Background: Cabozantinib is a small molecule tyrosine kinase inhibitor (TKI) of VEGFR2, MET and AXL that has shown a statistically significant improvement for mRCC patients in all three endpoints of clinical efficacy (objective response rate [ORR], progression free survival [PFS], and overall survival [OS]) in a phase III randomized trial compared to everolimus, as well as a significant clinical benefit in PFS and ORR over sunitinib as first-line therapy in patients with IMDC intermediate- or poor-risk. Although no robust evidence is available, CN remains as the standard of care in patients who will be treated with VEGF TKI. CABOPRE is a multicenter, non-randomized, uncontrolled phase II trial that evaluates the efficacy and safety of cabozantinib as perioperative therapy in patients with advanced RCC who are candidates for CN. Methods: Eligible patients are aged ≥ 18 years, mRCC with a component of clear cell, suitable for CN with acceptable risk for surgery, PS 0-1, no prior systemic therapy. Cabozantinib 60mg PO QD is administered for 12 weeks before CN (cabozantinib is stopped at least 72 hours before CN). A 14-day treatment break is required after surgery and then cabozantinib is continued until progression disease or toxicity. The primary endpoint is ORR by RECIST 1.1 at 12 weeks after initiation of therapy. Secondary endpoints include PFS at 12 months and OS. Based on Simon two-stage minimax design (p0 = 0.25, p1 = 0.45, alpha = 0.05, power = 90%) up to 50 patients will be recruited consecutively. Tumor biopsies and peripheral blood will be collected to assess changes in tumor microenvironment at 3 different time points: 1) at baseline, prior to initiation of cabozantinib, 2) before cytoreductive nephrectomy 3) at disease progression. Biomarkers study will include, but not limited to the expression of c-MET and AXL in exosomes derived from tumor cells.