Use of biomarkers and imaging to evaluate the treatment effect of AUY922, an HSP90 inhibitor, in patients with HER2+ or ER+ metastatic breast cancer.

Abstract

e11024 Background: Thorough biomarker assessments are increasingly considered vital for compounds in early clinical development to demonstrate proof of drug target modulation. HSP90 chaperones key client proteins that drive breast cancer (BC) including HER2, and estrogen receptor (ER). Inhibition of HSP90 leads to the degradation of these client proteins and induction of co-chaperones, such as HSP70. AUY922 is a highly potent, non-geldanamycin HSP90 inhibitor, and data from a Phase I study in patients with advanced solid tumors resulted in a recommended AUY922 Phase II dose of 70mg/m2. Patients with HER2+ or ER+ metastatic BC (mBC), who are refractory to standard treatment, have been enrolled into the ongoing Phase II part of the study, which includes a comprehensive biomarker evaluation to demonstrate the effect of AUY922 on key HSP90 client proteins. Methods: Single-agent AUY922 was administered by IV infusion 70 mg/m2 once a week in 28 day cycles to pts with HER2+ or ER+ BC. HSP70 and soluble HER2 (HER2-ECD) levels were quantitated by ELISA assays in peripheral blood mononuclear cells (PBMCs) and serum samples, respectively. Molecular imaging with FDG-PET and radiolabeled trastuzumab- or bevacizumab-PET (for HER2+ or ER+ mBC, respectively) was performed prior to, and during, treatment. Results: 10 pts have been treated to date (8 HER2+ and 2 ER+), and biomarker and imaging data are partially reported due to various technical and logistical challenges with each type of assessment. The maximum increase of HSP70 fold change ranged 1.9–10.4, with a median of 6.4 and mean of 5.9 fold, which is similar to previous observations. Soluble HER2 levels decreased ~45% and ~80% in 2 HER2+ patients who remained on study >5 cycles and both had partial metabolic responses by FDG-PET, and 1 had a confirmed partial response by RECIST as per investigator’s assessment. In 3 pts, follow-up trastuzumab-PETs were assessable, indicating heterogeneous expression of HER2 in various lesions, and heterogeneous response in these lesions to therapy. Conclusions: AUY922 has shown preliminary activity in HER2+ or ER+ mBC and has demonstrated target modulation in keeping with its mechanism of action.