title: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.
abstract: BACKGROUND
  No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib.
  
  
  METHODS
  Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218.
  
  
  RESULTS
  312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea.
  
  
  CONCLUSIONS
  We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.
authors.affiliation: Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Allan T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Garrett
authors.forename: Martin E
authors.initials: ME
authors.lastname: Blackstein
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Grant
authors.initials: G
authors.lastname: McArthur
authors.forename: Ian R
authors.initials: IR
authors.lastname: Judson
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Bello
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Charles M
authors.initials: CM
authors.lastname: Baum
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D004311:Double-Blind Method; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D000077210:Sunitinib