Background: In ccRCC, HIF-2α is involved in the activation of genes such as VEGFA, cyclin D1, and CXCR4, which are associated with angiogenesis, tumor progression, and metastasis. HIF-2α can accumulate and be overactivated due to the inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in most RCC cases. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α that has shown antitumor activity in a phase I/II study in patients with pretreated, advanced ccRCC (NCT02974738). In the study, the objective response rate was 24%, the disease control rate was 80%, and the safety profile was acceptable. Methods: A phase III, open-label, multicenter, randomized, active-controlled study (NCT04195750) will evaluate the efficacy and safety of MK-6482 versus everolimus as second- to third-line therapy in advanced ccRCC. Eligibility criteria include age ≥18 years; unresectable, locally advanced, or metastatic ccRCC; measurable disease per RECIST v1.1; and a history 1 to 3 systemic regimens for locally advanced or metastatic RCC—including at least 2 doses of a PD-L1 inhibitor and a VEGF-targeted therapy alone or in combination, which resulted in progression. Exclusion criteria include diagnosis of hypoxia defined by pulse oximetry <92% at rest or requiring supplemental oxygen, prior HIF or mTOR inhibitor therapy, kinase inhibitors within 2 weeks of randomization and any systemic anticancer antibody within 4 weeks, and known central nervous system metastases and/or carcinomatous meningitis. The study will enroll approximately 736 patients, who will be randomly assigned 1:1 to MK-6482 120 mg or everolimus 10 mg, both orally once daily until documented disease progression, withdrawal of consent, or other discontinuation event. Stratification factors for this study are International Metastatic RCC Database prognostic scores (0 versus 1-2 versus 3-6) and the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 versus 2-3). The planned imaging (CT/MRI) for response evaluation per RECIST v1.1 by blinded independent central review is as follows: imaging at week 8 from the date of randomization, then every 8 weeks through week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). Progression-free survival per RECIST v1.1 and overall survival will be the dual primary endpoints. Objective response rate, duration of response, patient-reported outcomes, and safety will be secondary endpoints. Event rates over time will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. Stratified Miettinen and Nurminen method will be used for analysis of ORR. Recruitment began in December 2019. Clinical trial information: NCT04195750.