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)

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

Official Title
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A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Axitinib
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab+Axitinib Combination Therapy<br>Participants receive pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Biological: Pembrolizumab<br>* Intravenous infusion<br>* Other names: KEYTRUDA®;Drug: Axitinib<br>* Oral tablet<br>* Other names: INLYTA®;|
| Active Comparator: Sunitinib Monotherapy<br>Participants receive sunitinib 50 mg orally once daily for 4 weeks and then are off treatment for 2 weeks. | Drug: Sunitinib<br>* Oral capsule<br>* Other names: SUTENT®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The PFS for participants is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The OS for participants is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review | ORR was determined per RECIST 1.1 and was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR was calculated using the Miettinen & Nurminen method stratified by International Metastatic Renal Cell Carcinoma (RCC) Database Consortium (IMDC) risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). The percentage of participants who experienced a CR or PR is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review | DCR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions), Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), or Stable Disease (SD) per RECIST 1.1 for ≥6 months. The DCR was calculated using the Miettinen & Nurminen method stratified by International Metastatic Renal Cell Carcinoma (RCC) Database Consortium (IMDC) risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). The percentage of participants who experienced a CR, PR, or SD is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review | DOR was defined as the time from first documented evidence of a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 until progressive disease (PD) or death due to any cause, whichever occurred first. PD was defined per RECIST 1.1 as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. The DOR for all participants who experienced a CR or PR is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Number of Participants Who Discontinued Study Drug Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Progression Free Survival Rate (PFS Rate) at Month 12 in All Participants | The PFS rate was determined in all participants at Month 12. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. The PFS rate at Month 12 is presented. | Month 12 | 
| Progression Free Survival Rate (PFS Rate) at Month 18 in All Participants | The PFS rate was determined in all participants at Month 18. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. The PFS rate at Month 18 is presented. | Month 18 | 
| Progression Free Survival Rate (PFS Rate) at Month 24 in All Participants | The PFS rate was determined in all participants at Month 24. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. | Month 24 | 
| Overall Survival (OS) Rate at Month 12 in All Participants | The OS rate was determined for all participants at Month 12 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. The OS rate at Month 12 is presented. | Month 12 | 
| Overall Survival (OS) Rate at Month 18 in All Participants | The OS rate was determined for all participants at Month 18 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. The OS rate at Month 18 is presented. | Month 18 | 
| Overall Survival (OS) Rate at Month 24 in All Participants | The OS rate was determined for all participants at Month 24 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. | Month 24 | 
| Time to True Deterioration (TTD) of the Functional Assessment of Cancer Therapy Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) Score | TTD was defined as time (in months) from the first dose of study treatment to the date of deterioration of FKSI-DRS Score. The FKSI-DRS was a questionnaire that asked the participant to rate 9 kidney cancer-related symptoms: lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine. Each item was scored on a 5-point scale (0=not at all to 4=very much). FKSI-DRS total score ranged from 0 (most severe symptoms) to 36 (no symptoms) with a higher score indicating a better outcome. Deterioration was defined as a 3-point decrease (i.e. lower score) in symptom score and the time to true deterioration was the time to first onset of 3 or more decreases from baseline with confirmation under right-censoring rule (the last observation). The time to true deterioration as measured in months is presented. | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | 
| Least Squares (LS) Mean Change From Baseline to Week 54 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 54 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD1, PD-1, PDL1, PD-L1, PDL2, PD-L2, VEGFR TKI