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

Abstract

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.

Fig. 1.

Protocol schema for N057K.

Fig. 2.

OS and PFS for N057K (dashed lines for 95% CIs).

Fig. 3.

OS and PFS by MGMT status (dashed lines for 95% CIs).

Fig. 4.

OS and PFS by hyperlipidemia status (dashed lines for 95% CIs).

Fig. 5.

Heat map of sequencing (top left), IHC (middle left), and ¹⁸FLT-PET (bottom left) results for the 6 patients with PET and sequencing data. Top right panel demonstrates representative images from an ¹⁸FLT-PET responder (ΔSUV_max = −42%) vs nonresponder (ΔSUV_max = −14%). Bottom right panels demonstrate hematoxylin and eosin (H&E), PTEN, pAkt, pS6, and Ki67 staining for the 2 representative patients. Scale bar = 100 µm. CCND1, cyclin D1; FGFR, fibroblast growth factor receptor.