Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02

Abstract

Background: Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.

Methods: We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.

Results: Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.

Conclusion: Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.

Keywords: anaplastic glioma; clinical trial; epidermal growth factor; erlotinib; glioblastoma; temsirolimus.

Fig. 1.

Kaplan–Meier survival plot stratified by histology.

Fig. 2.

Pharmacodynamic analysis of surgical biopsy tissue from patients treated with erlotinib and temsirolimus. Tissue samples taken from 3 patients prior to treatment with erlotinib and temsirolimus (S1) were compared with those taken after treatment for 7 days (S2 drug). Two GBM patients showed no evidence of histologic progression (GBM.64 and GBM.69), while an AG patient (AG.60) showed increased atypia, density consistent with histologic progression. No significant change in pS6^S235/236 staining was noted in paired samples. Qualitative increase in pAkt^S473 staining was noted in GBM.64 and AG.60 compared with pretreatment biopsies. H&E, hematoxylin and eosin.