Background: Over the past decade, treatment options for advanced RCC have evolved to include multiple agents targeting the vascular endothelial growth factor (VEGF) pathway. In addition, the recent innovation of treating cancer with immunotherapy has further expanded the therapeutic armamentarium. Biomarker studies suggest that promotion of an immune suppressive tumor microenvironment can contribute to anti-VEGF therapy resistance and point to a rationale for combining anti-VEGF therapy with immunotherapy. Cabozantinib, a tyrosine kinase inhibitor with targets including VEGF receptor, MET and the TAM receptor family has shown immunomodulatory properties suggestive of synergistic effects with immune checkpoint inhibitors. Indeed, in a recent phase 1 study, combination of the programmed death-1 (PD-1) inhibitor nivolumab with cabozantinib showed encouraging antitumor activity in pretreated patients with metastatic RCC and other advanced genitourinary tumors (Nadal et al. ASCO GU 2018). This phase 3 study will assess nivolumab plus cabozantinib vs sunitinib in previously untreated patients with advanced or metastatic RCC (NCT03141177). Methods: Key inclusion criteria: Measurable disease with a clear-cell component, no prior systemic therapy for RCC, evaluable tumor biopsy, and age ≥18 years. Key exclusion criteria: Active CNS metastases and autoimmune disease. Patients will be randomized 1:1 to either nivolumab plus cabozantinib or sunitinib. Treatment will continue until disease progression or unacceptable toxicity (maximum nivolumab treatment of 2 years). Stratification factors: International Metastatic RCC Database Consortium (IMDC) risk score, PD-1 ligand 1 (PD-L1) tumor expression, and geographic region. Primary endpoint: Progression-free survival by blinded independent central review (BICR) in all randomized patients; secondary endpoints: Overall survival and objective response rate by BICR in all randomized patients, and safety/tolerability in all treated patients. Enrollment began August 2017 with a target of 580 randomized patients. Clinical trial information: NCT03141177