The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy as a first-line treatment for participants with advanced/metastatic renal cell carcinoma (mRCC).

The primary hypotheses of this study are: 1) The combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Progression-Free Survival (PFS) as assessed by blinded independent central imaging review per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and 2) the combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Overall Survival (OS).

Inclusion Criteria:

• Has histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features.
• Has locally advanced/metastatic disease (i.e., Stage IV RCC per American Joint Committee on Cancer) or has recurrent disease.
• Has measurable disease per RECIST 1.1 as assessed by the investigator/site radiologist.
• Has received no prior systemic therapy for advanced RCC.
• Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Has Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior to randomization.
• If receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have been on stable doses for 4 weeks prior to randomization.
• 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 study drug.
• Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug.

Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization.
• Has had major surgery within 4 weeks prior to randomization or radiation therapy within 2 weeks prior to randomization, or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
• Has had prior treatment with any anti-programmed cell death (anti-PD-1), or programmed cell death ligand 1 (PD-L1), or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms.
• Has received prior therapy with vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) or mechanistic target of rapamycin (mTOR) targeting agents.
• Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to axitinib or sunitinib.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization, except in the case of central nervous system (CNS) metastases.
• Has an active autoimmune disease requiring systemic treatment with in the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Note: Participants with vitiligo, diabetes Type I, resolved childhood asthma/atopy, hypothyroidism stable on hormone replacement, or Sjøgren's syndrome are not excluded.
• Has a known additional malignancy that has progressed or has required active treatment in the last 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or carcinoma in situ are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has known active Hepatitis B or Hepatitis C infection.
• Has received a live virus vaccine within 30 days of randomization.
• Has a clinically significant gastrointestinal (GI) abnormality including:
• Inability to take oral medication
• Requirement for intravenous alimentation
• Prior surgical procedures affecting absorption including total gastric resection
• Treatment for active peptic ulcer within the past 6 months
• Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy
• Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation, or history of GI perforation
• Malabsorption syndromes
• Inflammatory bowel disease
• Has QT interval corrected for heart rate (QTc) ≥480 msec.
• Has a history of any of the following cardiovascular conditions within 12 months of screening:
• Myocardial infarction
• Unstable angina pectoris
• Cardiac angioplasty or stenting
• Coronary/peripheral artery bypass graft
• Class III or IV congestive heart failure per New York Heart Association
• Cerebrovascular accident or transient ischemic attack
• Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening.
• Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg.
• Has evidence of inadequate wound healing.
• Has active bleeding disorder or other history of significant bleeding episodes within 30 days of randomization.
• Has hemoptysis within 6 weeks prior to randomization.
• Has current use or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors.
• Has current use or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital,phenytoin, rifabutin, rifampin, and St. John's wort.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Has had a prior solid organ transplant.
• 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 study drug.
• Is, at the time of signing informed consent, a known regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.