A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K

Neuro Oncol. 2015 Sep;17(9):1261-9. doi: 10.1093/neuonc/nou328. Epub 2014 Dec 18.


Background: The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy.

Methods: Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3'-deoxy-3'-(18)F-fluorothymidine ((18)FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis.

Results: This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had (18)FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that (18)FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders.

Conclusion: Combining everolimus with conventional chemoradiation had moderate toxicity. (18)FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.

Keywords: FLT-PET; everolimus; glioblastoma; mTOR.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / radiotherapy*
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Drug Therapy, Combination
  • Everolimus / therapeutic use*
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / radiotherapy*
  • Humans
  • Positron-Emission Tomography
  • Prognosis
  • Survival Analysis
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Temozolomide
  • Treatment Outcome


  • Antineoplastic Agents
  • Dacarbazine
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Temozolomide