title: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
abstract: BACKGROUND
  The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.
  
  
  METHODS
  We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.
  
  
  RESULTS
  The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.
  
  
  CONCLUSIONS
  Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).
authors.affiliation: Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy, France. eric.raymond@bjn.aphp.fr
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Raoul
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Ivan
authors.initials: I
authors.lastname: Borbath
authors.forename: Catherine
authors.initials: C
authors.lastname: Lombard-Bohas
authors.forename: Juan
authors.initials: J
authors.lastname: Valle
authors.forename: Peter
authors.initials: P
authors.lastname: Metrakos
authors.forename: Denis
authors.initials: D
authors.lastname: Smith
authors.forename: Aaron
authors.initials: A
authors.lastname: Vinik
authors.forename: Jen-Shi
authors.initials: JS
authors.lastname: Chen
authors.forename: Dieter
authors.initials: D
authors.lastname: Hörsch
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Shem
authors.initials: S
authors.lastname: Patyna
authors.forename: Dongrui Ray
authors.initials: DR
authors.lastname: Lu
authors.forename: Carolyn
authors.initials: C
authors.lastname: Blanckmeister
authors.forename: Richard
authors.initials: R
authors.lastname: Chao
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib