Study of Pembrolizumab With or Without Platinum-based Combination Chemotherapy Versus Chemotherapy Alone in Urothelial Carcinoma (MK-3475-361/KEYNOTE-361)

The purpose of this study is to determine the efficacy and safety of pembrolizumab (pembro, MK-3475) with or without chemotherapy versus chemotherapy alone in participants with advanced or metastatic urothelial carcinoma (bladder cancer).

The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in all participants, and that pembrolizumab alone is superior to chemotherapy alone with respect to OS in all participants and in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score \[CPS\] ≥10%).

As specified by the protocol, the study hypotheses will be evaluated by comparing the pembro combo arm or pembro arm separately to the chemo arm.

Eligibility Criteria:
Inclusion Criteria:

* Has a histologically or cytologically confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter \[upper urinary tract\], bladder, or urethra. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
* Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment.
* Has received no prior systemic chemotherapy for advanced or metastatic urothelial carcinoma, with the following exceptions:

  * Neoadjuvant platinum-based chemotherapy with recurrence \>12 months from completion of therapy is permitted.
  * Adjuvant platinum-based chemotherapy following radical cystectomy with recurrence \>12 months from completion of therapy is permitted.
* Has provided tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated from a muscle invasive urothelial carcinoma or a metastatic biopsy, originally from the original tumor.
* Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
* Demonstrates adequate organ function.
* Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.
* Male participants of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.

Exclusion Criteria:

* Has disease that is suitable for local therapy administered with curative intent.
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug.
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
* Has an active autoimmune disease that has required systemic treatment in the past 2 years.
* Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to the first dose of study drug (6 weeks for nitrosoureas or mitomycin C) or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events (AEs) due to mAbs administered more than 4 weeks earlier.
* Has not recovered (i.e., AE ≤ Grade 1 or at Baseline) from AEs due to a previously administered agent.
* Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.

  * Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  * A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤6; Prostate-specific Antigen (PSA) level undetectable.
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* Has a known history of active tuberculosis (TB).
* Has an active infection requiring systemic therapy.
* Has a history of severe hypersensitivity reaction (e.g. generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, gemcitabine, carboplatin, or cisplatin or their analogs and/or to any of their excipients.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is a known regular user (including "recreational use") of any illicit drug(s) or had a recent history (within the last year) of drug or alcohol abuse.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy treatment.
* Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137).
* Has a known history of human immunodeficiency virus (HIV).
* Has known active hepatitis B or hepatitis C.