title: Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082).
abstract: OBJECTIVE
  EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.
  
  
  METHODS
  Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.
  
  
  RESULTS
  Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2-82.2] in the temozolomide arm and 69.6% (95% CI, 55.8-79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77-1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04-0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.
  
  
  CONCLUSIONS
  Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797-806. ©2016 AACR.
authors.affiliation: Neurology Clinic, University of Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: European Organisation for Research and Treatment of Cancer (EORTC), Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bady
authors.affiliation: Neurology Clinic, University of Heidelberg, Heidelberg, Germany. CCU Brain Tumor Immunology, DKFZ, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Department of Neurology/Neuro-Oncology, Erasmus MC - Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.affiliation: Neuro-oncology Unit, MC Haaglanden, The Hague, the Netherlands.
authors.forename: Martin J B
authors.initials: MJ
authors.lastname: Taphoorn
authors.affiliation: European Organisation for Research and Treatment of Cancer (EORTC), Lausanne, Switzerland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Steuve
authors.affiliation: Department of Medical Oncology, Ospedale Bellaria, Bologna, Italy.
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
authors.affiliation: Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland. Department of Neurosurgery, CHUV, Lausanne, Switzerland.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hamou
authors.affiliation: Neurology Clinic, University of Heidelberg, Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Wick
authors.affiliation: Pfizer, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kosch
authors.affiliation: Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Department of Neurosurgery, CHUV, Lausanne, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: European Organisation for Research and Treatment of Cancer (EORTC), Lausanne, Switzerland.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Golfinopoulos
authors.affiliation: 1-Institut de Cancérologie de l'OUEST, Saint Herblain-Nantes Cedex, France.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Frenel
authors.affiliation: 1-Institut de Cancérologie de l'OUEST, Saint Herblain-Nantes Cedex, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, UMR8257 MD4 Cognac G, CNRS, Service de Santé des Armées, Université Paris Descartes, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Ricard
authors.affiliation: General Hospital AKH, Medical University Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.affiliation: Institut Catala d'Oncologia (ICO), Hospital Germans Trias Pujol, Badalona, Barcelona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Villa
authors.affiliation: Department of Neurosurgery, Medical Center, University of Freiburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.affiliation: University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre, Bristol, United Kingdom.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hopkins
authors.affiliation: Department of Oncology, CHUV, Lausanne, Switzerland.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Homicsko
authors.affiliation: Institute of Pathology, CHUV, Lausanne, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lhermitte
authors.affiliation: Department of Radio-oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pesce
authors.affiliation: Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland. Department of Neurosurgery, CHUV, Lausanne, Switzerland.
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D059248:Chemoradiotherapy / Q000379:methods*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; C401859:temsirolimus; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D020123:Sirolimus; D000077204:Temozolomide