title: Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study.
abstract: BACKGROUND
  Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population.
  
  
  METHODS
  In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783.
  
  
  RESULTS
  Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0).
  
  
  CONCLUSIONS
  Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.
  
  
  BACKGROUND
  Novartis Pharmaceuticals Corporation.
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jyao@mdanderson.org.
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.affiliation: Istituto Europeo di Oncologia, IRCCS, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.affiliation: Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
authors.forename: Simron
authors.initials: S
authors.lastname: Singh
authors.affiliation: Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Buzzoni
authors.affiliation: IRCCS Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Carnaghi
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Wolin
authors.affiliation: Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Tomasek
authors.affiliation: Univ. Klinik f. Innere Medizin I, AKH, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Raderer
authors.affiliation: Universitaetsklinikum Essen, Zentrum f. Innere Medizin, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Lahner
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Lida Bubuteishvili
authors.initials: LB
authors.lastname: Pacaud
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rouyrre
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Carolin
authors.initials: C
authors.lastname: Sachs
authors.affiliation: Institute of Cancer Studies, University of Manchester, The Christie Hospital, Manchester, UK.
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.affiliation: Azienda Ospedaliera Sant'Andrea, Università La Sapienza, Rome, Italy.
authors.forename: Gianfranco Delle
authors.initials: GD
authors.lastname: Fave
authors.affiliation: University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Nederlands Kanker Instituut, Antoni van Leeuwenhoek, Amsterdam, Netherlands.
authors.forename: Margot
authors.initials: M
authors.lastname: Tesselaar
authors.affiliation: National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Seoul National University Hospital, Seoul, South Korea.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Strosberg
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.affiliation: Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Pavel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality*; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus