title: Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.
abstract: BACKGROUND
  Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs.
  
  
  METHODS
  In this randomised, open-label, multicentre, phase 3 trial (ENESTg1), participants from academic centres were aged 18 years or older and had previously untreated, histologically confirmed, metastatic or unresectable GISTs. Patients were stratified by previous adjuvant therapy and randomly assigned (1:1) via a randomisation list to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. The primary endpoint was centrally reviewed progression-free survival. Efficacy endpoints were assessed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00785785.
  
  
  RESULTS
  Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April, 2011. Between March 16, 2009, and April 21, 2011, 647 patients were enrolled; of whom 324 were allocated nilotinib and 320 were allocated imatinib. At final analysis of the core study (data cutoff, October, 2012), 2-year progression-free survival was higher in the imatinib group (59·2% [95% CI 50·9-66·5]) than in the nilotinib group (51·6% [43·0-59·5]; hazard ratio 1·47 [95% CI 1·10-1·95]). In the imatinib group, the most common grade 3-4 adverse events were hypophosphataemia (19 [6%]), anaemia (17 [5%]), abdominal pain (13; 4%), and elevated lipase level (15; 5%), and in the nilotinib group were anaemia (18; 6%), elevated lipase level (15; 5%), elevated alanine aminotransferase concentration (12; 4%), and abdominal pain (11; 3%). The most common serious adverse event in both groups was abdominal pain (11 [4%] in the imatinib group, 14 [4%] in the nilotinib group).
  
  
  CONCLUSIONS
  Nilotinib cannot be recommended for broad use to treat first-line GIST. However, future studies might identify patient subsets for whom first-line nilotinib could be of clinical benefit.
  
  
  BACKGROUND
  Novartis Pharmaceuticals.
authors.affiliation: Centre Léon-Bérard, University Claude Bernard Lyon I, Lyon, France. Electronic address: jean-yves.blay@lyon.unicancer.fr.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GastrointestinaI Oncology, Peking University Cancer Hospital and Institute, Haidian, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.affiliation: PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, Jiangsu, China.
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.affiliation: Department of Clinical Pharmacology and Chemotherapy, Blokhin Cancer Research Center, Moscow, Russia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Nosov
authors.affiliation: Department of Colorectal Surgery, Cancer Center, Sun Yat-sen University, State Key Laboratory in Southern China, Guangzhou, China.
authors.forename: Desen
authors.initials: D
authors.lastname: Wan
authors.affiliation: Sylvester Cancer Center, University of Miami, Miami, Florida, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Trent
authors.affiliation: Medical Oncology Division, Siriraj Hospital, Bangkoknoi, Bangkok, Thailand.
authors.forename: Vichien
authors.initials: V
authors.lastname: Srimuninnimit
authors.affiliation: Military Hospital-State Health Centre Oncology Department, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Pápai
authors.affiliation: Department of Medicine, Institut Gustave Roussy, Villejuif, France.
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Novick
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Lilia
authors.initials: L
authors.lastname: Taningco
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Mo
authors.affiliation: Novartis Pharma AG, Postfach, Basel, Switzerland.
authors.forename: Steven
authors.initials: S
authors.lastname: Green
authors.affiliation: Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, and Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib