States
Toledo Clinic Cancer Center
Toledo, Ohio, United States
Hillman Cancer Center / University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Saint Francis Hospital / Bon Secours - South Carolina
Greenville, South Carolina, United States
West Cancer Center & Research Institute
Germantown, Tennessee, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
UT Health East Texas Hope Cancer Center
Tyler, Texas, United States
Huntsman Cancer Institute
Salt Lake City, Utah, United States
University of Virginia
Charlottesville, Virginia, United States
Seattle Cancer Care Alliance / University of Washington
Seattle, Washington, United States
Site AR54008
Buenos Aire, , Argentina
Site AR54011
CABA, , Argentina
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Córdoba, , Argentina
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La Rioja, , Argentina
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Mendoza, , Argentina
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Rosario, , Argentina
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San Miguel, , Argentina
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San Miguel de Tucumán, , Argentina
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Viedma, , Argentina
Site AU61003
Box Hill, , Australia
Site AUS61001
Douglas, , Australia
Site AUS61004
Heidelberg, , Australia
Site AUS61002
Macquarie Park, , Australia
Site AUS61006
South Australia, , Australia
Site AU61005
South Brisbane, , Australia
Site BE32003
Brussels, , Belgium
Site BE32002
Ghent, , Belgium
Site BE32001
Liège, , Belgium
Site BE32007
Lueven, , Belgium
Site BE32006
Roeselare, , Belgium
Site CA11004
Calgary, Alberta, Canada
Site CA11003
Edmonton, Alberta, Canada
Site CA11006
Vancouver, British Columbia, Canada
Site CA11002
Hamilton, Ontario, Canada
Site CA11009
London, Ontario, Canada
Site CA11011
Oshawa, Ontario, Canada
Site CA11012
Toronto, Ontario, Canada
Site CA11005
Toronto, Ontario, Canada
Site CA11010
Montreal, Quebec, Canada
Site CA11001
Montreal, Quebec, Canada
Site CA11008
Québec, , Canada
Site CN86009
Beijing, , China
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Beijing, , China
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Beijing, , China
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Beijing, , China
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Bengbu, , China
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Changchun, , China
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Changsha, , China
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Changsha, , China
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Chengdu, , China
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Chongqing, , China
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Chongqing, , China
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Fuzhou, , China
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Guangzhou, , China
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Gunagzhou, , China
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Hangzhou, , China
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Hangzhou, , China
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Hangzhou, , China
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Hefei, , China
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Jinan, , China
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Nanjing, , China
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Nanjing, , China
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Ningbo, , China
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Shanghai, , China
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Shenyang, , China
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Tianjin, , China
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Tianjin, , China
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Wenzhou, , China
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Wuhan, , China
Site CN86030
Xicheng District, , China
Site CN86026
Xuzhou, , China
Site CZ42006
Brno, , Czechia
Site CZ42001
Hradec Králové, , Czechia
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Olomouc, , Czechia
Site CZ42005
Praha 4-Krc, , Czechia
Site DK45001
Aalborg, , Denmark
Site DK45003
Aarhus N, , Denmark
Site FR33014
Bordeaux, , France
Site FR33016
Lyon, , France
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Nice, , France
Site FR33020
Pierre-Bénite, , France
Site FR33013
Strasbourg, , France
