Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)

Running, not enrolling · Phase 3

Conditions studied: Urinary Bladder Cancer, Muscle-invasive

In brief

This is a study of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab in participants who are cisplatin-ineligible or decline cisplatin with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plus pelvic lymph node dissection (PLND) and perioperative enfortumab vedotin in combination with pembrolizumab plus RC+PLND will achieve superior event-free survival (EFS) compared with RC+PLND alone. With Amendment 5, outcome measures for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) were removed. With Amendment 8, the primary outcome measure of pathologic complete response (pCR) rates was changed to a secondary outcome measure.

Key facts

Study ID: NCT03924895
Run by: Merck Sharp & Dohme LLC
People needed: 595
Starts: 2019-07-24
Expected to finish: 2027-12-15
Last updated by the study team: 2026-06-30

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

Have a histologically confirmed diagnosis of urothelial carcinoma/muscle-invasive bladder cancer [MIBC] (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology to be confirmed by Blinded Independent Central Review (BICR) (central pathology and/or imaging).
Clinically nonmetastatic bladder cancer determined by imaging
Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), and agreement to undergo curative intent standard RC + PLND (including prostatectomy if applicable)
Ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria OR be eligible for treatment with cisplatin but decline treatment with cisplatin-based chemotherapy:
Impaired renal function with measured or calculated creatinine clearance (CrCl) 30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet of Renal Disease [MDRD] equations, or measured by 24-hour urine collection)
Eastern Cooperative Oncology Group (ECOG) Performance Status 2
Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric hearing loss
New York Heart Association (NYHA) Class III heart failure
Transurethral resection (TUR) of a bladder tumor that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression assessment
ECOG performance status of 0, 1, or 2
Adequate organ function
A male participant is eligible to participate if he agrees to use contraception and refrain from donating sperm during the intervention period and for at least 180 days after the last dose of enfortumab vedotin. If the male participants are receiving pembrolizumab only or undergoing surgery only, there are no contraception requirements
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a (woman of childbearing potential) WOCBP or a WOCBP who agrees to use a highly effective contraceptive method or be abstinent from heterosexual intercourse (as their preferred and usual lifestyle) during the intervention period and for at least 120 days after the last dose of pembrolizumab and at least 180 days after the last dose of enfortumab vedotin; whichever comes last. A female participant must agree not to donate eggs during this period as well
A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

You may not qualify if…

Known additional nonurothelial malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization, with certain exceptions
Has ≥ N2 or metastatic disease (M1) as identified by imaging
Received any prior systemic treatment, chemoradiation, and/or radiation therapy for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC)
Received prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor
Received prior systemic anticancer therapy including investigational agents within 3 years prior to randomization
Received any prior radiotherapy to the bladder
Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder cancer (NMIBC) or MIBC
Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
Current participation in or participation in a study of an investigational agent or use of an investigational device within 4 weeks prior to the first dose of study intervention
Ongoing sensory or motor neuropathy Grade 2 or higher
Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained in the drug formulation of enfortumab vedotin
Active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator
Active autoimmune disease that has required systemic therapy in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic therapy and is allowed
Has uncontrolled diabetes
History of (noninfectious) pneumonitis that required steroids, or current pneumonitis
Active infection requiring systemic therapy
Has had an allogeneic tissue/solid organ transplant

Where it is running

CARTI Cancer Center ( Site 1577) — Little Rock, Arkansas, United States
St. Joseph Heritage Healthcare ( Site 0046) — Fullerton, California, United States
Scripps MD Anderson ( Site 0010) — La Jolla, California, United States
Hoag Memorial Hospital Presbyterian ( Site 1595) — Newport Beach, California, United States
John Wayne Cancer Institute ( Site 0075) — Santa Monica, California, United States
University of Colorado Hospital ( Site 0098) — Aurora, Colorado, United States
Georgetown University Medical Center ( Site 0022) — Washington D.C., District of Columbia, United States
Emory School of Medicine ( Site 0006) — Atlanta, Georgia, United States
John H. Stroger Jr. Hospital of Cook County ( Site 1551) — Chicago, Illinois, United States
University of Chicago ( Site 0068) — Chicago, Illinois, United States
Parkview Cancer Institute ( Site 0077) — Fort Wayne, Indiana, United States
Indiana University Melvin and Bren Simon Comprehensive Cancer Center ( Site 0004) — Indianapolis, Indiana, United States
Wichita Urology Group ( Site 0059) — Wichita, Kansas, United States
Tulane University School of Medicine ( Site 0088) — New Orleans, Louisiana, United States
New England Cancer Specialists ( Site 0070) — Westbrook, Maine, United States
Greater Baltimore Medical Center ( Site 0014) — Baltimore, Maryland, United States
Dana-Farber Cancer Institute ( Site 1596) — Boston, Massachusetts, United States
M Health Fairview Ridges Hospital ( Site 1555) — Burnsville, Minnesota, United States
Morristown Medical Center ( Site 0015) — Morristown, New Jersey, United States
UNM Comprehensive Cancer Center-Clinical Research Office ( Site 0045) — Albuquerque, New Mexico, United States
Northwell Health - Monter Cancer Center ( Site 0083) — Lake Success, New York, United States
New York University Perlmutter Cancer Center ( Site 0008) — New York, New York, United States
Icahn School of Medicine at Mount Sinai ( Site 0031) — New York, New York, United States
Cleveland Clinic Main ( Site 1576) — Cleveland, Ohio, United States
University of South Alabama, Mitchell Cancer Institute ( Site 1582) — Mobile, Alabama, United States

Full record on ClinicalTrials.gov

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