Phase III Trial of Bayer's Investigational Compound Regorafenib (BAY 73-4506) in Metastatic Colorectal Cancer Meets Primary Endpoint of Improving Overall Survival
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In this trial, the safety and tolerability of regorafenib were generally as expected. Data from the study are expected to be presented at a forthcoming scientific meeting. "These data are significant because they demonstrate that regorafenib increased overall survival in patients with heavily pretreated metastatic colorectal cancer, an area of high unmet medical need," said Kemal Malik, MD, Head of Global Development and member of the Bayer HealthCare Executive Committee.
Bayer will continue discussions with health authorities worldwide, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), regarding next steps in filing for approval of regorafenib in the treatment of mCRC.
Bayer recently entered into an agreement with Onyx Pharmaceuticals, Inc. under which Onyx will receive a royalty on any future global net sales of regorafenib in oncology.
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Int J Cancer. 2011 Jul 1;129(1):245-55. doi: 10.1002/ijc.25864. Epub 2011 Apr 22.
Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.
Wilhelm SM,
Dumas J,
Adnane L,
Lynch M,
Carter CA,
Schütz G,
Thierauch KH,
Zopf D.
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Bayer HealthCare Pharmaceuticals, Montville, NJ, USA.
Abstract
Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging.
Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice, with
tumor shrinkages observed in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2.
These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
Copyright © 2010 UICC.
- PMID:
- 21170960
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