Background: Most patients with intermediate- to high-risk advanced renal cell carcinoma (RCC) will progress within 3 years following nephrectomy. Novel treatments in the adjuvant setting are needed to prevent disease recurrence in these higher-risk patients. Upregulation of the programmed death 1 (PD-1) pathway is associated with more aggressive disease and poor prognosis. PD-1 inhibitors have demonstrated activity in metastatic RCC, and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab, a PD-1 inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Methods: KEYNOTE-564 (NCT03142334) is a randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate the efficacy and safety of pembrolizumab as adjuvant therapy in patients with RCC. Eligibility criteria include age ≥18 years; intermediate- to high-risk (T2 grade 4, T3), high-risk (T4, T), or M1 NED RCC with a clear cell component; no prior systemic therapy for advanced RCC; disease free following complete or partial nephrectomy (and metastasectomy in patients with M1 NED) with negative surgical margins; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1; and provision of a tumor sample for biomarker analyses. Patients will be randomly assigned (1:1) to pembrolizumab 200 mg administered intravenously every 3 weeks or placebo. Randomization will be stratified by metastasis stage (M0 vs M1 NED); within the M0 group, randomization will be further stratified by ECOG PS (0 vs 1) and region (US vs rest of world). Treatment will continue until disease recurrence, unacceptable toxicity, or the completion of 17 cycles (~1 year). Imaging will be performed every 12 weeks. The primary end point is disease-free survival (DFS) per investigator assessment. The key secondary end point is overall survival (OS). Other secondary objectives include safety, disease recurrence-specific survival, DFS and OS according to PD-L1 expression status, and patient-reported outcomes. Biomarkers that may be associated with response will be evaluated as an exploratory objective. Enrollment is ongoing and will continue until ~950 patients are enrolled. Clinical trial information: NCT03142334