Clin Cancer Res. 2016 May 3. pii: clincanres.3153.2015. [Epub ahead of print]

Wick W1, Gorlia T2, Bady P3, Platten M4, van den Bent MJ5, Taphoorn MJ6, Steuve J7, Brandes AA8, Hamou MF9, Wick A4, Kosch M10, Weller M11, Stupp R12, Roth P13, Golfinopoulos V7, Frenel JS14, Campone M15, Ricard D16, Marosi C17, Villa S18, Weyerbrock A19, Hopkins K20, Homicsko K21, Lhermitte B22, Pesce GA23, Hegi ME24.

 

Author information:

1Neurooncology, Neurology Clinic and National Center for Tumor Disease, University Hospital Heidelberg wolfgang.wick@med.uni-heidelberg.de.

2Data Center, European Organisation for Research and Treatment of Cancer.

3Swiss Institute of Bioinformatics, University of Lausanne.

4Neurooncology, University of Heidelberg.

5neuro-oncology, Daniel den Hoed Cancer Center/Erasmus University Medical Center.

6Neurology, Medisch Centrum Haaglanden.

7BTG, EORTC.

8Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL of Bologna.

9Neurosurgery, University Hospital Lausanne.

10Oncolocgy, Pfizer GmbH.

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

12Department of Oncology and Cancer Center, University Hospital Zurich.

13Neurology, University of Zurich.

14Medical Oncology, Institut de Cancerologie de l'Ouest.

15Department of Oncology, CRLCC René Gauducheau.

16Service de Neuro-oncologie, Hopital d'Instruction des Armées du Val-de-Grâce.

17Department of Internal Medicine, Medical University Vienna.

18Hospital Germans Trias Pujol, Institut Catala d'Oncologia.

19Department of Neurosurgery, University Medical Center Freiburg.

20NHS Foundation Trust - Bristol Haematology and Oncology, University Hospitals Bristol.

21Neurosciences, Centre Hospitalier Universitaire Vaudois.

22Neuropathology, Lausanne University Hospital.

23Department of Radio-oncology, Oncology Institute of Southern Switzerland.

24Clinical neurosciences-service of neurosurgery, Lausanne University Hospital.

 

Abstract

PURPOSE:

 

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

PATIENTS AND 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 non-comparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Pre-specified 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% CI (58.2-82.2)] in the temozolomide arm and 69.6% [95% CI (55.8-79.9)] in the temsirolimus arm [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.

 

Copyright ©2016, American Association for Cancer Research.

PMID: 27143690 [PubMed - as supplied by publisher]

7. Mol Cell Proteomics. 2016 May 3. pii: mcp.M116.060657. [Epub ahead o