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Clin Cancer Res. 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).

Author information

1
Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. carlos.arteaga@utsouthwestern.edu ingrid.mayer@vumc.org.
2
Translational 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.
3
Department of Gynecology and Obstetrics, Medical University of Innsbruck, Innsbruck, Austria.
4
Rainier Hematology-Oncology, Northwest Medical Specialties, Tacoma, Washington.
5
Department of Oncology, CIBERONC, Hospital Clínico Universitario de Valencia - INCLIVA, Valencia, Spain.
6
Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
7
Department of Gynecology and Obstetrics, University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, Germany.
8
Division of Medical Senology, European Institute of Oncology (IEO), IRCCS, Milan, and International Breast Cancer Study Group, Milan, Italy.
9
Department of Oncology, The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
11
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
12
Department of Medicine, University of California, Los Angeles, California.
13
Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain.
14
Gynecologic Oncology and Senology, Antwerp University Hospital, Edegem, Belgium.
15
Breast Unit, Kliniken Essen-Mitte, Essen, Germany.
16
Department of Obstetrics and Gynecology, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
17
Texas Oncology-Houston Memorial City and US Oncology Research Network, Houston, Texas.
18
Oncology Precision Medicine, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
19
Statistics, Novartis Pharma S.A.S., Rueil-Malmaison, France.
20
Oncology Global Development, Novartis Pharma AG, Basel, Switzerland.
21
Department of Medicine, UTSW Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas. carlos.arteaga@utsouthwestern.edu ingrid.mayer@vumc.org.

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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