title: Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib.
  
  
  METHODS
  We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712.
  
  
  RESULTS
  From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4-9·2) for regorafenib and 0·9 months (0·9-1·8) for placebo (hazard ratio [HR] 0·27, 95% CI 0·19-0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%).
  
  
  CONCLUSIONS
  The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients.
  
  
  BACKGROUND
  Bayer HealthCare Pharmaceuticals.
authors.affiliation: Ludwig Center at Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Leahy
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Badalamenti
authors.forename: Martin
authors.initials: M
authors.lastname: Blackstein
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.forename: Binh Bui
authors.initials: BB
authors.lastname: Nguyen
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: John
authors.initials: J
authors.lastname: Chung
authors.forename: Christian
authors.initials: C
authors.lastname: Kappeler
authors.forename: Iris
authors.initials: I
authors.lastname: Kuss
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D004311:Double-Blind Method; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D015996:Survival Rate; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C559147:regorafenib; D000068877:Imatinib Mesylate; D000077210:Sunitinib