TY - JOUR
T1 - 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)
AU - Mayer, Ingrid A.
AU - Prat, Aleix
AU - Egle, Daniel
AU - Blau, Sibel
AU - Alejandro Perez Fidalgo, J.
AU - Gnant, Michael
AU - Fasching, Peter A.
AU - Colleoni, Marco
AU - Wolff, Antonio C.
AU - Winer, Eric P.
AU - Singer, Christian F.
AU - Hurvitz, Sara
AU - Estevez, Laura García
AU - Van Dam, Peter A.
AU - Kummel, Sherko
AU - Mundhenke, Christoph
AU - Holmes, Frankie
AU - Babbar, Naveen
AU - Charbonnier, Laure
AU - Diaz-Padilla, Ivan
AU - Vogl, Florian D.
AU - Sellami, Dalila
AU - Arteaga, Carlos L.
N1 - Funding Information:
I.A. Mayer reports receiving commercial research grants from Genentech, Pfizer, and Novartis, and is a consultant/advisory board member for Novar-tis, Genentech, GlaxoSmithKline, Lilly, Immunomedics, Seattle Genetics, AstraZeneca, and MacroGenics. A. Prat has an immediate family member who is an employee of Novartis; is a consultant/advisory board member for Novartis, Roche, Pfizer, and NanoString Technologies; and reports receiving other remuneration from Oncolytics Biotech. D. Egle is a consultant/
Funding Information:
advisory board member for Roche, AstraZeneca, Novartis, Pfizer, Pierre Fabre, and Celgene. J.A. Pérez Fidalgo reports receiving speakers' bureau honoraria from AstraZeneca, PharmaMar, Pfizer, Roche, and Novartis; is a consultant/advisory board member for AstraZeneca, Clovis, PharmaMar, and Teva; and reports receiving other remuneration from AstraZeneca. M. Gnant reports receiving commercial research grants from AstraZeneca, Novartis, Pfizer, and Roche and is a consultant/advisory board member for Accelsiors, Amgen, AstraZeneca, GlaxoSmithKline, Novartis, OBI Pharma, and Roche. P.A. Fasching reports receiving speakers' bureau honoraria from Novartis, Celgene, Daiichi Sankyo, and Eisai, and is a consultant/advisory board member for Novartis, Roche, MSD, Merck Sharp & Dohme, Celgene, Teva, AstraZeneca, Puma, and Eisai. M. Colleoni reports receiving speakers' bureau honoraria from Novartis, and is a consultant/advisory board member for Pierre Fabre, Pfizer, OBI Pharma, Puma Biotechnology, Celldex, and AstraZeneca. E.P. Winer holds ownership interest (including patents) in Verastem, and is a consultant/advisory board member for Genentech, Lilly, Carrick Therapeutics, and GlaxoSmithKline. C.F. Singer reports receiving other commercial research support from Novartis, AstraZeneca, Roche, and Amgen; reports receiving speakers' bureau honoraria from Roche, Novartis, and AstraZeneca; and is a consultant/advisory board member for AstraZe-neca. S. Hurvitz reports receiving commercial research grants from Ambrx, Amgen, Bayer, Daiichi Sankyo, Genentech/Roche, Immunomedics, Lilly, MacroGenics, Novartis, Seattle Genetics, Pfizer, OBI Pharma, Pieris, and Puma. S. Ku€mmel is a consultant/advisory board member for Roche, Genomic Health, Novartis, AstraZeneca, Amgen, Celgene, Somatex, Daiichi Sankyo, Puma Technology, PFM Medical, Pfizer, and MSD Oncology, and reports receiving other remuneration from Roche and Daiichi Sankyo. C. Mundhenke reports receiving speakers' bureau honoraria from and is a consultant/advisory board member for Novartis. F. Holmes is a consultant/advisory board member for Novartis, Amgen, Myriad Genetics, Puma Biotechnology, Genomic Health and Agendia. C.L. Arteaga reports receiving research grants from Puma, Pfizer, Lilly, Radius, and Takeda; holds stock options in Provista and Y-TRAP; serves or has served as a consultant/advisory board member for Novartis, Merck, Lilly, Symphogen, Daiichi Sankyo, Radius, Taiho Oncology, AbbVie, H3 Biomedicine, Sanofi, OrigiMed, Athe-nex, and Puma Biotechnology; and is a member of the Scientific Advisory Board of the Komen Foundation. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors thank the patients who participated in NEO-ORB, and their families and caregivers. Medical writing assistance was provided by Cassandra Krone, PhD, and Jenny Winstanley, PhD, of Articulate Science Ltd. and was funded by Novartis Pharmaceuticals Corporation. The authors also thank the Avon Foundation for Women, Breast Cancer Research Foundation, and Susan G. Komen for their support of the Translational Breast Cancer Research Consortium in the US. I.A. Mayer, A.C. Wolff, E.P. Winer, and C.L. Arteaga are members of the Translational Breast Cancer Research Consortium (TBCRC), with whom this trial was conducted (trial number: TBCRC 025). This study was funded by Novartis Pharmaceuticals Corporation.
PY - 2019
Y1 - 2019
N2 - Purpose: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HRþ) 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 HRþ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting. Patients and Methods: Postmenopausal women with HRþ, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. Results: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade 3 adverse events (5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculopapular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. Conclusions: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HRþ early breast cancer.
AB - Purpose: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HRþ) 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 HRþ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting. Patients and Methods: Postmenopausal women with HRþ, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. Results: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade 3 adverse events (5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculopapular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. Conclusions: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HRþ early breast cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=85064941338&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-3160
DO - 10.1158/1078-0432.CCR-18-3160
M3 - Article
C2 - 30723140
AN - SCOPUS:85064941338
VL - 25
SP - 2975
EP - 2987
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 10
ER -