Background: Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class interleukin-2 (IL-2) receptor pathway agonist that activates and expands effector T cells and natural killer cells in the tumor microenvironment and increases tumor PD-L1 expression, making BEMPEG a promising agent for combination with immune checkpoint inhibitors. In a phase 1/2 study, BEMPEG plus nivolumab (NIVO) demonstrated an encouraging objective response rate (ORR) in first-line advanced RCC (46%) and a manageable safety profile. BEMPEG plus NIVO offers a potential novel immunooncology treatment option for patients with advanced RCC. Methods: A global, multicenter, randomized, open-label phase 3 study is evaluating the efficacy and safety of BEMPEG plus NIVO vs investigator’s choice of tyrosine kinase inhibitor (TKI; sunitinib [SUNI] or cabozantinib [CABO]) in patients with previously untreated advanced or metastatic RCC with a clear-cell component. Patients must not have had prior systemic therapy (including neoadjuvant, adjuvant or vaccine therapy) for RCC. Key exclusion criteria include active brain metastasis and autoimmune disease requiring systemic immunosuppressive agents. Approximately 600 patients will be randomized 1:1 to receive 0.006 mg/kg BEMPEG plus 360 mg NIVO intravenously every 3 weeks or TKI (50 mg SUNI [4 weeks on, 2 weeks off schedule] or 60 mg CABO; orally each day). Patients will be stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score (0 [favorable risk] vs 1-2 [intermediate risk] vs 3-6 [poor risk]) and TKI choice (SUNI vs CABO). Primary objectives are ORR by blinded independent central review (BICR) and overall survival in the IMDC intermediate/poor risk population and the intention-to-treat (ITT) population. Secondary objectives are progression-free survival by BICR in the IMDC intermediate/poor risk population and the ITT population, safety, PD-L1 expression as a predictive biomarker, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245