Background: Antiangiogenic agents, including sunitinib and axitinib, have shown clinically significant efficacy in patients (pts) with mRCC. Results from a phase 1b study in 52 pts suggest first-line pembro, an anti–programmed death 1 antibody, in combination with axitinib, has substantial antitumor activity in mRCC (objective response rate [ORR], 71%) and manageable toxicity. The phase 3, multicenter, open-label, randomized KEYNOTE-426 study (NCT02853331) is designed to evaluate the efficacy and safety of pembro plus axitinib versus sunitinib alone in pts with treatment-naive mRCC. Methods: Key eligibility criteria include age ≥18 years, histologically confirmed mRCC with clear cell component (with or without sarcomatoid features), measurable disease (RECIST v1.1, investigator review), no prior systemic therapy for advanced disease, Karnofsky performance status ≥70%, and provision of a tumor sample for biomarker analyses. Before randomization, pts will be stratified by International Metastatic RCC Database Consortium risk category and geographic region. 840 pts will be randomly assigned 1:1 to receive pembro 200 mg every 3 wk + axitinib 5 mg twice daily or sunitinib 50 mg once daily for 4 wk followed by 2 wk off. Treatment will continue until progressive disease, unacceptable adverse events (AEs), or withdrawal of consent. Pts in the pembro arm may receive up to 35 doses of pembro, after which axitinib-only treatment may continue. Imaging will be performed at wk 12, then every 6 wk for the first year, and every 12 wk thereafter. Bone scans will be performed at baseline, and if positive, repeated at wk 18, 30, 42, and 54, and every 24 wk thereafter. AEs will be monitored throughout and graded per National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Primary end points are to compare progression-free survival (RECIST v1.1, central review) and overall survival between treatment arms. Secondary end points include the comparison of ORR, duration of response, disease control rate, safety, and patient-reported outcomes between arms. Enrollment is ongoing. Clinical trial information: NCT02853331