Abstract LB-A01: Molecular subgroup analysis of a randomized trial (EORTC 26082-22081) testing temsirolimus and radiation therapy versus chemoradiotherapy with temozolomide in patients with newly diagnosed glioblastoma without methylation of the MGMT gene promoter
Authors: Hegi Monika E. , Gorlia Thierry , Bady Pierre , Platten Michael , van den Bent Martin J. , Taphoorn Martin JB , Steuve Jonathan , Brandes Alba A. , Hamou Marie-France , Kosch Markus , Golfinopoulos Vassilis , Campone Mario , Roth Patrick , Lhermitte Benoit , Stupp Roger , Pesce Gianfranco , Wick Wolfgang 
Published: May 2016

Abstract
Background:
Preclinical data indicate activity of mammalian target of rapamycin (mTOR) inhibitors, as well as synergistic activity together with radiotherapy in glioblastoma. The aim of this non-comparative randomized phase II trial (NCT01019434) was to assess the therapeutic activity of the mTOR inhibitor temsirolimus, in patients with newly diagnosed glioblastoma with unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter. These patients are in particular need for new treatment options as they derive little if any benefit from the currently standard temozolomide treatment.
Methods:
Patients were registered and their tumors were centrally reviewed and tested for the MGMT status. Participation to the trial was offered to patients with histologically confirmed glioblastoma harboring an unmethylated MGMT promoter. Patients (n = 111) were randomized 1:1 between standard of care of radiotherapy (60 Gy; 5 times 2 Gy per week) plus concomitant and six cycles of maintenance temozolomide (TMZ/RT/→TMZ) or radiotherapy plus weekly temsirolimus at 25 mg flat dose to be continued until progression or undue toxicity. Primary endpoint was overall survival at 12 months (OS12). For a representative subgroup of 88 patients sufficient tumor tissue was available for pre-specified post hoc analyses of a panel of markers considered to be relevant for the activity of mTOR inhibition in order to identify a subgroup of patients potentially sensitive to temsirolimus.
Findings:
Both therapies were properly administered with a median of 13 weeks of maintenance temsirolimus or 4 cycles of TMZ. In the intention to treat population OS12 was 69.6% [95% CI (55.8-79.9) in the temsirolimus arm and 72.2% [95% CI (58.2, 82.2)] in the temozolomide arm [HR = 1.16 95% CI (0.77-1.76), p = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, the phosphorylation status of mTOR [HR = 0.13, 95% CI (0.04-0.47), p = 0.002], but no clinical factor was a significant predictor in the temsirolimus arm. There was a significant interaction between treatment and phosphorylated mTOR (p-mTOR) (p = 0.047). The median overall survival in the temsirolimus group was 17.8 months (CI, 14.1-28.0) for patients with p-mTOR positive tumors and 13.11 (CI, 9.7-15.1) in the negative subgroup. In the RT/TMZ→TMZ control arm the median survival in the p-mTOR positive group was 14.0 months (CI, 9.6-19.6) and 16.5 months (CI, 9.5-18.8) in the p-mTOR negative subgroup.
Interpretation:
The therapeutic activity of temsirolimus is too low in the whole cohort of patients with newly diagnosed glioblastoma with an unmethylated MGMT promoter. However, the phosphorylation status of mTOR may identify a subgroup that benefits from temsirolimus, while the same treatment may be detrimental to patients with p-mTOR negative tumors.
Funding:
Pfizer provided an unrestricted academic grant. Molecular subgroup analysis was funded by the Swiss National Science Foundation (FN31003A-138116 to M.E.H).
Previously presented in part at ASCO 2014 (abstract #2003)
Citation Format: Monika E. Hegi, Thierry Gorlia, Pierre Bady, Michael Platten, Martin J. van den Bent, Martin JB Taphoorn, Jonathan Steuve, Alba A. Brandes, Marie-France Hamou, Markus Kosch, Vassilis Golfinopoulos, Mario Campone, Patrick Roth, Benoit Lhermitte, Roger Stupp, Gianfranco Pesce, Wolfgang Wick. Molecular subgroup analysis of a randomized trial (EORTC 26082-22081) testing temsirolimus and radiation therapy versus chemoradiotherapy with temozolomide in patients with newly diagnosed glioblastoma without methylation of the MGMT gene promoter. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A01.