Phase II trial of the dual IGF-1R/IR inhibitor BMS-754807 with or without letrozole in aromatase inhibitor-resistant breast cancer.

Abstract

TPS111 Background: Resistance to endocrine therapy in breast cancer is a major clinical problem. Evidence shows that insulin-like growth factor (IGF) pathway signaling contributes to tamoxifen resistance. Thus, blockade of IGF signaling may enhance the activity and reverse resistance to endocrine therapy. Preclinical evaluation with the oral IGF-1R/insulin receptor (IR) kinase inhibitor BMS-754807 showed synergistic in vitro anti-proliferative activity in combination with tamoxifen, letrozole or fulvestrant in the aromatase expressing breast cancer model, MCF-7/AC-1. In treatment-naïve tumors and in tamoxifen- or letrozole-resistant tumors, the combination of letrozole with BMS-754807 induced significant tumor regression in vivo, which was not observed with an anti-IGF-1R monoclonal antibody. The lack of activity of the IGF-1R specific antibody and IR isoform expression analyses suggested that IR-isoform A blockade was important for this synergy. Methods: These preclinical data led us to start a phase II non-comparative clinical trial investigating the combination of BMS-754807 and 2.5 mg letrozole or single agent BMS-754807 in patients with locally advanced/metastatic, estrogen receptor-positive, non-steroidal aromatase inhibitor resistant breast cancer. The primary objective is 6-month progression free survival for the combination. Secondary endpoints include response rate, safety profile, and the 6-month treatment failure rate for BMS-754807 and for the combination. The Study will accrue through sites in the US, including the Translational Breast Cancer Research Consortium. Tumor biopsy and serum assessments will be made prior to and during (Day 28) treatment to determine the effects of BMS-754807 ± letrozole on IR isoforms expression and activity of IGF pathway components in tumor tissue and circulating tumor cells (CTCs), serum levels of receptor ligands and IGF binding proteins, and numbers of total and IGF-1R positive CTCs. Pre-study and Day 14 FLT-PET will assess anti-proliferative effects of single agent and combination treatment. Clinical Trials.gov #: NCT01225172. Funded by Bristol-Myers Squibb and NIH (CA116201 and CA090628).