Background: Bempegaldesleukin (NKTR-214) is a CD122-preferential IL-2 pathway agonist that stimulates proliferation and activation of tumor antigen-specific CD8⁺ T cells and natural killer cells within the tumor microenvironment and increases PD-1/PD-L1 expression. These properties make bempegaldesleukin (NKTR-214) a potentially promising agent for combination therapy with checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway. In phase 1 studies, NKTR-214 plus nivolumab demonstrated encouraging objective response rates (ORR) in first-line renal cell carcinoma (RCC) and an acceptable safety profile. Immunotherapy with NKTR-214 plus nivolumab may lead to greater clinical benefit than tyrosine kinase inhibitors (TKIs), standard-of-care agents, in this patient population. Methods: This multicenter, randomized, open-label phase 3 study (NCT03729245) will evaluate the efficacy and safety of bempegaldesleukin (NKTR-214) plus nivolumab compared with investigator’s choice of TKI (sunitinib or cabozantinib) in patients with previously untreated advanced or metastatic RCC with clear cell component. Exclusion criteria include active brain metastasis and autoimmune disease. Approximately 600 patients will be randomized in a 1:1 ratio, stratified by PD-L1 status (≥1% vs < 1% or indeterminate), International Metastatic RCC Database Consortium prognostic score (1-2 [intermediate risk] vs 3-6 [poor risk]); and TKI (sunitinib or cabozantinib; cabozantinib percentage to be capped at 50%). Combination therapy will consist of bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenously (IV) every 3 weeks (Q3W) plus nivolumab 360 mg IV Q3W until progression or death or maximum of 2 years. TKI therapy will consist of sunitinib 50 mg orally once daily (QD) for 4 weeks followed by 2 weeks off or cabozantinib 60 mg orally QD. Primary objectives are ORR by blinded independent central radiology (BICR) assessment and overall survival. Secondary objectives are progression-free survival by BICR, safety, predictive value of PD-L1 expression, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245