TY - JOUR
T1 - Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082)
AU - Wick, Wolfgang
AU - Gorlia, Thierry
AU - Bady, Pierre
AU - Platten, Michael
AU - Van Den Bent, Martin J.
AU - Taphoorn, Martin J B
AU - Steuve, Jonathan
AU - Brandes, Alba A.
AU - Hamou, Marie France
AU - Wick, Antje
AU - Kosch, Markus
AU - Weller, Michael
AU - Stupp, Roger
AU - Roth, Patrick
AU - Golfinopoulos, Vassilis
AU - Frene, Jean Sebastien
AU - Campone, Mario
AU - Ricard, Damien
AU - Marosi, Christine
AU - Villa, Salvador
AU - Weyerbrock, Astrid
AU - Hopkins, Kirsten
AU - Homicsko, Krisztian
AU - Lhermitte, Benoit
AU - Pesce, Gianfranco
AU - Hegi, Monika E.
N1 - Funding Information:
This work was supported by Pfizer who provided an unrestricted academic grant. Swiss National Science Foundation (FN31003A-138116 to M.E. Hegi) and the Swiss Cancer Ligue (KFS 02670-08-2010 to M.E. Hegi) supported the biomarker analyses.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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. Clin Cancer Res; 22(19); 4797-806.
AB - 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. Clin Cancer Res; 22(19); 4797-806.
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U2 - 10.1158/1078-0432.CCR-15-3153
DO - 10.1158/1078-0432.CCR-15-3153
M3 - Article
C2 - 27143690
AN - SCOPUS:84991211405
SN - 1078-0432
VL - 22
SP - 4797
EP - 4806
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -
