title: Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.
abstract: BACKGROUND
  Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid).
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061.
  
  
  RESULTS
  429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%).
  
  
  CONCLUSIONS
  Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome.
  
  
  BACKGROUND
  Novartis Pharmaceuticals.
authors: Charité-Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany.
authors: Marianne E
authors: ME
authors: Pavel
authors: Sarah Cannon Research Institute, Nashville, TN, USA.
authors: John D
authors: JD
authors: Hainsworth
authors: Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France.
authors: Eric
authors: E
authors: Baudin
authors: Department of Oncology, Antwerp University Hospital, Edegem, Belgium.
authors: Marc
authors: M
authors: Peeters
authors: Klinik für Innere Medizin, Gastroenterologie und Endokrinologie, Zentrum für Neuroendokrine Tumore, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; Ochsner Kenner Medical Center, Kenner, LA, USA.
authors: Dieter
authors: D
authors: Hörsch
authors: Novartis Oncology, Florham Park, NJ, USA.
authors: Robert E
authors: RE
authors: Winkler
authors: Novartis Oncology, Florham Park, NJ, USA.
authors: Judith
authors: J
authors: Klimovsky
authors: Novartis Oncology, Florham Park, NJ, USA.
authors: David
authors: D
authors: Lebwohl
authors: Novartis Pharma AG, Basel, Switzerland.
authors: Valentine
authors: V
authors: Jehl
authors: Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors: Edward M
authors: EM
authors: Wolin
authors: Department of Endocrine Oncology, University Hospital, Uppsala, Sweden.
authors: Kjell
authors: K
authors: Öberg
authors: University Hospital Gasthuisberg, Leuven, Belgium.
authors: Eric
authors: E
authors: Van Cutsem
authors: University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jyao@mdanderson.org.
authors: James C
authors: JC
authors: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000473:pathology; D003692:Delayed-Action Preparations; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008303:Malignant Carcinoid Syndrome / Q000188:drug therapy*; D008875:Middle Aged; D015282:Octreotide / Q000627:therapeutic use*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D000068338:Everolimus; D015282:Octreotide; D020123:Sirolimus