Site FR33017
Tours, , France
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Villejuif-Cedex-France, , France
Site DE49003
Berlin, , Germany
Site DE49013
Bielefeld, , Germany
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Düsseldorf, , Germany
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Erlangen, , Germany
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Essen, , Germany
Site DE49007
Frankfurt am Main, , Germany
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Göttingen, , Germany
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Heidelberg, , Germany
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Herne, , Germany
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Jena, , Germany
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Lübeck, , Germany
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Magdeburg, , Germany
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Mannheim, , Germany
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München, , Germany
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Tübingen, , Germany
Site DE49010
Ulm, , Germany
Site HU36003
Budapest, , Hungary
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Budapest, , Hungary
Site HU36006
Debrecen, , Hungary
Site HU36001
Nyíregyháza, , Hungary
Site HU36005
Szolnok, , Hungary
Site IL97203
Beersheba, , Israel
Site IL97201
Haifa, , Israel
Site IL97209
Holon, , Israel
Site IL97206
Jerusalem, , Israel
Site IL97202
Kfar Saba, , Israel
Site IL97208
Petah Tikva, , Israel
Site IL97211
Rehovot, , Israel
Site IL97210
Tel Aviv, , Israel
Site IL97204
Tel Litwinsky, , Israel
Site IL97205
Ẕerifin, , Israel
Site IT39005
Areezo, , Italy
Site IT39008
Candiolo, , Italy
Site IT39009
Cremona, , Italy
Site IT39006
Genova, , Italy
Site IT39003
Meldola, , Italy
Site IT39014
Milan, , Italy
Site IT39007
Milan, , Italy
Site IT39004
Pisa, , Italy
Site IT39002
Terni, , Italy
Site IT39011
Torrette, , Italy
Site IT39001
Verona, , Italy
Site JP81002
Bunkyō City, , Japan
Site JP81009
Chiba, , Japan
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Chiba, , Japan
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Fukuoka, , Japan
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Fukuoka, , Japan
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Hirosaki, , Japan
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Kawasaki-shi, , Japan
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Kōtoku, , Japan
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Kyoto, , Japan
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Niigata, , Japan
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Okayama, , Japan
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Osaka, , Japan
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Osakasayama-Shi, , Japan
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Sapporo, , Japan
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Sendai, , Japan
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Tokushima, , Japan
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Tokyo, , Japan
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Toyama, , Japan
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Tsukuba, , Japan
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Ube, , Japan
Site NL31002
Amsterdam, , Netherlands
Site NL31001
Amsterdam, , Netherlands
Site NL31005
Amsterdam, Noord-Holland, , Netherlands
Site NL31007
Leeuwarden, , Netherlands
Site NL31004
Nieuwegein, , Netherlands
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Rotterdam, , Netherlands
Site NL31006
Utrecht, , Netherlands
Site PL48002
Warsaw, , Poland
Site RU70016
Arkhangelsk, , Russia
Site RU70013
Barnaul, , Russia
Site RU70020
Ivanovo, , Russia
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Krasnoyarsk, , Russia
Site RU70006
Leningradskaya Oblast', , Russia
Site RU70004
Moscow, , Russia
Site RU70011
Moscow, , Russia
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Moscow, , Russia
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Nizhny Novgorod, , Russia
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Omsk, , Russia
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Pyatigorsk, , Russia
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Saint Petersburg, , Russia
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Saint Petersburg, , Russia
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Saint Petersburg, , Russia
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Saint Petersburg, , Russia
