title: Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Few treatment options remain for patients with metastatic or unresectable gastrointestinal stromal tumours (GIST) after objective progression on approved tyrosine-kinase inhibitors. We aimed to assess efficacy of imatinib rechallenge in these patients.
  
  
  METHODS
  In our prospective, randomised, double-blind trial, we enrolled adults (≥18 years) who had previously benefited from first-line imatinib (initial response or stable disease for ≥6 months) but whose metastatic or unresectable GIST had progressed on at least imatinib and sunitinib. We randomly allocated participants in a 1:1 ratio, with a centralised computer-generated allocation procedure (random permuted blocks of two, four, and six) and stratified by previous treatment and Eastern Cooperative Oncology Group performance status, to receive best supportive care with imatinib 400 mg per day or matched placebo. Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. The primary endpoint was progression-free survival (PFS), as determined by a masked external radiological review. All analyses were done for all patients who received at least one dose of study drug.
  
  
  RESULTS
  Between July 20, 2010, and Jan 17, 2013, we randomly allocated 41 patients to the imatinib group and 40 patients to the placebo group. After a median follow-up of 5·2 months (IQR 3·4-9·4), median PFS was 1·8 months (95% CI 1·7-3·6) with imatinib compared with 0·9 months (0·9-1·7) with placebo (hazard ratio for progression or death 0·46, 95% CI 0·27-0·78; p=0·005). 37 (93%) patients in the placebo group crossed over to open-label imatinib after progression. The most common grade 3 or worse adverse events were anaemia (12 [29%] of 41 patients in the imatinib group vs three [8%] of 40 in the placebo group), fatigue (four [10%] vs none), and hyperbilirubinaemia (three [7%] vs one [3%]).
  
  
  CONCLUSIONS
  In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to harbour many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: ykkang@amc.seoul.kr.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Ryu
authors.forename: Changhoon
authors.initials: C
authors.lastname: Yoo
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jong Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Byung-Ho
authors.initials: BH
authors.lastname: Nam
authors.forename: Nikhil
authors.initials: N
authors.lastname: Ramaiya
authors.forename: Jyothi
authors.initials: J
authors.lastname: Jagannathan
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D056910:Republic of Korea; D000077210:Sunitinib; D013997:Time Factors; 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