On April 20, 2016 – OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), presented new biomarker research associated with its clinical programs for anti-RSPO3 (OMP-131R10) and vantictumab (anti-FZD7, OMP-18R5), as well as new preclinical mechanism-of-action data for demcizumab (anti-DLL4, OMP-18M21), at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Meeting (Press release, OncoMed, APR 20, 2016, View Source [SID:1234511148]). All three presentations support ongoing clinical trials: anti-RSPO3 in a Phase1a/b trial in advanced solid tumor and colorectal cancer; vantictumab in a Phase 1b trial in pancreatic cancer; and demcizumab in a Phase 2 randomized study in first-line non-small cell lung cancer (NSCLC).
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Based on preclinical work in patient-derived xenograft models that demonstrated a correlation between RSPO3 gene expression and anti-RSPO3 antibody efficacy, researchers at OncoMed set out to develop predictive biomarker assays. A CLIA-validated RSPO3 assay and a gene fusion detection workflow have both been developed and are now being deployed in OncoMed’s Phase 1a/1b dose escalation study of anti-RSPO3 in advanced solid tumors and in combination with FOLFIRI in metastatic colorectal cancer. Data detailing the validation of the predictive biomarker tests were presented in Abstract 404: "Development of a RSPO3 CLIA-validated assay as a predictive biomarker for response to anti-RSPO3 antibody treatment in patients with solid tumors".
Abstract 3129: "Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) using primary patient-derived human pancreatic tumor xenografts" reviewed the identification of a distinct three-gene signature as a predictive biomarker for response to vantictumab combined with gemcitabine plus Abraxane. The three-gene biomarker has been validated in multiple patient-derived xenograft models and is now being utilized in an ongoing Phase 1b study of vantictumab in combination with standard-of-care therapy in patients with previously untreated Stage IV pancreatic cancer.
"Whenever possible, we strive to identify and validate possible predictive biomarkers that may be able to serve as companion diagnostics early on in the clinical development process. We are optimistic about the correlation observed between RSPO3 gene expression and anti-RSPO3’s efficacy and have begun using these assays in our ongoing Phase 1a/1b clinical trial," said Ann Kapoun, PhD, Vice President, Translational Medicine. "Vantictumab is another candidate that has proven amenable to the identification of predictive biomarkers. In addition to the three-gene pancreatic assay now being utilized in our Phase 1b clinical trial, last year we presented data on a six-gene biomarker for breast cancer, which is also now being assessed in the clinic. Data from our ongoing clinical trials of anti-RSPO3 and vantictumab are anticipated later in 2016."
Anti-DLL4 was evaluated in a series of NSCLC patient-derived xenografts to model demcizumab treatment in humans as a single-agent and in combination with standard-of-care carboplatin/pemetrexed. Data presented detailed anti-DLL4’s multi-pronged mechanism of action. Notch pathway and stem-cell related genes were down-regulated and a decrease in tumor-initiating cells was observed in anti-DLL4-treated tumors. Evidence of anti-DLL4’s vascular mechanism of action was affirmed by observations of up-regulation of endothelial-related genes, increases in blood vessel density and modification of hypoxia-related gene expression. Studies in humanized mice, created by engraftment of human hematopoietic stem cells with patient-derived xenograft tumors allowed researchers to observe an increase anti-DLL4’s immune activity in the presence of human lymphocytes, including up-regulation of human CD45+ cells and down-regulation of human CD33+ cells in tumors. Anti-DLL4 showed tumor growth inhibition and the combination with chemotherapy demonstrated improved activity. These findings provide additional evidence supporting demcizumab as a potential treatment for NSCLC. Data were presented in Abstract 4652: "Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors". A Phase 2 trial (DENALI) testing demcizumab in combination with chemotherapy is currently enrolling.