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PUBLIC RELEASE DATE:
12-Dec-2013

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Contact: Jeremy Moore
jeremy.moore@aacr.org
215-446-7109
American Association for Cancer Research

New drug combination delayed disease progression for subgroup of women with metastatic breast cancer

SAN ANTONIO Adding the drug dasatinib to a standard antihormone therapy, letrozole, doubled the time before disease progressed for women with hormone receptor-positive, HER2-negative metastatic breast cancer, according to results of a phase II clinical trial presented here at the 2013 San Antonio Breast Cancer Symposium, held Dec. 10-14.

Dasatinib is approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. One of the ways it works is by blocking the activity of a protein called Src, which has been recently implicated in the spread of breast cancer to bones.

"Patients with metastatic breast cancer desperately need new treatment options that can lengthen and improve the quality of their lives," said Dev Paul, D.O., Ph.D., breast oncologist at U.S. Oncology and Rocky Mountain Cancer Centers in Denver, Colo. "Because several studies have linked high levels of Src activity to breast cancer metastasis to the bone, we wanted to see whether combining letrozole and dasatinib as first-line treatment for metastatic breast cancer would improve the clinical-benefit rate and progression-free survival compared with letrozole alone.

"We are encouraged to see that the combination doubled progression-free survival time," he added. "But this was a small study, and we really need a biomarker to measure Src activity in breast tumors, so that we can better determine which patients will be most likely to benefit from the addition of dasatinib to letrozole."

Paul and colleagues enrolled 120 postmenopausal women with locally recurrent or metastatic hormone receptor-positive, HER2-negative breast cancer in the phase II clinical trial. They randomly assigned 63 participants to letrozole and 57 to letrozole plus dasatinib. The primary aim of the study was to determine whether adding dasatinib to letrozole increased the clinical-benefit rate. The clinical-benefit rate is the number of patients who had a complete response, plus the number who had a partial response, plus the number who had stable disease for six or more months.

The researchers found that adding dasatinib to letrozole did not increase the clinical-benefit rate compared with letrozole alone. When a second measure of the study's outcome was analyzed, the combination therapy was shown to dramatically improve progression-free survival. Progression-free survival for patients receiving dasatinib and letrozole was 20.1 months compared with 9.9 months for letrozole alone.

Patients receiving dasatinib plus letrozole did experience additional side effects but none were considered severe adverse events, according to Paul, and most patients tolerated the full dose of dasatinib.

"Although these data suggest that adding dasatinib to letrozole improves progression-free survival for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer, we would like to find a biomarker for Src activity in the breast before conducting larger clinical studies of this drug combination," said Paul.

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This study was supported by funds from Bristol-Myers Squibb. Paul declared no conflicts of interest.

This research will be presented at the 2013 San Antonio Breast Cancer Symposium Thursday, Dec. 12, 7:30 a.m. CT, during a press conference hosted by Carlos L. Arteaga, M.D., president-elect of the AACR and associate director for translational/clinical research and director of the Breast Cancer Program at Vanderbilt-Ingram Comprehensive Cancer Center. Press conferences will be held in Room 217D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

Reporters who cannot attend in person can call into the press conferences using the following information:

To interview Dev Paul, contact Liz May at liz.may@usoncology.com or 303-518-9860. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

The mission of the 2013 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www.sabcs.org.

Publication Number: S3-07

Presenter: Dev Paul, D.O., Ph.D.

Title: Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy

Authors: Devchand Paul1,2, Sasha J Vukelja1,3, Frankie Ann Holmes1,4, Joanne Blum1,5, Kristi J McIntyre1,6, Aparna R Kumar1,3, Deborah L Lindquist1,7, Cynthia R Osborne1,5, Ines J Sanchez1,8, Jerome H Goldschmidt1,9, Yunfei Wang1, Lina Asmar1, Michael E Lee1,10, Nini Wu1,11, Keith Logie1,12 and Joyce O'Shaughnessy1,5. 1US Oncology Research, McKesson Specialty Health, The Woodlands, TX; 2Rocky Mountain Cancer Center, Denver, CO; 3Texas Oncology - Tyler, Tyler, TX; 4Texas Oncology - Houston Memorial City, Houston, TX; 5Texas Oncology-Baylor Sammons Cancer Center, Dallas, TX; 6Texas Oncology - Dallas Presbyterian Hospital, Dallas, TX; 7Arizona Oncology Associates, Sedona, AZ; 8Texas Oncology - El Paso West, El Paso, TX; 9Blue Ridge Cancer Care- Christiansburg Office, Christiansburg, VA; 10Virginai Oncology Associates, Norfold, VA; 11New York Oncology Hematology -Albany Medical Center, Albany, NY and 12Central Indiana Cancer Centers, Fishers, IN.

Introduction Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity.

Methods This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs >2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy.

Results Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p=.05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction.

Conclusion The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p=.05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013.



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