Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082)

• Published in: Clinical cancer research 2016-10, Vol.22 (19), p.4797-4806
• Main Authors: Wick, Wolfgang, Gorlia, Thierry, Bady, Pierre, Platten, Michael, van den Bent, Martin J, Taphoorn, Martin J B, Steuve, Jonathan, Brandes, Alba A, Hamou, Marie-France, Wick, Antje, Kosch, Markus, Weller, Michael, Stupp, Roger, Roth, Patrick, Golfinopoulos, Vassilis, Frenel, Jean-Sebastien, Campone, Mario, Ricard, Damien, Marosi, Christine, Villa, Salvador, Weyerbrock, Astrid, Hopkins, Kirsten, Homicsko, Krisztian, Lhermitte, Benoit, Pesce, Gianfranco, Hegi, Monika E
• Format: Article
• Language: English
• Subjects: Adult; Aged; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain Neoplasms - radiotherapy; Chemoradiotherapy - methods; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; DNA Methylation; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Female; Glioblastoma - drug therapy; Glioblastoma - mortality; Glioblastoma - radiotherapy; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Promoter Regions, Genetic - genetics; Proportional Hazards Models; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Tumor Suppressor Proteins - genetics; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-3153

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