Background: Cabozantinib, a tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptors, MET and AXL, is approved for the treatment of advanced RCC (in the USA) in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy (in Europe). Here we present the design of the CaboPoint study evaluating the efficacy and safety of cabozantinib in patients with clear-cell metastatic RCC, whose disease progressed after CPI therapy. Methods: CaboPoint is a phase II, open-label (OL), single-arm study of cabozantinib in adults with unresectable, locally advanced or metastatic RCC with a clear-cell component, whose disease progressed after CPI therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate, evaluated by independent review committee. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. Change in disease-related symptoms and safety/tolerability will also be assessed. During the pre-treatment period, potential participants will attend a screening visit within 15 days of treatment initiation to determine eligibility status. During the treatment period, a target of 250 eligible patients (n = 125 per cohort) at 50 sites across AT, CH, DE, ES, FR, NL and UK will receive OL cabozantinib (60 mg once daily; self-administered at home) for up to 18 months after the last recruited patient has received their first dose. Safety assessments will be conducted every 2 weeks up to week 4, and every 4 weeks thereafter. Patients may continue on cabozantinib after disease progression if clinical benefit is observed. During the post-treatment follow-up period, patients who discontinue early will be contacted at visits every 12 weeks to assess survival status and subsequent anticancer therapy. Each cohort will have an interim analysis when 60% of the patients have reached 12 months of follow-up. The study is funded by Ipsen Pharma. Clinical trial information: NCT03945773