Biomarker Study Of Vantictumab Plus Paclitaxel In Her2-Breast Cancer Patients

Introduction: We have developed a monoclonal antibody, vantictumab, that blocks canonical Wnt/β-catenin signaling through binding of five FZD receptors (1, 2, 5, 7, and 8). This antibody inhibits the growth of several tumor types, including breast. Vantictumab reduces tumor-initiating cell frequency and exhibits synergistic activity with standard-of-care (SOC) agents (Gurney et al., 2012). To confirm the mechanism of action and to potentially target breast cancer patients most likely to respond to vantictumab, we undertook a biomarker study. Methods: We previously identified a 6-gene Wnt pathway-related signature, FBXW2, CCND2, RHOU, CTBP2, WIF1, and DKK1, based on microarray gene expression data from 8 BC patient-derived xenograft (PDX) models with established in vivo response to vantictumab plus SOC. This signature successfully predicted the response of 8 additional and independent PDX breast tumors. We further developed a qPCR Research Use Only (RUO) assay for the 6 genes for use on FFPE human breast tumor samples. This assay was evaluated in the phase 1b study of vantictumab in combination with paclitaxel in locally recurrent or metastatic HER2- breast cancer (NCT01973309) and the signature was refined using a Lasso model with overall survival as the outcome. A repeated 10 fold cross-validation was used to evaluate the performance of the gene signature. The association of the signature with progression-free survival (PFS) and overall survival (OS) was examined (n=40 patients). Furthermore, pharmacodynamic (PD) biomarker analyses were performed on tumor biopsies and hair follicles by comparing gene expression data from post-treatment time points versus baseline data (Affymetrix U133 plus 2 Microarrays). Results: A potential predictive 6-gene Wnt pathway biomarker was identified based on preclinical data and the biomarker was evaluated and refined in a phase 1b study of vantictumab in combination with paclitaxel in HER2- breast cancer. In the phase 1b study, AUC = 75% with repeated 10 fold cross-validation measuring the performance of the gene signature. Based on this analysis, two genes, RHOU and DKK1, were dropped from the preclinical gene signature, which was consistent with the feature ranking in the preclinical qPCR data. The refined 4-gene signature was significantly associated with both PFS and OS at a 50% percentile cut-off. In addition, analysis of PD biomarkers demonstrated that Wnt pathway target genes including AXIN2, LEF1, and CTNNB1 were downregulated while differentiation markers, e.g., KRT19 and Wnt pathway inhibitors, e.g., SFRP1, DKK3 were upregulated by vantictumab plus paclitaxel. Conclusions: We developed a 4-gene signature as a potential predictive biomarker for the response to vantictumab plus paclitaxel in HER2- breast cancer. PD biomarker analysis in tumors and hair follicles confirmed the mechanism of action of vantictumab in patient samples. Preliminary efficacy of vantictumab plus paclitaxel in the phase 1b study was encouraging, particularly in breast cancer patients positive for the 4-gene signature. Updated biomarker and PK/PD data from the phase 1b trial (NCT01973309) will also be presented. Citation Format: Chun Zhang, William R. Henner, Min Wang, Fiore Cattaruzza, Pete Yeung, Gilbert O9Young, Yuwang Liu, Gretchen Argast, Lu Xu, Shailaja Uttamsingh, John Lewicki, Ann M. Kapoun. Biomarker study of vantictumab plus paclitaxel in HER2- breast cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A030.