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

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. Clin Cancer Res; 22(19); 4797-806. ©2016 AACR.

• Authors: Wolfgang Wick, Thierry Gorlia, Pierre Bady, Michael Platten, Martin J van den Bent, Martin J B Taphoorn, Jonathan Steuve, Alba A Brandes, Marie-France Hamou, Antje Wick, Markus Kosch, Michael Weller, Roger Stupp, Patrick Roth, Vassilis Golfinopoulos, Jean-Sebastien Frenel, Mario Campone, Damien Ricard, Christine Marosi, Salvador Villa, Astrid Weyerbrock, Kirsten Hopkins, Krisztian Homicsko, Benoit Lhermitte, Gianfranco Pesce, Monika E Hegi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 19 Pg. 4797-4806 (Oct 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27143690 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Tumor Suppressor Proteins
• temsirolimus
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes
• Sirolimus
• Temozolomide

Topics

• Adult
• Aged
• Brain Neoplasms (drug therapy, mortality, radiotherapy)
• Chemoradiotherapy (methods)
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Dacarbazine (administration & dosage, analogs & derivatives)
• Female
• Glioblastoma (drug therapy, mortality, radiotherapy)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Promoter Regions, Genetic (genetics)
• Proportional Hazards Models
• Sirolimus (administration & dosage, analogs & derivatives)
• Temozolomide
• Tumor Suppressor Proteins (genetics)
• Young Adult