Background: The perioperative safety of cabozantinib and nivolumab in mccRCC, and the optimal timing to hold cabozantinib prior to surgery, are unknown. Methods: In this phase 2 trial, patients with mccRCC are given cabozantinib (40mg daily) and nivolumab (480mg q4 weeks) for 12 weeks prior to cytoreductive nephrectomy. Post-operatively, patients resume treatment with cabozantinib and nivolumab until disease progression. A 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabozantinib and nephrectomy. Evaluable patients completed at least 10 of 14 cabozantinib doses prior to the pre-specified period of stopping pre-operative cabozantinib. Surgical complications assessed using the Clavien-Dindo classification system is a secondary endpoint of this study. Results: 16 patients have been enrolled and 14 completed nephrectomy to date. 12 (75%) of patients are male, 4 (25%) female, ages 44-77 years old with median age at diagnosis 58.5 years old. BMIs ranged from 17.8 kg/m2 to 39.3 kg/m2 with median BMI of 28.7kg/m2. 63% of patients were classified by IMDC as intermediate-risk and 37% as poor-risk disease. Dose reductions of cabozantinib occurred in 14% of patients who completed nephrectomy and cabozantinib held in 42% of nephrectomy patients during the course of treatment. Three evaluable patients completed nephrectomy within the 21-day interval and 5 within the 14-day interval after discontinuation of cabozantinib. There were no treatment-related surgical complications in patients who completed nephrectomy and there were no delays in resuming combination systemic therapy after surgery. Conclusions: Combination cabozantinib and nivolumab can be safely administered up to 14 days prior to cytoreductive nephrectomy. Clinical Trial Information: NCT04322955 Clinical trial information: NCT04322955.