NCT03924895 · CITED IN SOURCE DOCUMENTS

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)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: ACTIVE NOT RECRUITING
Registry last update: 2026-06-30

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-Free Survival (EFS) Between Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery and Arm B: Surgery Alone

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outcome · NOT POSTED

EFS Between Arm A and Arm B

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outcome · NOT POSTED

Overall Survival (OS) Between Arm C and Arm B

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outcome · NOT POSTED

OS Between Arm A and Arm B

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outcome · POSTED

Pathologic Complete Response (pCR) Rate Between Arm C and Arm B

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outcome · NOT POSTED

pCR Rate Between Arm A and Arm B

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outcome · NOT POSTED

Disease-Free Survival (DFS)

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outcome · NOT POSTED

Pathologic Downstaging (pDS) Rate Between Arm A and Arm B

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outcome · POSTED

Pathologic Downstaging {pDS) Rate Between Arm C and Arm B

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outcome · NOT POSTED

Number of Participants Experiencing Adverse Events (AEs)

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outcome · NOT POSTED

Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs)

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outcome · NOT POSTED

Number of Participants Experiencing Perioperative Complications

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * 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 Exclusion Criteria: * 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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.
intervention Names
Drug: Pembrolizumab
Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
label
Arm A: Pembrolizumab + Surgery
type
EXPERIMENTAL
description
Participants receive standard of care surgery alone.
intervention Names
Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
label
Arm B: Surgery alone
type
ACTIVE_COMPARATOR
description
Participants receive 3 preoperative cycles of enfortumab vedotin + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative enfortumab vedotin + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days.
intervention Names
Drug: Enfortumab Vedotin
label
Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery
type
EXPERIMENTAL

interventions

arm Group Labels
Arm A: Pembrolizumab + Surgery
description
Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.
name
Pembrolizumab
other Names
KEYTRUDA®
MK-3475
type
DRUG
arm Group Labels
Arm A: Pembrolizumab + Surgery
Arm B: Surgery alone
description
Surgical RC+PLND will be done in accordance with the American Urological Association (AUA)/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) guidelines.
name
Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
type
PROCEDURE
arm Group Labels
Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery
description
Enfortumab vedotin 1.25 mg/kg by intravenous (IV) infusion, given on Days 1 and 8 of each 21-day cycle.
name
Enfortumab Vedotin
other Names
Padcev
ASG-22CE
ASG-22ME
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 595
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
EFS is defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy + pelvic lymph node dissection (RC + PLND) surgery, failure to undergo RC + PLND surgery in participants with residual disease and any radiographic disease present (biopsy-proven muscle-invasive bladder cancer \[MIBC\] will be considered an event regardless of radiographic findings), gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy, or death due to any cause.
measure
Event-Free Survival (EFS) Between Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery and Arm B: Surgery Alone
time Frame
Up to approximately 53 months

secondary Outcomes

description
EFS is defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes RC surgery or failure to undergo RC surgery in participants with residual disease (biopsy-proven muscle-invasive bladder cancer \[MIBC\] will be considered an event regardless of radiographic findings), gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy, or death due to any cause.
measure
EFS Between Arm A and Arm B
time Frame
Up to approximately 6.75 years
description
OS is defined as the time from randomization to death due to any cause.
measure
Overall Survival (OS) Between Arm C and Arm B
time Frame
Up to approximately 7.6 years
description
OS is defined as the time from randomization to death due to any cause.
measure
OS Between Arm A and Arm B
time Frame
Up to approximately 7.6 years
description
Pathologic complete response rate is defined as the percentage of participants having pCR. pCR is defined as absence of viable tumor (pT0N0) in examined tissue from RC and PLND, as assessed by blind independent central review (BICR).
measure
Pathologic Complete Response (pCR) Rate Between Arm C and Arm B
time Frame
Up to approximately 53 monhts
description
Pathologic complete response rate is defined as the percentage of participants having pCR. pCR is defined as absence of viable tumor (pT0N0) in examined tissue from RC and PLND, as determined centrally.
measure
pCR Rate Between Arm A and Arm B
time Frame
Up to approximately 5.7 years
description
DFS is defined as the time from first post-surgery baseline scan until: * local or distant recurrence as assessed by imaging and/or biopsy * Death due to any cause
measure
Disease-Free Survival (DFS)
time Frame
Up to approximately 6.75 years
description
Pathologic downstaging rate is defined as the percentage of participants having pDS. pDS is defined as participants with a tumor classification of \<pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC and PLND.
measure
Pathologic Downstaging (pDS) Rate Between Arm A and Arm B
time Frame
Up to approximately 5.7 years
description
Pathologic downstaging (pDS) is defined as participants with a tumor classification of \<pT2. The pathologic stage \<pT2 includes pT0 (No residual primary tumor found in the tissue examined), pTis (carcinoma in situ; a flat, non-invasive cancer confined to the epithelial lining), pTa (Non-invasive papillary carcinoma limited to the urothelium) pT1 (tumor has invaded the connective tissue beneath the urothelium, but not the muscle layer) and N0 (No cancer found in the examined lymph nodes) in examined tissue from RC and PLND. The \<pT2 category represents a better outcome than participants with residual muscle-invasive disease (pT2 or higher) and/or any nodal involvement (N1/N2). The percentage of participants with pDS is presented.
measure
Pathologic Downstaging {pDS) Rate Between Arm C and Arm B
time Frame
Up to approximately 53 months
description
An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
measure
Number of Participants Experiencing Adverse Events (AEs)
time Frame
Up to approximately 7.6 years
description
An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
measure
Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs)
time Frame
Up to approximately 1 year
description
The number of participants who experience perioperative complications will be presented.
measure
Number of Participants Experiencing Perioperative Complications
time Frame
Up to approximately 1 year

Full study description

brief Summary: 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.

Source references

references

citation
Vulsteke C, Adra N, Danchaivijitr P, Sabadash M, Rodriguez-Vida A, Zhang Z, Atduev V, Goger YE, Rausch S, Kang SH, Loriot Y, Bedke J, Galsky MD, O'Donnell PH, von Amsberg G, Alimohamed N, Sulimka G, Gupta S, Paramonov V, Nakane K, Mihm M, Meng C, Huang CD, Ramamurthy C, Homet Moreno B, Ullen A; KEYNOTE-905/EV-303 Investigators. Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer. N Engl J Med. 2026 Apr 2;394(13):1257-1269. doi: 10.1056/NEJMoa2511674. Epub 2026 Feb 18.
pmid
41707170
type
DERIVED
citation
Galsky MD, Hoimes CJ, Necchi A, Shore N, Witjes JA, Steinberg G, Bedke J, Nishiyama H, Fang X, Kataria R, Sbar E, Jia X, Siefker-Radtke A. Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. Future Oncol. 2021 Aug;17(24):3137-3150. doi: 10.2217/fon-2021-0273. Epub 2021 May 19.
pmid
34008425
type
DERIVED