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1078-0432.CCR-18-3160.Full.Pdf Author Manuscript Published OnlineFirst on February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3160 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB) Ingrid A. Mayer1, Aleix Prat2, Daniel Egle3, Sibel Blau4, J. Alejandro Perez Fidalgo5, Michael Gnant6, Peter A. Fasching7, Marco Colleoni8, Antonio C. Wolff9, Eric P. Winer10, Christian F. Singer11, Sara Hurvitz12, Laura Garcia Estevez13, Peter A. van Dam14, Sherko Kümmel15, Christoph Mundhenke16, Frankie Holmes17, Naveen Babbar18, Laure Charbonnier19, Ivan Diaz-Padilla20, Florian D. Vogl20, Dalila Sellami18, Carlos L. Arteaga21 1Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Translational Genomics and Targeted Therapeutics in Solid Tumors, Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; 3Department of Gynecology and Obstetrics, Medical University of Innsbruck, Innsbruck, Austria; 4Rainier Hematology-Oncology, Northwest Medical Specialties, Tacoma, Washington; 5Department of Oncology, CIBERONC, Hospital Clínico Universitario de Valencia - INCLIVA, Valencia, Spain; 6Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 7Department of Gynecology and Obstetrics, University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, Germany; 8Division of Medical Senology, European Institute of Oncology (IEO), IRCCS, Milan, and International Breast Cancer Study Group, Milan, Italy; 9Department of Oncology – The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 11Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 12Department of Medicine, University of California, Los Angeles, California; 13Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain; 14Gynecologic Oncology and Senology, Antwerp University Hospital, Edegem, Belgium; 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3160 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 15Breast Unit, Kliniken Essen-Mitte, Essen, Germany; 16Department of Obstetrics and Gynecology, Universitätsklinikum Schleswig-Holstein, Kiel, Germany; 17Texas Oncology-Houston Memorial City and US Oncology Research Network, Houston, Texas; 18Oncology Precision Medicine, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; 19Statistics, Novartis Pharma S.A.S., Rueil-Malmaison, France; 20Oncology Global Development, Novartis Pharma AG, Basel, Switzerland; 21Department of Medicine, UTSW Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas Financial support: Novartis Pharmaceuticals Corporation. Corresponding authors: Ingrid A. Mayer, MD, MSCI Vanderbilt University Medical Center/ Vanderbilt-Ingram Cancer Center 2220 Pierce Ave. 777 PRB Nashville, Tennessee 37232 [email protected] Tel 615-936-2033 Fax 615-343-7602 Carlos L. Arteaga, MD (listed on submission site) UTSW Harold C. Simmons Comprehensive Cancer Center 5323 Harry Hines Blvd. Dallas, Texas 75390-8590 [email protected] Tel 214-648-1677 Fax 214-648-7084 Disclosure of Potential Conflicts of Interest: I.A. Mayer has received consultancy/advisory fees from AstraZeneca, Novartis, Genentech, Eli Lilly, Immunomedics, MacroGenics, and GlaxoSmithKline, and received research funding from Novartis, Genentech, and Pfizer; A. Prat has received consultancy/advisory fees and received research funding from Nanostring Technologies, and received lecture fees from Novartis and Pfizer; D. Egle has received consultancy/advisory fees from AstraZeneca, Novartis, Pfizer, and Roche; J. Alejandro Perez Fidalgo has received consulting/advisory fees from Clovis and PharmaMar, and received speakers’ bureaus fees from AstraZeneca, Novartis, and Roche; M. Gnant has received consultancy/advisory fees from Accelsiors, Amgen, AstraZeneca, GlaxoSmithKline, Novartis, OBI Pharma, and Roche, and received research funding from AstraZeneca, Novartis, Pfizer, and Roche; P.A. Fasching has received grants/fees from Amgen, Celgene, Novartis, Pfizer, Puma Biotechnology, Roche, and Teva 2 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3160 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Pharmaceutical Industries; M. Colleoni has received consultancy/advisory fees from AstraZeneca, Celldex Therapeutics, Novartis, OBI Pharma, Pfizer, Pierre Fabre Laboratories, and Puma Biotechnology; A.C. Wolff has received research funding from Pfizer; E.P. Winer has received consultancy/advisory fees from Genentech, Leap Therapeutics, and Tesaro, and received research funding from Genentech and Merck; C.F. Singer has received consultancy/advisory fees from Amgen, AstraZeneca, Novartis, Pfizer, Roche, and Teva Pharmaceutical Industries, and received research funding from Roche and Novartis; S. Hurvitz has received research funding from Amgen, Bayer, Boehringer Ingelheim, Cascadian Therapeutics, Dignitana, Eli Lilly, Genentech/Roche, Merrimack Pharmaceuticals, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, and Seattle Genetics; P.A. van Dam has received consultancy/advisory fees from Amgen, Novartis, and Roche, and received research funding from Amgen and Roche; S. Kuemmel has received consultancy/advisory fees from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health, Novartis, Pfizer, Roche, and Teva Pharmaceutical Industries, and received research funding from Roche; C. Mundhenke has received consultancy/advisory and speakers’ bureaus fees from Novartis and Pfizer, and received research funding from Novartis; F. Holmes has received consultancy/advisory fees from Myriad Genetics, Novartis, and Puma Biotechnology; N. Babbar, L. Charbonnier, I Diaz-Padilla, and F.D. Vogl are employees of Novartis; D. Sellami is an employee and owns stocks/shares in Novartis; C.L. Arteaga receives or has received research funding from Bayer, Eli Lilly, Pfizer, Radius Health, and Takeda; he serves or has served in advisory roles to Symphogen, Daiichi Sankyo, TAIHO Oncology, Novartis, Merck, PUMA Biotechnology, Eli Lilly, Radius Health, Sanofi, OrigiMed, AbbVie, and H3 Biomedicine; he holds stock options in Provista and Y-TRAP. S. Blau and L. Garcia Estevez declare no conflicts of interest. Word count: 5,368 Number figures/tables: 6 (plus 7 Supplementary figs/tables) Running title (max 60 characters): Neoadjuvant letrozole plus alpelisib for breast cancer Key words: alpelisib, PI3K inhibitor, PIK3CA, breast cancer, neoadjuvant treatment 3 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3160 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance Neoadjuvant endocrine therapy is a valuable treatment option for patients with HR+ breast cancer; however, complete pathologic response rates remain low. Genetic alterations of the PI3K pathway, including in PIK3CA, are common in HR+ breast cancer and have been linked to endocrine therapy resistance. Previous studies have suggested that adding the PI3K inhibitor alpelisib to endocrine therapy (letrozole or fulvestrant) leads to improved clinical activity in advanced/metastatic breast cancer, with a trend towards improved benefit in patients with PIK3CA-mutant tumors. Indeed, the phase III SOLAR-1 trial demonstrated a significant and clinically meaningful improvement in progression-free survival with addition of alpelisib to fulvestrant for patients with PIK3CA-mutant metastatic tumors. In this trial, we show that adding alpelisib to 24 weeks of neoadjuvant letrozole treatment does not improve response rate, regardless of PIK3CA mutational status. These data suggest a different role for PI3K pathway alterations in early breast cancer compared with metastatic disease. 4 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3160 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine if addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting. Experimental
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