A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)

A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel or Vinflunine in Subjects With Recurrent or Progressive Metastatic Urothelial Cancer

Participants with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy will be randomly assigned to receive Investigator's choice of paclitaxel, docetaxel, or vinflunine (Control), or pembrolizumab. The primary study hypotheses are that pembrolizumab will prolong Overall Survival (OS) and Progression-free Survival (PFS) compared to paclitaxel, docetaxel, or vinflunine.

For the purposes of this study, participants with a programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥10% were considered to have a strongly PD-L1 positive tumor status and participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status.

Effective with Amendment 15, eligible participants who are allocated to the Control arm (Investigator's Choice) and experience disease progression will be provided with the opportunity to switch over to receive pembrolizumab 200 mg one time every three weeks (Q3W) for up to two years of treatment.

Inclusion criteria:

• Histologically- or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra, that is transitional cell or mixed transitional/non-transitional (predominantly transitional) cell type
• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen (e.g cisplatin, carboplatin) for metastatic or inoperable locally advanced disease; or adjuvant platinum-based therapy following cystectomy for localized muscle-invasive urothelial cancer with recurrence/progression <=12 months following completion of therapy; or neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer with recurrence <=12 months following completion of therapy
• No more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer
• Able to provide tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Measureable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate organ function
• Female participants of childbearing potential have a negative urine or serum pregnancy test; or are surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
• Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine

Exclusion criteria:

• Urothelial cancer that is suitable for local therapy administered with curative intent
• Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial medication
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
• Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from adverse events due to agents administered more than 4 weeks earlier
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events due to a previously administered agent
• Prior therapy with all choices of active comparator
• Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cancer; or prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer that is Stage T2N0M0 or lower, Gleason score<= 6, or prostatic-specific antigen (PSA) undetectable
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
• Active cardiac disease
• Evidence of interstitial lung disease or active non-infectious pneumonitis
• Active infection requiring systemic therapy
• History of severe hypersensitivity reaction to paclitaxel, docetaxel, or to other drugs formulated with polysorbate 80 or polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids
• Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome 3A4 (CYP3A4) enzymes
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
• Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor
• Human immunodeficiency virus (HIV)
• Active hepatitis B or hepatitis C
• Received a live virus vaccine within 30 days of planned start of trial treatment