Background: New treatments for first and subsequent lines of therapy for ccRCC are needed. An adaptive, open-label, rolling-arm, multicenter, phase 1b/2 umbrella platform trial in advanced ccRCC is being conducted to evaluate the safety and efficacy of multiple combinations of investigational agents targeting CTLA-4 (quavonlimab [MK-1308]), hypoxia-inducible factor 2α (belzutifan [MK-6482]), lymphocyte-activation gene 3 (favezelimab [MK-4280]), immunoglobulinlike transcript 4 (MK-4830), PD-1 (pembrolizumab), and vascular endothelial growth factor–tyrosine kinase inhibitor (VEGF-TKI; lenvatinib) for advanced ccRCC. Substudy 03A (NCT04626479) will evaluate first-line therapy combinations, and substudy 03B (NCT04626518) will evaluate therapies in patients experiencing progression on PD-1/PD-L1 inhibitors and VEGF-TKIs in combination or in sequence. Methods: Adults with histologically confirmed ccRCC and KPS score ≥70% are eligible. Patients in substudy 03A cannot have previously received systemic therapy for advanced ccRCC. Patients in substudy 03B must have progression (per RECIST v1.1) on or after treatment with a PD-1/PD-L1 inhibitor and a VEGF-TKI for advanced ccRCC. Both substudies will have a safety lead-in phase for experimental combinations with investigational agents to establish a recommended phase 2 dose, followed by an efficacy phase. Experimental arms will enroll approximately 80 (03A) and 50 (03B) patients. Patients will be randomly assigned 2:1 (03A) or 1:1 (03B) to an experimental arm or a reference arm (pembrolizumab 400 mg IV every 6 weeks [Q6W] + lenvatinib 20 mg orally once daily [QD]). Experimental arms in 03A are MK-1308A (coformulation of quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W) + lenvatinib (20 mg orally QD), MK-4280A (coformulation of favezelimab 800 mg and pembrolizumab 200 mg IV every 3 weeks [Q3W]) + lenvatinib (20 mg orally QD), and belzutifan (120 mg orally QD) + lenvatinib (20 mg orally QD) + pembrolizumab (400 mg Q6W IV). Experimental arms in 03B are MK-1308A, MK-4280A, pembrolizumab (400 mg Q6W IV) + belzutifan (120 mg orally QD), lenvatinib (20 mg orally QD) + belzutifan (120 mg orally QD), and pembrolizumab (200 mg IV Q3W) + MK-4830 (800 mg IV Q3W). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Primary end points for the safety lead-in phase are safety and tolerability; coprimary end points for the efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival (RECIST v1.1 by BICR), clinical benefit rate, and overall survival. Both substudies are recruiting patients in Australia, Canada, France, Israel, South Korea, Spain, New Zealand, the United Kingdom, and the United States. Clinical trial information: NCT04626479; NCT04626518.