A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)

Study Overview
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Brief Summary
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The goal of this study is to evaluate the efficacy and safety of pembrolizumab plus belzutifan plus lenvatinib or pembrolizumab/quavonlimab plus lenvatinib versus pembrolizumab plus lenvatinib as first-line treatment in participants with advanced clear cell renal cell carcinoma (ccRCC). The primary hypotheses are (1) pembrolizumab plus belzutifan plus lenvatinib is superior to pembrolizumab plus lenvatinib with respect to progression-free survival (PFS) and overall survival (OS), in advanced ccRCC participants; and (2) pembrolizumab/quavonlimab plus lenvatinib is superior to pembrolizumab plus lenvatinib with respect to PFS and OS, in advanced ccRCC participants.

Official Title
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An Open-label, Randomized Phase 3 Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or MK-1308A in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, as First-Line Treatment in Participants With Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Belzutifan
* Biological: Pembrolizumab/Quavonlimab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically confirmed diagnosis of RCC with clear cell component. Has received no prior systemic therapy for advanced ccRCC Male participants are abstinent from heterosexual intercourse or agree to use contraception during and for at least 7 days after last dose of study intervention with belzutifan and lenvatinib. Female participants are not pregnant or breastfeeding and are either not a woman of child-bearing potential (WOCBP) or use a contraceptive method that is highly effective or are abstinent from heterosexual intercourse during the intervention period and for at least 120 days after pembrolizumab or pembrolizumab/quavonlimab or for at least 30 days after last dose of lenvatinib or belzutifan, whichever occurs last Has adequately controlled blood pressure with or without antihypertensive medications Has adequate organ function. Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks prior to randomization/allocation Exclusion Criteria: Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Has had major surgery, other than nephrectomy within 4 weeks prior to randomization Has known central nervous system (CNS) metastases and/or carcinomatous meningitis Has received prior radiotherapy within 2 weeks prior to first dose of study intervention Has hypoxia or requires intermittent supplemental oxygen or requires chronic supplemental oxygen Has clinically significant cardiac disease within 12 months from first dose of study intervention Has a history of interstitial lung disease Has symptomatic pleural effusion; a participant who is clinically stable following treatment of this condition is eligible Has preexisting gastrointestinal or non-gastrointestinal fistula Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment Has a known psychiatric or substance abuse disorder that would interfere with requirements of the study Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug; killed vaccines are allowed Has an active autoimmune disease that has required systemic treatment in the past 2 years Has a history of noninfectious pneumonitis that required steroids or has current pneumonitis Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known history of Hepatitis B Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel Has clinically significant history of bleeding within 3 months prior to randomization Has had an allogenic tissue/solid organ transplant

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 + Belzutifan + Lenvatinib<br>Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 18 administrations (up to  2 years). Belzutifan and lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation. | Biological: Pembrolizumab<br>* Pembrolizumab 400 mg administered Q6W via IV infusion<br>* Other names: KEYTRUDA®;Drug: Belzutifan<br>* Belzutifan 120 mg administered QD via oral tablet<br>* Other names: WELIREG™;Drug: Lenvatinib<br>* Lenvatinib 20 mg administered QD via oral capsule<br>* Other names: LENVIMA®;|
| Experimental: Pembrolizumab/Quavonlimab + Lenvatinib<br>Participants will receive pembrolizumab/quavonlimab (co-formulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered IV Q6W for up to 18 administrations (up to  2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation. | Biological: Pembrolizumab/Quavonlimab<br>* Pembrolizumab/quavonlimab is a co-formulated product composed of pembrolizumab 400 mg in combination with quavonlimab 25 mg, administered Q6W via IV infusion<br>* Other names: MK-1308A;Drug: Lenvatinib<br>* Lenvatinib 20 mg administered QD via oral capsule<br>* Other names: LENVIMA®;|
| Active Comparator: Pembrolizumab + Lenvatinib<br>Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 18 administrations (up to  2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation. | Biological: Pembrolizumab<br>* Pembrolizumab 400 mg administered Q6W via IV infusion<br>* Other names: KEYTRUDA®;Drug: Lenvatinib<br>* Lenvatinib 20 mg administered QD via oral capsule<br>* Other names: LENVIMA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. 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 is also considered PD. PFS as assessed by BICR based on RECIST 1.1 will be presented. | Up to approximately 46 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 66 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | ORR is defined as the percentage of participants who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience a CR or PR as assessed by BICR based on RECIST 1.1 will be presented. | Up to approximately 46 months | 
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. 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 is also considered PD. The DOR as assessed by BICR based on RECIST 1.1 will be presented. | Up to approximately 66 months | 
| Number of Participants Who Experienced At least One Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience at least one AE will be presented. | Up to approximately 66 months | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 66 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Hypoxia inducible factor (HIF), Hypoxia inducible factor 1B (HIF-1B), Hypoxia inducible factor 2 alpha (HIF-2 alpha)