Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent Glioblastoma Multiforme: Interim results

1558 Background: Erlotinib (Tarceva, OSI-774) is an orally available small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. We have initiated the first phase II trial of erlotinib in single agent therapy of recurrent glioblastoma multiforme (GBM). Methods: Patients with documented recurrent or progressive GBM who have received previous radiation therapy and cytotoxic chemotherapy were eligible for enrollment. No enzyme-inducing anti-epileptic agents were allowed. Patients were treated with 150 mg of erlotinib per day until tumor progression or study withdrawal. Tumor response was determined by MRI. Analysis for EGFR amplification was performed. Results: Interim analysis has been performed on a total of 16 of 31 planned patients as of December, 2003. Of these, 4 patients have shown partial responses, 1 showed a partial response of his original tumor but then developed a separate unresponsive focus and 4 have had disease stabilization for greater than 3 months. Seven patients have had tumor progression within 3 months of starting erlotinib. Although a response has been seen in 50% of patients (4 PR + 4 SD), the responses have not been durable; the median time to progression of responders has been 145 days after the start of therapy. Eleven patients have died since the start of the study. The pattern of subsequent treatment failure in responders has suggested a diffuse spread of tumor (e.g. gliomatosis cerebri or leptomeningeal spread). One patient had a tumor-associated cyst in which the steady state OSI-774 level was determined and found to be approximately 40% of that observed in plasma. Approximately one-half of the tumors have had EGFR amplification, but EGFR amplification has not ensured a response to erlotinib and responses have been observed in the absence of amplification. Conclusions: Although these results are preliminary in nature, we are encouraged by the response rate observed to date. The apparent lack of durability of response and the pattern of post-response failure may be due, in part, to reduced drug penetration into the brain, an inadequate dose and/or tumor heterogeneity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech