Background: First-line treatment landscape of metastatic renal cell carcinoma (mRCC) is evolving with strong evidence in favour of PD-1/PD-L1 combinations over tyrosine kinase inhibitors (TKIs). No prospective data about efficacy of TKIs post immune-checkpoint inhibitor (CPI) combinations are available. Among TKIs, cabozantinib has demonstrated progression-free survival (PFS) and overall survival (OS) benefit over everolimus in pre-treated mRCC patients (pts). Methods: Overall 49 mRCC pts who received a previous CPI (anti PD-1/PD-L1) will be treated with cabozantinib. Pts will be stratified according to Heng prognostic group, duration of first-line and type of previous therapy received (CPI+CPI or CPI+TKI or CPI+anti-VEGF or CPI monotherapy). Key inclusion criteria include: one previous treatment with a PD-1/PD-L1 inhibitor in first-line and histological diagnosis of clear-cell RCC. The primary endpoint is to assess the efficacy of cabozantinib based on PFS. Secondary endpoints include evaluation of OS, objective response rate and safety profile of the drug. Exploratory endpoints include evaluation of PD-L1 levels by immunohistochemistry in tumor samples; the analysis of the immunological signature/profile of tumor cells; the state of circulating immune cells, as well as the modulating activity of cabozantinib on systemic tumor immunity; the evaluation of bone formation and reabsorption markers in pts with or without bone involvement. Cabozantinib will be administered orally at a dose of 60 mg/day continuously until evidence of disease progression or onset of unacceptable toxicity. Statistical design: By the methodology of Brookmeyer and Crowley, assuming an accrual period of 18 months and a minimum follow-up of 10 months (mos), 49 pts are necessary to detect an increment of the median PFS time from 3.8 mos to 7.4 mos with a power of 90% and one-sided alpha of 5%. The large sample critical value detecting the increment of the PFS median survival time will be 5.54 mos. To date, 2 pts have been enrolled. Clinical trial information: NCT03463681