Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas Abstract— Malignant gliomas are frequently characterized by amplification of the epidermal growth factor receptor (EGFR) and loss of PTEN tumor suppres- sor gene. Twenty-eight heavily pretreated patients with recurrent malignant gliomas were administered EGFR inhibitors (gefitinib or erlotinib) in combina- tion with the mTOR (mammalian target of rapamycin) inhibitor sirolimus. The regimens were reasonably well tolerated. Nineteen percent of patients experi- enced a partial response and 50% had stable disease. Six-month progression- free survival for glioblastoma patients was 25%. NEUROLOGY 2006;67:156–158 L. Doherty, NP; D.C. Gigas, RN; S. Kesari, MD, PhD; J. Drappatz, MD; R. Kim, PhD; J. Zimmerman; L. Ostrowsky; and P.Y. Wen, MD Despite optimal therapy with surgery, radiotherapy, and chemotherapy, the prognosis of malignant glio- mas remains poor. Patients with glioblastoma (GBM) have a median survival of approximately 9 to 15 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months. 1 Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks. 2 There is a need for more effective, novel forms of therapy. Human cancers, including malignant gliomas, result from aberrations in cell signaling. Specific inhibitors of tyrosine kinases and signaling pathways have demon- strated therapeutic efficacy in an increasing number of cancers. Recently, there has been growing interest in the use of these targeted molecular agents for the treatment of malignant gliomas. 3 The major molecular abnormalities in GBM are amplification of the epider- mal growth factor receptor (EGFR) and inactivation of the phosphatase and tensin homologue deleted on chro- mosome 10 (PTEN) gene. 4,5 EGFR is amplified in 40 to 50%, and overexpressed in 60% of GBMs. 4,5 Approxi- mately 40% of tumors with EGFR amplification have a constitutively active mutation (EGFR vIII). 4 Approxi- mately 40 to 50% of GBMs have PTEN deletions or mutations. 4 These molecular abnormalities result in overactivity of the Ras/mitogen-activated protein ki- nase and the phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways, resulting in tumor proliferation, angiogenesis, and in- hibition of apoptosis. Studies with single-agent mTOR and EGFR inhib- itors have shown only limited activity in malignant gliomas with response rates of 10 to 15% or less, and no significant prolongation of survival. 3,5-8 These re- sults are not surprising given the complexity of the molecular derangements in malignant gliomas and the presence of redundant signaling pathways. In a recent study correlating response to EGFR inhibitors and tumor genotype, GBMs expressing the EGFR- vIII mutation and intact PTEN were found to have an increased response rate. 8 This suggests that tu- mors with loss of PTEN and activation of the PI3K/ Akt/mTOR pathway were unlikely to respond to EGFR inhibitors alone. It is possible that combina- tions of targeted molecular agents inhibiting comple- mentary molecular pathways may have greater therapeutic efficacy. 3,9 In this pilot study, we re- viewed our experience with the combination of EGFR inhibitors gefitinib and erlotinib with the mTOR in- hibitor sirolimus in a heavily pretreated group of patients with recurrent malignant gliomas. Methods. We performed a retrospective review of 28 consecu- tive patients with a histologic diagnosis of malignant gliomas and radiographic documentation of recurrent disease treated between October 2004 and December 2005. All patients had prior treat- ment with radiotherapy, baseline MRI within 2 weeks of initiating therapy on stable dose of corticosteroids for 5 days, age 18 years and older, Karnofsky Performance Status 50, absolute neutro- phil count 1,500/mm 3 , platelets 100,000/mm 3 , normal renal and liver function, and no prior therapy with EGFR or mTOR inhibitors. There was no limit on the number of prior therapies. Because gefitinib (IRESSA), erlotinib (Tarceva), and sirolimus (Rapamune) are all cytochrome P-450 3A4 substrates, patients could not be on enzyme-inducing antiepileptic drugs for at least 10 days before beginning therapy. The endpoints were evaluation of toxicity, progression-free survival at 6 months (6M-PFS), and re- sponse as determined by the MacDonald et al. criteria. 10 Patients were treated with either gefitinib 500 mg or erlotinib 150 mg orally once daily in combination with sirolimus. Sirolimus was administered at a dose of 6 mg orally the first day followed by 4 mg orally once daily thereafter. Both medications were given con- tinuously every day in 28-day cycles. Complete blood counts, liver function tests, lipid profile, and sirolimus levels were obtained every 2 weeks. The sirolimus dose was adjusted to ensure that trough drug levels were in the mid to high therapeutic range. Neuroimaging studies were obtained every 8 weeks. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (CTC Version 3.0). Results. We studied 28 patients (16 men and 12 women) (table) The median age was 56 years (range 34 to 87) and From the Center for Neuro-Oncology (L.D., D.C.G., S.SK, J.D., R.K., J.Z., L.O., P.Y.W.), Dana Farber/Brigham and Women’s Cancer Center and Divi- sion of Cancer Neurology (S.K., J.D., P.Y.W.), Department of Neurology, Brigham and Women’s Hospital, Boston, MA. Supported by the Amos Wasgatt, Will Kraft, and Samuel Longo Brain Tumor Research Funds. Disclosure: The authors report no conflicts of interest. Received January 12, 2006. Accepted in final form March 13, 2006. Address correspondence and reprint requests to Dr. Patrick Y. Wen, Center for Neuro-Oncology, Dana Farber/Brigham and Women’s Cancer Center, SW430D, 44 Binney Street, Boston, MA 02115; e-mail: pwen@partners.org 156 Copyright © 2006 by AAN Enterprises, Inc.