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Clinical Trial
. 2019 May 15;25(10):2975-2987.
doi: 10.1158/1078-0432.CCR-18-3160. Epub 2019 Feb 5.

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 Mayer  1 , Aleix Prat  2 , Daniel Egle  3 , Sibel Blau  4 , J Alejandro Pérez Fidalgo  5 , Michael Gnant  6 , Peter A Fasching  7 , Marco Colleoni  8 , Antonio C Wolff  9 , Eric P Winer  10 , Christian F Singer  11 , Sara Hurvitz  12 , Laura García Estévez  13 , Peter A van Dam  14 , Sherko Kümmel  15 , Christoph Mundhenke  16 , Frankie Holmes  17 , Naveen Babbar  18 , Laure Charbonnier  19 , Ivan Diaz-Padilla  20 , Florian D Vogl  20 , Dalila Sellami  18 , Carlos L Arteaga  21
Affiliations
Clinical Trial

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 Mayer et al. Clin Cancer Res. .

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 whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, 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 maculo-papular 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 HR+ early breast cancer.

Trial registration: ClinicalTrials.gov NCT01923168.

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Conflict of interest statement

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 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.

Figures

Figure 1.
Figure 1.
CONSORT diagram aEnrollment in the buparlisib arm was discontinued on 22 December 2015 and patients randomized after this date were assigned 1:1 to either alpelisib plus letrozole or placebo plus letrozole.
Figure 2.
Figure 2.
Changes from baseline in phospho-AKT and Ki-67 levels following treatment with alpelisib plus letrozole or placebo plus letrozole. A, phospho-AKT level at baseline and Cycle 1 Day 15 for each patient; B, mean percentage change from baseline in phospho-AKT level at Cycle 1 Day 15; C, mean percentage change from baseline in phospho-AKT level at end of treatment; D, Ki-67 level at baseline and Cycle 1 Day 15 for each patient; E, mean percentage change from baseline in Ki-67 level at Cycle 1 Day 15; F, mean percentage change from baseline in Ki-67 level at end of treatment.
See this image and copyright information in PMC

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