Abstract S3-07: 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: Paul D , Vukelja SJ , Holmes FA , Blum J , McIntyre KJ , Kumar AR , Lindquist DL , Osborne CR , Sanchez IJ , Goldschmidt JH , Wang Y , Asmar L , Lee ME , Wu N , Logie K , O'Shaughnessy J 
Published: August 2014

Abstract
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 &gt;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.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-07.