Abstract OT3-2-11: A phase II study of letrozole and lapatinib followed by an addition of everolimus in postmenopausal women with advanced endocrine resistant breast cancer (BC)
Authors: Chumsri S , Tait N , Shetty J , Lewis J , Medeiros M , Bao T , Goloubeva O , Singh H , Sivasailam S , Sabnis G , Kazi A , Mann D , Kesmodel S , Brodie A , Tkaczuk K 
Published: August 2014

Abstract
Background: Several preclinical studies demonstrated that crosstalk between growth factor receptor pathways, particularly HER2, and ER signaling confers resistance to endocrine therapy (ET). There are emerging data showing the involvement of immune system and miRNA with endocrine resistance. EGF30008 trial showed a benefit of lapatinib in combination with letrozole, mainly in HER2-positive (HER+) metastatic BC (MBC) while a subset analysis of this trial showed that HER2-negative (HER2-) patients (pts) with acquired endocrine resistance may also benefit from this combination. Our preclinical study suggests that everolimus is synergistic with letrozole and lapatinib.
Trial Design: This is a single arm phase II study for postmenopausal women with hormone receptor-positive MBC progressing after aromatase inhibitor, tamoxifen, or fulvestrant. The total target accrual is 76 pts (38 HER2+ pts and 38 HER- pts). In the first phase of the study, pts will be treated with letrozole and lapatinib (1,500 mg daily). Upon disease progression, pts will enter the second phase where everolimus (5 mg daily) will be added to letrozole and the dose of lapatinib will be reduced to 1,250 mg daily. For correlative studies, peripheral blood samples will be serially collected to evaluate for serum HER2 extracellular domain (ECD), circulating miRNAs, PC cell-derived growth factor (GP88), immune regulatory cells including myeloid-derived suppressor cells, NK cells, and Treg cells. These parameters will be correlated with tumor response. In pts with accessible tumors, optional serial biopsies will be performed at baseline and upon progression in each phase of the study. The tumor tissue will be tested for total HER1, HER2, and HER2 expressions as well as HER2:HER2 homodimers, HER2:HER3 heterodimers, HER1:HER2 heterodimers, p95, and HER3/PI3K (p85 subunit) using VeraTag assay.
Statistical Method: The primary objective is to evaluate the clinical benefit rate (CBR: CR, PR, SD &gt; 24 weeks) of the combination of letrozole and lapatinib as well as the combination of everolimus, letrozole, and lapatinib. This is a three-stage design which is an extension of the Simon's two-stage design. The sample size is based on the assumption that a CBR below 10% (null hypothesis) would indicate ineffective therapy and the statistical power is set at a higher CBR of 30% which we consider is plausible. Therefore, if 0 of the first 10 pts in each cohort have clinical benefit, the study will be closed; otherwise additional 8 pts will be enrolled. If ≤ 1 of the total 18 pts has clinical benefit, the study will be closed; otherwise an additional 9 pts will be enrolled. If ≤ 5 pts have clinical benefit the therapy is considered not promising; and if ≥ 6 pts of the total of 27 have clinical benefit, the therapy is considered worth pursuing. This design has ∼90% probability to accept the therapy for further trials if the true CBR is indeed at least 30% and 10% probability to accept it if the true clinical benefit is indeed below 10%.
To date, there are a total of 6 pts enrolled. Accrual is currently ongoing. Please contact ntait@umm.edu for further information.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-11.