title: Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial.
abstract: BACKGROUND
  Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma.
  
  
  METHODS
  Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326.
  
  
  RESULTS
  The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7-34·4, IQR 2·5-18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7-52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug.
  
  
  CONCLUSIONS
  Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring.
authors.affiliation: Cambridge University Health Partners, Cambridge, UK. tgqe2@medschl.cam.ac.uk
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Paul D
authors.initials: PD
authors.lastname: Nathan
authors.forename: Peter G
authors.initials: PG
authors.lastname: Harper
authors.forename: Marek Z
authors.initials: MZ
authors.lastname: Wojtukiewicz
authors.forename: Steve
authors.initials: S
authors.lastname: Nicholson
authors.forename: Amit
authors.initials: A
authors.lastname: Bahl
authors.forename: Piotr
authors.initials: P
authors.lastname: Tomczak
authors.forename: Seppo
authors.initials: S
authors.lastname: Pyrhonen
authors.forename: Kate
authors.initials: K
authors.lastname: Fife
authors.forename: Petri
authors.initials: P
authors.lastname: Bono
authors.forename: Jane
authors.initials: J
authors.lastname: Boxall
authors.forename: Andrea
authors.initials: A
authors.lastname: Wagner
authors.forename: Michael
authors.initials: M
authors.lastname: Jeffers
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lin
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib