title: Regorafenib for treatment of advanced gastrointestinal stromal tumors.
abstract: BACKGROUND
  Gastrointestinal stromal tumors (GISTs) are abdominal sarcomas which are extremely refractory to chemotherapy treatment. The treatment of GISTs has been revolutionized by use of KIT/platelet-derived growth factor receptor-α (PDGFRA) kinase inhibitors. Unfortunately, most tumors develop resistance to front-line (imatinib) or second-line (sunitinib) therapy. Regorafenib, a KIT/PDGFRA/vascular endothelial growth factor receptor (VEGFR) oral kinase inhibitor, has been shown to improve progression-free survival in the third- or fourth-line setting.
  
  
  METHODS
  This review covers the preclinical and clinical studies of regorafenib for treatment of GIST. A literature search on regorafenib was carried out using the PubMed database up to October 2013.
  
  
  CONCLUSIONS
  Currently, imatinib and sunitinib represent the only proven first- and second-line therapies, respectively, for advanced GISTs. Based on the results of a Phase III study, regorafenib is now established as the only proven third-line therapy. Regorafenib activity in this setting is believed to be due to its activity against oncogenic forms of KIT/PDGFRA. Although side effects are common with this agent, they can be effectively managed with a combination of supportive care, dose interruptions/reductions. The toxicity profile is similar to other oral kinase inhibitors with anti-VEGFR activity. Regorafenib is mainly metabolized by CYP3A4, and concomitant use of strong inducers/inhibitors of this enzyme should be avoided.
authors.affiliation: Portland VA Medical Center, Oregon Helath & Science University and OHSU Knight Cancer Institute , 3710 SW US Veterans Hospital Rd., Building 103 Lab E223, R&D 19, Portland OR 97239-2999 , USA +1 503 220 3405 ; +1 503 273 5158 ; Heinrich@ohsu.edu.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Overton
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib