Abstract 1612: 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
Emanuel F. Petricoin, Julia Dianne Wulfkuhle, Tamas Hickish, Iman A. El‐Hariry, V. Reichert, Vojislav M. Vukovic, David Cameron, Ahmad Hussein Awada, Neil L. Spector · Cancer Research · 2014
Abstract 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