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Background: Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1-based ICBs., Methods: We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated., Results: Eighty-six patients were included in the analysis; the median age was 63 years (range 33-84) and the median number of prior therapies was 2 (range 1-10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26-47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3-8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41-66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%)., Conclusions: Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies., Competing Interests: Conflict of interest statement B.A.M. is reports serving as a consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono and reports receiving research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis andSeattle Genetics. A.-K.AL. reports serving as a consultant for AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche and TerSera and reports receiving research grants (institution or personal) from Bristol-Myers Squibb, Novartis, Roche andIpsen. D.A.B. reports receiving non-financial support from Bristol-Myers Squibb and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group and Insight Strategy, outside the submitted work. X.X.W. reports receiving research support to DFCI from Bristol Myers Squibb. L.C.H. reports serving as a consultant for Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano and Ology Medical Education; reports receiving research funding to the institution (DFCI) from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer and Endocyte (Novartis) and reports receiving financial support for research travel from Bayer and Genentech. M.A.B. reports serving as a consultant for Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receiving institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. T.K.C. reports serving as a consultant for Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology and receiving research support to DFCI from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis andTakeda. All remaining authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)