title: Everolimus for advanced pancreatic neuroendocrine tumors.
abstract: BACKGROUND
  Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.
  
  
  METHODS
  We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.
  
  
  RESULTS
  The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).
  
  
  CONCLUSIONS
  Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jyao@mdanderson.org
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Catherine Lombard
authors.initials: CL
authors.lastname: Bohas
authors.forename: Edward M
authors.initials: EM
authors.lastname: Wolin
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hobday
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Jaume
authors.initials: J
authors.lastname: Capdevila
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Paola
authors.initials: P
authors.lastname: Tomassetti
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Pavel
authors.forename: Sakina
authors.initials: S
authors.lastname: Hoosen
authors.forename: Tomas
authors.initials: T
authors.lastname: Haas
authors.forename: Jeremie
authors.initials: J
authors.lastname: Lincy
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Kjell
authors.initials: K
authors.lastname: Öberg
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; D000068338:Everolimus; D005260:Female; D006801:Humans; 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*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus