Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426)
Condition: Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Pembrolizumab; Axitinib; Sunitinib
Intervention description: Intravenous infusion; Oral tablet; Oral capsule
Intervention MeSH terms: Pembrolizumab; Sunitinib; Axitinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 861.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PD1; PD-1; PDL1; PD-L1; PDL2; PD-L2; VEGFR TKI

Summary:

      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)

        2. The combination therapy of pembrolizumab plus axitinib is superior to sunitinib
           monotherapy with respect to Overall Survival (OS).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has histologically confirmed diagnosis of RCC with clear cell component with or
             without sarcomatoid features

          -  Has locally advanced/metastatic disease (i.e., newly diagnosed 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 therapy initiated at least 2 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, received radiation therapy within 2 weeks prior
             to randomization, or 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 systemic anti-cancer therapy for RCC 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 a systemic steroid therapy
             exceeding physiologic corticosteroid dose 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 2 years
             OR a documented history of clinically severe autoimmune disease. Note: Participants
             with vitiligo, Sjøgren's syndrome, Type 1 diabetes, resolved childhood asthma/atopy,
             hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone
             replacement, are not excluded.

          -  Has a known additional malignancy that has progressed or has required active treatment
             in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma
             of the skin, superficial bladder cancer, or carcinoma in situ such as breast cancer in
             situ are acceptable if they have undergone potentially curative therapy.

          -  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:

          -  Malabsorption, total gastric resection

          -  Or any condition that might affect the absorption of orally taken medication

          -  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

          -  Has QT interval corrected for heart rate (QTc) ≥480 msec.

          -  Has a history of any of the following cardiovascular conditions within 12 months of
             randomization:

          -  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 (within 7 days of randomization) or anticipated need for treatment
             with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors.

          -  Has current use (within 7 days of randomization) 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; or
             drugs that are known with proarrhythmic potential.

          -  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.