A Randomized Phase III 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 Summary
To evaluate perioperative pembrolizumab with radical cystectomy + pelvic lymph node dissection (RC+PLND) versus RC+PLND alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC). To see if pembrolizumab before and after surgery is more effective than surgery alone in patients with muscle-invasive bladder cancer (MIBC). This will be measured by tissue samples that are taken during surgery as well as imaging performed at different time points Test the safety of the study drug, pembrolizumab, given before and after surgery. To see how well your body handles pembrolizumab, before and after surgery. To see if pembrolizumab and surgery, compared to surgery alone, helps patients have a better quality of life. To see if pembrolizumab helps patients live longer. To Assess the efficacy and safety of perioperative pembrolizumab plus RC + PLND versus perioperative EV with pembrolizumab plus RC + PLDN versus RC + PLND alone for patients with MIBC. To evaluate the efficacy and safety of perioperative pembro alone or in combination with EV compared with RC + PLND alone in pts with MIBC who are ineligible for or decline cisplatin-based treatment. Assessments and follow-up On-study tumor imaging assessments to evaluate disease status will be conducted with contrast until an EFS event or discontinuation occurs or at withdrawal of consent All surgical specimens obtained during RC + PLND will be assessed centrally to determine pathologic response Patients with new recurrent/metastatic disease at the 6-week (±14 days) postcystectomy imaging will have met the primary EFS end point and will not receive additional trial therapy but will transition to survival follow-up stage until death, withdrawal of consent, or the end of the study All patients will be followed up for OS status until death, withdrawal of consent, or end of study, whichever occurs first AEs will be monitored and assessed by the investigator per CTCAE v4.0 from randomization for up to 30 days after the last dose of study treatment (90 days for serious AES) Analyses Efficacy The intention-to-treat population (all randomly assigned patients regardless of whether they received treatment) will serve as the analysis population for EFS and OS Patients who discontinue for reasons other than an EFS event will be followed up for posttreatment disease status until an EFS event occurs The nonparametric Kaplan-Meier method will be used to estimate EFS and OS curves in each treatment group; treatment differences in EFS and OS will be assessed using the stratified log-rank test and will be estimated using the stratified Cox model with the Efron method of handling ties PCR and pDS rates will be analyzed using the stratified Miettinen and Nurminen method with strata weighting by sample size Safety Safety and tolerability analyses (clinical review of all relevant parameters, including AEs, laboratory tests, vital signs, and electrocardiographic measurements) will be conducted on data from all randomly assigned patients who received at least 1 dose of study treatment To evaluate neoadjuvant and adjuvant PADCEV in combination with KEYTRUDA or neoadjuvant and adjuvant KEYTRUDA versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy.
To evaluate efficacy and safety of periop EV + pembro and RC + PLND vs RC + PLND in adult pts with MIBC (T2-T4aN0M0 or T1-T4aN1M0) who were cisplatin-ineligible or declined cisplatin.
- 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 non-metastatic 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:
- Ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
- 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 > or = 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.
- Adults who are cisplatin ineligible or decline cisplatin-based treatment with treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0), have an Eastern Cooperative Oncology Group performance status score of 0-2, and have a predominant (≥50%) urothelial histology
- Known additional non-urothelial malignancy that is progressing or has required active anticancer treatment < or = 3 years of study randomization, with certain exceptions
- Has > or = 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 co-inhibitory 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 vaccine within 30 days prior to 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 (> or = 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.
- History of uncontrolled diabetes
- History of (noninfectious) pneumonitis that required steroids, or current pneumonitis.
- Active infection requiring systemic therapy
- Has had an allogenic tissue/solid organ transplant
- Cisplatin ineligibility will be defined as meeting ≥1 of the following criteria: impaired renal function with calculated creatinine clearance 30-59 mL/min; ECOG PS 2; grade ≥2 audiometric hearing loss per CTCAE v4.0; or NYHA class III heart failure.
Clinical Study Information for Healthcare Providers
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