Background: For advanced clear cell RCC (ccRCC), first-line treatment with PD-1/PD-L1 inhibitors in combination with CTLA-4 inhibitors or VEGF TKIs are established treatment options. However, patients eventually experience progression; therefore, more effective therapies are needed. This umbrella platform study is an open-label, rolling-arm, multicenter, phase 1b/2 trial with an adaptive design that will evaluate the safety and efficacy of experimental combinations of investigational agents in advanced ccRCC based on their mechanisms of action and toxicity profile. Substudy 03A (NCT04626479) will evaluate treatment combinations as first-line therapy for patients with advanced ccRCC. Given promising results of the phase 1b/2 KEYNOTE-146 (NCT02501096) and phase 3 KEYNOTE-581/CLEAR (NCT02811861) studies, pembrolizumab (400 mg IV Q6W) + lenvatinib (20 mg orally QD) will be used as the reference arm. Methods: Patients must be aged ≥18 years with histologically confirmed ccRCC, measurable disease per RECIST v1.1, and KPS score ≥70 and must have not received prior systemic therapy for advanced RCC (neoadjuvant therapy is acceptable if completed ≥12 mo before randomization). The study will comprise a safety lead-in phase for experimental combinations with investigational agents without an established recommended phase 2 dose (RP2D) and an efficacy phase. Patients will be randomly assigned 2:1 to an experimental arm or a reference arm. Each experimental arm will contain approximately 80 patients. During the efficacy phase, if more than 1 experimental arm is open for enrollment, patients in the reference arm can be shared. Treatments in the experimental arms are composed of the following: MK-1308A (coformulation of quavonlimab [MK-1308] 25 mg + pembrolizumab 400 mg IV Q6W) + lenvatinib (20 mg orally QD), MK-4280A (coformulation of MK-4280 800 mg + pembrolizumab 200 mg IV Q3W) + lenvatinib (20 mg orally QD), and pembrolizumab (400 mg Q6W IV) + belzutifan (MK-6482, 120 mg orally QD) + lenvatinib (20 mg orally QD). Treatment with pembrolizumab (including coformulations with MK-1308 and MK-4280) will continue up to 2 years, whereas treatment with lenvatinib and belzutifan will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by IMDC risk group (favorable vs intermediate/poor). Tumor imaging will occur 12 weeks after randomization, then Q6W until week 54, and Q12W thereafter. Coprimary end points are safety and tolerability, establishing the RP2D during the safety lead-in phase (if applicable) and objective response rate per RECIST v1.1 by blinded independent central review (BICR) during the efficacy phase. Secondary end points during the efficacy phase are duration of response, progression-free survival and clinical benefit rate per RECIST v1.1 (BICR), and overall survival. Clinical trial information: NCT04626479