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Saransk, , Russia
Site RU70015
Tyumen, , Russia
Site RU70005
Ufa, , Russia
Site SG65001
Singapore, , Singapore
Site SG65002
Singapore, , Singapore
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Singapore, , Singapore
Site KR82001
Daejeon, , South Korea
Site KR82002
Goyang-si, , South Korea
Site KR82008
Hwasun, , South Korea
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Seongnam-si, , South Korea
Site KR82003
Seoul, , South Korea
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Seoul, , South Korea
Site KR82007
Seoul, , South Korea
Site KR82006
Seoul, , South Korea
Site ES34017
Barcelona, , Spain
Site ES34010
Barcelona, , Spain
Site ES34006
Barcelona, , Spain
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Barcelona, , Spain
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Barcelona, , Spain
Site ES34013
Córdoba, , Spain
Site ES34021
Lugo, , Spain
Site ES34018
Madrid, , Spain
Site ES34002
Madrid, , Spain
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Madrid, , Spain
Site ES34015
Madrid, , Spain
Site ES34004
Manresa, , Spain
Site ES34020
Pamplona, , Spain
Site ES34016
Sabadell, , Spain
Site ES34012
Santander, , Spain
Site ES34007
Seville, , Spain
Site ES34019
Valencia, , Spain
Site ES34009
Valencia, , Spain
Site CH41004
Basel, , Switzerland
Site CH41002
Bern, , Switzerland
Site CH41001
Chur, , Switzerland
Site CH41003
Winterthur, , Switzerland
Site TW88603
Kaohsiung City, , Taiwan
Site TW88602
Kweishan, , Taiwan
Site TW88607
Taichung, , Taiwan
Site TW88606
Taichung, , Taiwan
Site TW88604
Tainan City, , Taiwan
Site TW88605
Taipei, , Taiwan
Site TW88601
Taipei, , Taiwan
Site TH66004
Bangkok, , Thailand
Site TH66003
Bangkok, , Thailand
Site TH66006
Bangkok, , Thailand
Site TH66005
Chiang Mai, , Thailand
Site TH66002
Hat Yai, , Thailand
Site TH66007
Muang, , Thailand
Site TH66001
Ratchathewi, , Thailand
Site TR90007
Ankara, , Turkey (Türkiye)
Site TR90009
Ankara, , Turkey (Türkiye)
Site TR90005
Antalya, , Turkey (Türkiye)
Site TR90004
Edirne, , Turkey (Türkiye)
Site TR90008
Istanbul, , Turkey (Türkiye)
Site TR90003
Istanbul, , Turkey (Türkiye)
Site TR90002
Istanbul, , Turkey (Türkiye)
Site TR90001
Konya, , Turkey (Türkiye)
Site TR90006
Malatya, , Turkey (Türkiye)
Site UK44005
Glasgow, , United Kingdom
Site UK44001
London, , United Kingdom
Site UK44009
London, , United Kingdom
Site UK44006
Oxford, , United Kingdom
Site UK44010
Plymouth, , United Kingdom
Site UK44002
Preston, , United Kingdom
Site UK44003
Sheffield, , United Kingdom
Site UK44008
Southampton, , United Kingdom
Countries
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References
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Meng Y, Zhang S, Aout M, Babcock A, Li H, Lai Y, Brand-Wiita S, Notinger S, Bavle A, Mamtani R. Cost-effectiveness of enfortumab vedotin plus pembrolizumab as a first-line treatment of locally advanced or metastatic urothelial carcinoma in the United States. J Med Econ. 2025 Oct 3:1-18. doi: 10.1080/13696998.2025.2567190. Online ahead of print.
Gupta S, Loriot Y, Van der Heijden MS, Bedke J, Valderrama BP, Kikuchi E, Flechon A, Petrylak D, De Santis M, Galsky MD, Lee JL, Swami U, Sridhar SS, De Giorgi U, Wright P, Shih V, Lu YT, Guan X, Dillon R, Shetty A, Moreno BH, Beaumont JL, Purnajo I, McManus S, Powles T. Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2025 Jun;26(6):795-805. doi: 10.1016/S1470-2045(25)00158-5.
Niegisch G. Enfortumab Vedotin and Pembrolizumab - A New Perspective on Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):944-946. doi: 10.1056/NEJMe2400311. No abstract available.
Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gumus M, Mar N, Loriot Y, Flechon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. doi: 10.1056/NEJMoa2312117.
Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. doi: 10.1200/JCO.22.01643. Epub 2022 Aug 30.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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2019-004542-15
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
MK-3475-A39
Identifier Type: OTHER
Identifier Source: secondary_id
KEYNOTE KN-A39
Identifier Type: OTHER
Identifier Source: secondary_id
jRCT2031200284
Identifier Type: REGISTRY
Identifier Source: secondary_id
CTR20220974
Identifier Type: OTHER
Identifier Source: secondary_id
SGN22E-003
Identifier Type: -
Identifier Source: org_study_id
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