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The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher's exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0-35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials., Competing Interests: Competing interests: LCB declares the following relationships: consulting with Seattle Genetics. KD declares the following relationship: consulting with Tyra BioSciences. WW declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. EK declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. CK declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. DG declares the following relationships: Acerta Pharmaceuticals—Research, American Association for Cancer Research—Sr Editor, Astellas—Consultant, Research, Advisory Board, Astrazeneca—Consultant, Advisory Board, Axess Oncology—Independent Contractor, Bayer H/C Pharmaceuticals—Research, Consultant, Speaker, Honorarium, Travel accommodations, SC, BMS—Consultant, Research, Steering Committee, Calithera—Research, Capio Biosciences—Scientific Advisory Board, EMD Serono—Honorarium, Exelixis—Research, Consultant, Speaker, Honorarium, Travel accommodations, Flatiron—Consultant, Ipsen—Honorarium, Janssen Pharmaceuticals—Research, Consultant, Independent Data Monitoring Committee (IDMC), Leidos Biomedical Research—Consultant, Merck Sharp & Dohme—Consultant, Michael J Hennessey Associates—Honorarium, Consultant, Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—Co-Editor-in-Chief, Modra Pharmaceuticals B.V.—Advisory Board, Myovant Sciences—Consultant, Nektar Therapeutics—Steering Committee, Novartis—Research, Physician Education Resource—Consultant, Pfizer—Research, Consultant, Steering Committee, Honorarium, Sanofi—Research, Consultant, Speaker, Honorarium, Travel accommodations, UroGPO—Honorarium, UroToday—Honorarium, Travel accommodations, Vizuri Health Sciences—Consultant, NCI—Steering Committee. BR declares the following relationships: Research funding (to Vanderbilt University) from Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Taris, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive and Exelixis; Consulting with Bristol Myer Squibb, Pfizer, Roche/Genentech, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai. Stock ownership in PTC Therapeutics. MCO declares the following relationships: Consulting with BMS, Merck, Pfizer, Aveo, Exelixis and Eisai. TZ declares the following relationships: Research funding (to Duke University) from Pfizer, Janssen, Acerta, Abbvie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas and Genentech; Speaking with Genomic Health and Sanofi Aventis; Consulting with AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Merck, Amgen, MJH Associates, and BMS. Stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics and Nanorobotics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches., Methods: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1., Results: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event., Conclusion: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Patient selection is critical to determine who benefits from initial cytoreductive nephrectomy and who benefits from initial systemic treatment. Cytoreductive nephrectomy can no longer be considered a one-size-fits-all approach. Multidisciplinary evaluation is key., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)