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)

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Phase 3 Study Evaluating Cystectomy With Perioperative Pembrolizumab and Cystectomy With Perioperative Enfortumab Vedotin and Pembrolizumab Versus Cystectomy Alone in Participants Who Are Cisplatin-Ineligible or Decline Cisplatin With Muscle-Invasive Bladder Cancer (KEYNOTE-905/EV-303)

Conditions
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Urinary Bladder Cancer, Muscle-invasive

Intervention / Treatment
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* Drug: Pembrolizumab
* Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
* Drug: Enfortumab Vedotin


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Pembrolizumab + Surgery<br>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. | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: MK-3475;Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])<br>* 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.<br>|
| Active Comparator: Arm B: Surgery alone<br>Participants receive standard of care surgery alone. | Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])<br>* 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.<br>|
| Experimental: Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery<br>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. | Drug: Enfortumab Vedotin<br>* Enfortumab vedotin 1.25 mg/kg by intravenous (IV) infusion, given on Days 1 and 8 of each 21-day cycle.<br>* Other names: ASG-22ME;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) between Arm C and Arm B | 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, 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. | Up to approximately 7.7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS between Arm A and Arm B | 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, 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. | Up to approximately 7.7 years | 
| Overall Survival (OS) between Arm C and Arm B | OS is defined as the time from randomization to death due to any cause. | Up to approximately 8.4 years | 
| OS between Arm A and Arm B | OS is defined as the time from randomization to death due to any cause. | Up to approximately 8.4 years | 
| Pathologic Complete Response (pCR) Rate between Arm C and Arm B | 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. | Up to approximately 5.7 years | 
| pCR Rate between Arm A and Arm B | 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. | Up to approximately 5.7 years | 
| Disease-Free Survival (DFS) | 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 | Up to approximately 7.7 years | 
| Pathologic Downstaging (pDS) Rate between Arm A and Arm B | 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. | Up to approximately 5.7 years | 
| pDS Rate between Arm C and Arm B | 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. | Up to approximately 5.7 years | 
| Number of Participants Experiencing Adverse Events (AEs) | 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. | Up to approximately 8.4 years | 
| Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) | 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. | Up to approximately 1 year | 
| Number of Participants Experiencing Perioperative Complications | The number of participants who experience perioperative complications will be presented. | Up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Muscle-Invasive Bladder Cancer (MIBC), Enfortumab vedotin (EV), Pembrolizumab (MK-3475)