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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)
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)
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Study Details
This is a study investigating perioperative EV in combination with pembrolizumab or perioperative pembrolizumab in participants who are cisplatin ineligible or decline cisplatin with MIBC. The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plus pelvic lymph node dissection (PLND) and perioperative EV in combination with pembrolizumab plus RC+PLND will achieve superior pathologic complete response (pCR) rates (based on central pathologic review) and 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.
Study Phase
3
Medical Condition
MIBC
Intervention Type
Parallel Assignment
Arms and Interventions
| Arm | Intervention |
|---|---|
Experimental: Pembrolizumab + SurgeryParticipants 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: PembrolizumabPembrolizumab 200 mg by intravenous (IV) infusion, given on day 1 of each 21-day cycle. Procedure: SurgerySurgical 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. |
Active Comparator: Surgery aloneParticipants receive standard of care surgery alone. |
Procedure: SurgerySurgical 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. |
Experimental: EV + Pembrolizumab + SurgeryParticipants receive 3 preoperative cycles of EV + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative EV + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days. |
Drug: EVEV 1.25 mg/kg by IV infusion, given on days 1 and 8 of each 21-day cycle. Drug: PembrolizumabPembrolizumab 200 mg by intravenous (IV) infusion, given on day 1 of each 21-day cycle. Procedure: SurgerySurgical RC+PLND will be done in accordance with AUA, ASCO, ASTRO, and SUO guidelines. |
Inclusion Criteria
- Have a histologically confirmed diagnosis of urothelial carcinoma (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 RC+PLND
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Ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria, OR
be eligible for treatment with cisplatin (by NOT meeting at least one of the following criteria) but
decline treatment with cisplatin-based chemotherapy:
- Impaired renal function with measured or calculated creatinine clearance (CrCl) 30-59 mL/min
- Eastern Cooperative Oncology Group performance status (ECOG PS) 2
- Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric hearing loss
- New York Heart Association (NYHA) Class III heart failure
- ECOG performance status of 0, 1, or 2
- 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
- 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 EV. 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 EV; 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 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 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 EV or any excipient contained in the drug formulation of EV
- 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 (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, 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
Primary Outcomes
- Event-Free Survival (EFS)
Secondary Outcomes
- EFS between Arm A and Arm B
- Overall Survival (OS)
- Disease-Free Survival
- Pathologic Complete Response (pCR) Rate between Arm C and Arm B
- Pathologic Downstaging (pDS) Rate
- Number of Participants Experiencing Adverse Events (AEs)
- Pathologic Downstaging (pDS) Rate between Arm A and Arm B
- Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs)
- Number of Participants Experiencing Perioperative Complications
The safety and efficacy of these investigational compounds, or investigational uses of marketed products, have not been established. For an agent(s) whose safety and efficacy have not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.
Learn how to refer your patients for the EV-303 study.
Visit ClinicalTrials.govReference: ClinicalTrials.gov. 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-3474-905/KEYNOTE-905/EV-303) (04-23-2019). https://clinicaltrials.gov/ct2/show/nct03924895. Accessed 04-18-2022.
