Document Detail


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.
MedLine Citation:
PMID:  23177515     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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%).
INTERPRETATION: 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.
FUNDING: Bayer HealthCare Pharmaceuticals.
Authors:
George D Demetri; Peter Reichardt; Yoon-Koo Kang; Jean-Yves Blay; Piotr Rutkowski; Hans Gelderblom; Peter Hohenberger; Michael Leahy; Margaret von Mehren; Heikki Joensuu; Giuseppe Badalamenti; Martin Blackstein; Axel Le Cesne; Patrick Schöffski; Robert G Maki; Sebastian Bauer; Binh Bui Nguyen; Jianming Xu; Toshirou Nishida; John Chung; Christian Kappeler; Iris Kuss; Dirk Laurent; Paolo G Casali;
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Publication Detail:
Type:  Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-22
Journal Detail:
Title:  Lancet     Volume:  381     ISSN:  1474-547X     ISO Abbreviation:  Lancet     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-02-07     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985213R     Medline TA:  Lancet     Country:  England    
Other Details:
Languages:  eng     Pagination:  295-302     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 Elsevier Ltd. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT01271712
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MeSH Terms
Descriptor/Qualifier:
Aged
Antineoplastic Agents / adverse effects,  therapeutic use*
Benzamides
Double-Blind Method
Female
Gastrointestinal Neoplasms / drug therapy*,  mortality,  pathology
Gastrointestinal Stromal Tumors / drug therapy*,  mortality,  secondary
Humans
Indoles / therapeutic use*
Male
Middle Aged
Phenylurea Compounds / adverse effects,  therapeutic use*
Piperazines / therapeutic use*
Protein Kinase Inhibitors / adverse effects,  therapeutic use
Pyridines / adverse effects,  therapeutic use*
Pyrimidines / therapeutic use*
Pyrroles / therapeutic use*
Survival Rate
Treatment Failure
Grant Support
ID/Acronym/Agency:
1P50CA127003-05/CA/NCI NIH HHS; P50 CA127003/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzamides; 0/Indoles; 0/Phenylurea Compounds; 0/Piperazines; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/Pyrimidines; 0/Pyrroles; 0/sunitinib; 24T2A1DOYB/regorafenib; BKJ8M8G5HI/imatinib
Investigator
Investigator/Affiliation:
Hellmut Samonigg / ; Thomas Brodowicz / ; Wolfgang Eisterer / ; Patrick Schöffski / ; Martin Blackstein / ; Karen Mulder / ; Jawaid Younus / ; Jin Li / ; Shukui Qin / ; De Sen Wan / ; Jianming Xu / ; Heikki Joensuu / ; Jean-Yves Blay / ; Binh Bui Nguyen / ; Antoine Adenis / ; Oscar Lambret / ; Axel Le Cesne / ; Peter Reichardt / ; Jens Chemnitz / ; Sebastian Bauer / ; Peter Hohenberger / ; Viktor Grünwald / ; Frank Mayer / ; Jochen Schütte / ; Ofer Merimsky / ; Paolo Casali / ; Guido Biasco / ; Massimo Aglietta / ; Giuseppe Badalamenti / ; Paolo Giaccone / ; Toshihiko Doi / ; Tatsuo Kanda / ; Toshirou Nishida / ; Yasuhide Yamada / ; Yoshito Komatsu / ; Akira Sawaki / ; Hans Gelderblom / ; Winette Van der Graaf / ; Piotr Rutkowski / ; Richard Quek / ; Yoon-Koo Kang / ; Hyuk Chan Kwon / ; Seock-Ah Im / ; Joon Oh Park / ; Sun Young Kim / ; Claudia M Valverde Morales / ; Xavier Garcia Del Muro / ; Ian Judson / ; Michael Leahy / ; Anne Thomas / ; George Demetri / ; Mary Louise Keohan / ; Michael Heinrich / ; Margaret von Mehren / ; Robin Jones / ; Bruce Brockstein / ; Pamela Kaiser / ; Keith Skubitz / ; Michael Gordon /
Comments/Corrections
Comment In:
Lancet. 2013 Jan 26;381(9863):273-5   [PMID:  23177516 ]
Nat Rev Clin Oncol. 2013 Jan;10(1):1   [PMID:  23229184 ]

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