Abstract 4663: Exploratory serum biomarker analysis in gastric cancer patients treated with GS-5745, an MMP9 Inhibitor, in combination with mFOLFOX6
Authors: Marianna Zavodovskaya, Yafeng Zhang, Yuanyuan Xiao, Julie Maltzman, Victoria Smith, Carrie Baker Brachmann, Scott D. Patterson
Journal: Cancer Research (2017)

Abstract In the tumor microenvironment, matrix metalloproteinase 9 (MMP9) cleaves and activates substrates such as VEGF, IL8 and TGFβ that promote tumor growth through angiogenesis and immune suppression. Data from preclinical models supports the hypothesis that inhibition of MMP9 reduces local immune suppression, resulting in increased anti-tumor immunity. GS-5745 is a monoclonal antibody in clinical development that is a selective inhibitor of MMP9. The effect of GS-5745 + mFOLFOX6 (GS+chemo) on systemic biomarkers related to MMP9 activity, and immune suppression and activation, was explored in samples from patients in the gastric cancer cohort of the phase 1b study, NCT01803282. Immunoassay analysis of a set of serum proteins based on MMP9 biology and preclinical data (including 10 MMP9 substrates, 5 MMP/TIMPs and 25 inflammatory markers) are reported; exploratory analyses of a larger set will be presented. Total and GS-5745-free MMP9 was measured using a proprietary validated assay. Serum was collected at baseline and the start of every 28-day cycle from 40 gastric cancer patients treated with GS+chemo every 2 weeks. Biomarker area under the curve (AUC) of fold change over time was tested using the Wilcoxon signed rank test. Multiple testing adjustment was based on false discovery rate. GS+chemo treatment resulted in a significant decrease of 3 MMP9 substrates in serum (TGFβ, VEGF and CXCL5), with non-significant trends observed for 3 others (Kit-L, IL8 and CXCL1). MMP3, associated with MMP9 activation, was significantly increased by the combination treatment. MMP2 (an MMP9 homolog) and its binding partner, TIMP2, also showed an increased trend over time. All MMP9 was bound by GS-5745 after one cycle of GS+chemo treatment, but total MMP9 was unchanged. Analysis of biomarkers in the inflammatory set primarily identified trends; factors (10) related to immunosuppressive monocyte chemoattraction or activation decreased, whereas a few markers (3) of immune activation increased. TIMP-2 and TPO were identified by random forests as key markers of a potential baseline biomarker signature to distinguish responders from non-responders (best overall response: n=20 and 9, respectively) with 82.8% accuracy (AUC of ROC=0.83). This exploratory analysis of serum proteins in gastric cancer patients treated with GS+chemo identified pharmacodynamic changes in biomarkers related to MMP9 biology, immune suppression and innate inflammation, consistent with the hypothesis of MMP9-inhibition based upon preclinical models. Modulation of these systemic biomarkers may reflect inhibition of MMP9 activity in the tumor consequent with reduced suppression of anti-tumor immunity; however, conclusions from this study are limited by the fact that all patients were treated with GS+chemo. Confirmation of these findings will require a controlled prospective study. First two authors contributed equally. Citation Format: Marianna Zavodovskaya, Yafeng Zhang, Yuanyuan Xiao, Julie Maltzman, Victoria Smith, Carrie Baker Brachmann, Scott D. Patterson. Exploratory serum biomarker analysis in gastric cancer patients treated with GS-5745, an MMP9 Inhibitor, in combination with mFOLFOX6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2017-4663