Background: Although targeting the vascular endothelial growth factor (VEGF) pathway is a valuable therapeutic option for treating advanced ccRCC, response rates are modest and patients eventually progress. The HIF-2α transcription factor is a key oncogenic driver for ccRCC. HIF-2α heterodimerizes with HIF-1β and activates the transcription of genes associated with tumor progression, including VEGFA. Targeting HIF-2α and VEGF may inhibit multiple oncogenic signaling pathways in ccRCC and improve response. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α that has been found to have activity in heavily pretreated patients with ccRCC. An open-label, phase 2 study (NCT03634540) will evaluate efficacy and safety of MK-6482 in combination with the VEGF receptor inhibitor cabozantinib in patients with ccRCC. Methods: Approximately 118 patients will be enrolled to receive MK-6482 120 mg orally once daily and cabozantinib 60 mg orally once daily. Dose evaluation will be performed to find a tolerable dose. Once a recommended phase 2 dose is established, patients will be enrolled in 1 of 2 cohorts (~50 patients each): cohort 1 will comprise patients who have not received prior systemic therapy for locally advanced/metastatic RCC; cohort 2 will comprise patients who have received prior immunotherapy and no more than 2 prior regimens for locally advanced/metastatic RCC. Patients must be ≥18 years of age with a diagnosis of ccRCC, have measurable disease per RECIST v1.1, and have an ECOG PS of 0/1. Patients who stop 1 of the 2 study drugs for reasons other disease progression can continue on single-agent treatment with the other drug. Antitumor activity will be assessed by CT/MRI at baseline, week 9, every 8 weeks until year 1, and every 12 weeks thereafter. Adverse event severity will be graded per CTCAE v5.0. The primary end point is ORR per RECIST v1.1. Secondary end points are DOR, PFS, OS, and safety. Clinical trial information: NCT03634540