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PD-L1 Expression and Clinical Outcomes to Cabozantinib

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PD-L1 Expression and Clinical Outcomes to Cabozantinib Author Manuscript Published OnlineFirst on August 1, 2019; DOI: 10.1158/1078-0432.CCR-19-1135 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. PD-L1 expression and clinical outcomes to cabozantinib, everolimus and sunitinib in patients with metastatic renal cell carcinoma: analysis of the randomized clinical trials METEOR and CABOSUN Abdallah Flaifel1, Wanling Xie2, David A. Braun3, Miriam Ficial1, Ziad Bakouny3, Amin H. Nassar3, Rebecca B. Jennings1, Bernard Escudier4, Daniel J. George5, Robert J. Motzer6, Michael J. Morris6, Thomas Powles7, Evelyn Wang8, Ying Huang9, Gordon J. Freeman3, Toni K. Choueiri*3, Sabina Signoretti*1,9 1Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2Department of Data Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 4Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France 5Department Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA 7Department of Experimental Cancer Medicine, Barts Cancer Institute, London, UK 8Exelixis Inc., South San Francisco, CA, USA 9Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA *equal contribution Correspondence: Toni K. Choueiri, M.D., Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 1230, 450 Brookline Ave, Boston, MA 02115; Phone: 617-632-5456; Fax: 617-632-2165 E-mail: [email protected] Or Sabina Signoretti, M.D., Department of Pathology, Brigham and Women's Hospital, Thorn Building 504A, 75 Francis Street, Boston, MA 02115; Phone: 617-525-7437; Fax: 617-264-5169 Email: [email protected] Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 1, 2019; DOI: 10.1158/1078-0432.CCR-19-1135 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running title: PD-L1 and clinical outcome to cabozantinib in renal cancer Keywords: Cabozantinib, Sunitinib, Everolimus, PD-L1, renal cell carcinoma, predictive biomarkers. Grant Support: NIH/NCI DF/HCC Kidney Cancer SPORE P50CA101942 (TKC, SS, GF), U10CA180821, U10CA031946, and Sponsored Research Agreement from Exelixis (TKC, SS). Word count: 3993 Total number of tables and figures: 2 figures and 3 tables (4 supplementary figures and 9 supplementary tables) Disclosure of Potential Conflicts of Interest: D.A. Braun is a consultant/advisory board member for Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnership, Charles River Associates/KC2 Medical, and Schlesinger Trinity Group. B. Escudier is a consultant/advisory board member for Pfizer, Novartis, Bristol-Myers Squibb, Exelixis, and Roche, and reports receiving speaker’s bureau honoraria from Pfizer and Novartis. D.J. George reports receiving commercial research support from Acerta Pharmaceuticals, Astellas, Bayer H/C Pharmaceuticals, Bristol-Meyers Squibb, Calithera, Dendreon, Exelixis, Innocrin, Janssen Pharmaceuticals, Novartis, Pfizer, and Sanofi, speakers bureau honoraria from Bayer H/C Pharmaceuticals, Sanofi, and Exelixis, and is a consultant/advisory board member for Astellas, Astrazeneca, Bayer H/C Pharmaceuticals, Bristol-Meyers Squibb, Capio Biosciences, Exelixis, Genentech, Innocrin, Janssen Pharmaceuticals, Merck Sharp & Dohme, Myovant Sciences, Pfizer, and Sanofi, receives other honorarium from EMD Serono, Michael J. Hennessey Associates, OncLive, Pfizer, and UroToday, is an independent contractor for Axess Oncology, is on the steering committees of NCI and Pfizer, and is on the independent data monitoring committees of Acceleron Pharmaceuticals and Janssen Pharmaceuticals. R.J. Motzer reports receiving commercial research grants from Bristol-Myers Squibb, Pfizer, Genentech/Roche, and Eisai, and is a consultant/advisory board member for Pfizer, Genentech/Roche, Novartis, Eisai, and Exelixis. M.J. Morris reports receiving research funding from Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 1, 2019; DOI: 10.1158/1078-0432.CCR-19-1135 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Bayer (Inst) Corcept Therapeutics (Inst), Endocyte (Inst), Progenics (Inst), Genentech/Roche (Inst), and Sanofi (Inst); and receiving funds for travel, accommodations, and expenses from Bayer and Endocyte; and is a consulting/advisory board member for Advanced Accelerator Applications, Astellas Pharma, Bayer, Blue Earth Diagnostics, Endocyte, Tokai Pharmaceuticals, and Tolmar Pharmaceuticals. T. Powles is a consultant/advisory board member for Novartis, Pfizer, and GlaxoSmithKline; has received company speaker honoraria from Novartis, Pfizer, GlaxoSmithKline, and Genentech; has participated in trials for GlaxoSmithKline, Pfizer, BMS, Genentech, and Genetech; and has received grants/research support from GlaxoSmithKline, Pfizer, and Novartis. E. Wang is an employee of Exilexis. G.J. Freeman reports receiving commercial research grants from Bristol-Myers Squibb, Roche/ Genentech, Novartis, VCB, and Ipsen; holds ownership interest (including patents) in Novartis, Roche/Genentech, Bristol-Myers Squibb, Amplimmune/ AstraZeneca, Merck, EMD Serono, Beohringer Ingelheim, and Dako; and is a consultant/advisory board member for Novartis, Lilly, Roche/Genentech, Bristol-Myers Squibb, Bethyl Laboratories, Xios Therapeutics, Quiet Therapeutics, and Seattle Genetics. T.K. Choueiri reports receiving commercial research grants from AstraZeneca, Alexion, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine, Exelixis, Ipsen, Tracon, Genentech, Roche, Hoffman-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda; and is a consultant/advisory board member for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine, Exelixis, Genentech, Heron Therapeutics, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus, Corvus, Ipsen, Up-to Date, NCCN, and Analysis Group. S. Signoretti reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, and Exelixis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, AACR, and NCI; and receives royalties from Biogenex. No potential conflicts of interest were disclosed by the other authors. Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 1, 2019; DOI: 10.1158/1078-0432.CCR-19-1135 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of translational relevance: Both cabozantinib and anti-PD-(L)1-based combination therapies (nivolumab plus ipilimumab pembrolizumab plus axitinib, and avelumab plus axitinib) are approved frontline treatments for metastatic renal cell carcinoma (mRCC). The magnitude of benefit from anti-PD-(L)1-based combination therapies does appear to be consistently greater in the patients with PD-L1 positive tumors. As cabozantinib is a multi-target tyrosine-kinase inhibitor with immunomodulatory functions, it is important to assess whether PD-L1 expression also predicts responses to cabozantinib. Using baseline tumor tissue from the METEOR and CABOSUN clinical trials, we demonstrate that patients expressing PD-L1 on TC experience worse clinical outcome, independent of the type of targeted therapy they received. Our data also show that cabozantinib is more effective than everolimus or sunitinib in the treatment of both PD-L1-positive and PD-L1-negative mRCC, supporting the use of this drug in a PD-L1 unselected population. As cabozantinib shows excellent efficacy in PD-L1-negative tumors, our findings argue that cabozantinib-based therapies should be evaluated as part of a first-line therapeutic option for patients with negative TC PD-L1 expression. Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 1, 2019; DOI: 10.1158/1078-0432.CCR-19-1135 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: PD-L1 status by immunohistochemistry (IHC) is prognostic in metastatic renal cell carcinoma (mRCC) and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents. Experimental Design: IHC double-staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR (n=306) and CABOSUN (n=110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression- free survival
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