title: Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial.
abstract: OBJECTIVE
  Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.
  
  
  METHODS
  Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible.
  
  
  RESULTS
  From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction.
  
  
  CONCLUSIONS
  Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute D1212, 450 Brookline Ave, Boston, MA, USA. suzanne_george@dfci.harvard.edu
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Meijun
authors.initials: M
authors.lastname: Zhu
authors.forename: James E
authors.initials: JE
authors.lastname: Butrynski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Yap
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Judith B
authors.initials: JB
authors.lastname: Manola
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Solomon
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C559147:regorafenib; D000068877:Imatinib Mesylate; D000077210:Sunitinib