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Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082)


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; Villà, Salvador; Weyerbrock, Astrid; Hopkins, Kirsten; Homicsko, Krisztian; Lhermitte, Benoit; Pesce, Gianfranco Angelo; Hegi, Monika E (2016). Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clinical Cancer Research, 22(19):4797-4806.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
Dewey Decimal Classification:610 Medicine & health
Date:3 May 2016
Deposited On:31 May 2016 16:10
Last Modified:08 Dec 2017 19:35
Publisher:American Association for Cancer Research
ISSN:1078-0432
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1078-0432.CCR-15-3153
PubMed ID:27143690

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