Background: In RCC, the Von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A (VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750.