Background: The chaperone protein HSP90 is required for the stabilization and activation of many client proteins critical to breast cancer growth and aggressiveness, such as HER2, HIF1-α, EGFR, ER, PI3K, AKT, P53 and VEGFR. Ganetespib, a novel triazolone inhibitor of HSP90, has shown activity in breast cancer in both preclinical models (HER2+, ER+/PR+ and TNBC), and in early clinical trials (patients with HER2+ disease, as well as TNBC). Ganetespib has been well tolerated in clinical trials with a favorable safety profile. The ENCHANT-1 trial was designed to further evaluate ganetespib single agent activity in metastatic breast cancer (mBC) and identify potential predictive biomarkers.

Methods: The ENCHANT-1 trial is an international, first-line phase 2 study in mBC patients: Cohort A, HER2+ (up to n=35) and Cohort B, TNBC (up to n=35). Patients with previously untreated metastatic disease are eligible for treatment with ganetespib at 150 mg/m2 twice weekly on 3 out of 4 wks. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include early metabolic effects as assessed by PET/CT at week 3. Tissue samples were collected from all pts at baseline prior to initiation of treatment; fresh biopsies at C1D18 and end of treatment were optional. Gene expression will be evaluated using RNAseq to survey mutations and gene expression levels in breast cancer genes. A reverse phase protein microarray assay will be used to map the activated protein signaling architecture of laser capture micro-dissected tumor cells from collected tissue samples to evaluate the level of phosphorylation/activation of HSP90 clients and coordinated signaling pathways. Analysis of ∼150 signaling proteins is planned.

Results and Conclusions: The study was initiated in 27 centers globally. At the time of submission, a total of 35 patients were enrolled; TNBC (n= 30) and HER2+ (n=5). In an interim analysis, of the evaluable 4 patients in HER2-positive cohort, 2 had objective response (OR), and 2 stable disease (SD). In the TNBC cohort, of the evaluable 10 patients, 2 had OR, 3 SD and 5 PD. Full molecular analysis to identify biomarkers of response is underway and will be reported at the meeting.

Citation Format: Emanuel F. Petricoin, Julia Wulfkuhle, Tamas Hickish, Iman El-Hariry, Vienna Reichert, Vojislav M. Vukovic, David A. Cameron, Ahmad Awada, Neil Spector. Gene expression and proteomic analysis to identify predictive biomarkers of response in the ENCHANT-1 Trial (NCT01677455), a Phase 2 Proof of Concept study evaluating first-line ganetespib monotherapy in women with metastatic HER2 positive or triple negat [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1612. doi:10.1158/1538-7445.AM2014-1612