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Abstract

PURPOSE:

EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.

EXPERIMENTAL DESIGN:

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.​ 

Author information​

Wick W1, Gorlia T2, Bady P3, Platten M4, van den Bent MJ5, Taphoorn MJ6, Steuve J2, Brandes AA7, Hamou MF8, Wick A9, Kosch M10, Weller M11, Stupp R12, Roth P11, Golfinopoulos V2, Frenel JS13, Campone M13, Ricard D14, Marosi C15, Villa S16, Weyerbrock A17, Hopkins K18, Homicsko K19, Lhermitte B20, Pesce G21, Hegi ME8.

1Neurology 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.

2European Organisation for Research and Treatment of Cancer (EORTC), Lausanne, Switzerland.

3SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland.

4Neurology Clinic, University of Heidelberg, Heidelberg, Germany. CCU Brain Tumor Immunology, DKFZ, Heidelberg, Germany.

5Department of Neurology/Neuro-Oncology, Erasmus MC - Cancer Institute, Rotterdam, the Netherlands.

6Neuro-oncology Unit, MC Haaglanden, The Hague, the Netherlands.

7Department of Medical Oncology, Ospedale Bellaria, Bologna, Italy.

8Neuroscience Research Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland. Department of Neurosurgery, CHUV, Lausanne, Switzerland.

9Neurology Clinic, University of Heidelberg, Heidelberg, Germany.

10Pfizer, Berlin, Germany.

11Department of Neurology, University Hospital and University of Zurich, Switzerland.

12Department of Neurosurgery, CHUV, Lausanne, Switzerland.

131-Institut de Cancérologie de l'OUEST, Saint Herblain-Nantes Cedex, France.

14AP-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.

15General Hospital AKH, Medical University Vienna, Austria.

16Institut Catala d'Oncologia (ICO), Hospital Germans Trias Pujol, Badalona, Barcelona, Spain.

17Department of Neurosurgery, Medical Center, University of Freiburg, Germany.

18University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre, Bristol, United Kingdom.

19Department of Oncology, CHUV, Lausanne, Switzerland.

20Institute of Pathology, CHUV, Lausanne, Switzerland.

21Department of Radio-oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.