Evaluating collagen neoepitopes as pharmacodynamic biomarkers of GS-5745, an MMP9 inhibitor, in advanced gastric cancer.

Abstract

58 Background: Cancer is characterized by continuous remodeling of the extracellular matrix (ECM) through a process of degradation and replacement of ECM components, such as collagens. Matrix-metalloproteinase 9 (MMP9) is involved in this remodeling and its inhibition is hypothesized to reduce ECM turnover. MMP9 expression is limited in healthy tissues, but high in tumor epithelia, infiltrating inflammatory cells and fibroblasts. Collagen I and III fragments (neoepitopes C1M and C3M) in blood may provide a measure of tumor MMP activity (BMC Cancer 13:554. 2013). GS-5745 is a monoclonal antibody that specifically inhibits MMP9 and has shown efficacy in combination with chemotherapy in advanced gastric cancer in an ongoing ph I study of multiple cancer types (NCT01803282). Exploratory analyses of collagen neoepitopes from patients in the gastric cancer cohort are reported here. Methods: C1M and C3M were measured by ELISA in serum samples (Nordic Bioscience). Healthy volunteer (HV) samples were age-matched. Pharmacodynamic evaluation and association with clinical outcomes were assessed by non-parametric tests; nominal p-values are reported. Results: Pharmacodynamic Evaluation (Table):Baseline (BL) levels of C1M and C3M were higher in gastric cancer patients than HVs. C1M and C3M displayed a pharmacodynamic response after 1 treatment cycle. Inhibition of C1M continued to decline with treatment. Association with Best Overall Response:There was no association of BL C1M or C3M level with best overall response. 13 of 20 responders had decreased C1M at C2D1; however, of the 3 patients with progressive disease, none had an on-treatment decrease in C1M. Conclusions: These data suggest an association between circulating C1M as a pharmacodynamic biomarker of GS-5745 in combination with chemotherapy in gastric cancer patients. Circulating neoepitope biomarkers will continue to be explored in all ongoing and future oncology GS-5745 studies. Clinical trial information: NCT01803282. [Table: see text]