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Erlotinib Demonstrates Objective Response Against Malignant Gliomas in Phase I Data

Erlotinib Demonstrates Objective Response Against Malignant Gliomas in Phase I Data

CHICAGO-Preliminary results from a phase I study of erlotinib (OSI-774,Tarceva) have shown a 16% response rate in malignant glioma patients, triggering plans for phase II studies of the novel agent alone and in combination with other therapies. Michael D. Prados, MD, of the Brain Tumor Research Program at the University of California, San Francisco, reported the data at ASCO (ASCO abstract 394) and at a post-ASCO, industry-sponsored, satellite symposium, "Targeting Critical Pathways in Oncology." Dr. Prados told ONI that the results exceeded expectations in one of the first trials to test erlotinib against gliomas. "I was very surprised, very happily surprised, that we actually saw objective response in patients using a single oral agent. I think that's quite unusual," he said. A small molecule, erlotinib inhibits the HER1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, which is often amplified in gliomas. Erlotinib is being developed by Genentech, Inc., and OSI Pharmaceuticals, Inc. All patients in the trial must have histologically proven malignant glioma and a Karnofsky performance score ≥ 60, but EGFR tumor status is not a criterion for enrollment. The ongoing study is testing erlotinib alone and in combination with temozolomide (Temodar), a common treatment for brain tumors. Of 66 patients enrolled so far, 49 were evaluable at the time of the report. Seven of the eight patients who responded had glioblastoma multiforme, and six had received erlotinib alone. Close to A Complete Response
Magnetic resonance images (MRIs) of a 55-year-old woman showed how she experienced close to a complete response at 4 months on erlotinib alone (see Figure 1). MRIs also demonstrated a partial response from a 50-yearold man with recurrent glioblastoma, who was taking 400 mg of erlotinib daily. Dr. Prados said the man has continued on the study for almost 11 months despite a rash at that dose. "It's rare to see responses in phase I. It's rare to see responses in glioblastoma even with the best drugs, and it was unanticipated in this because we weren't certain about all the pharmokinetics," Dr. Prados said. Investigators also subdivided both arms of the trial to assess the impact of enzyme-inducing antiepileptic drugs (EIAEDs), which some patients take to prevent seizures. The trial started at 100 mg/day of erlotinib, with the dose escalating by 50 mg/day for each cohort. Temozolomide was given in 28-day cycles, the dose starting at 150 mg/m2 for 5 days and escalating to 200 mg in cycle 2 with no further increases (see Table 1). For patients not on EIAIDs, doselimiting toxicity was reached at 250 mg of erlotinib in both arms. For patients on EIAIDs, the maximum tolerated dose has not been reached. Investigators are currently at a dose of 500 mg of erlotinib alone, or 350 mg of erlotinib with temozolomide and are still escalating the dose in patients on EIAIDs who are receiving both erlotinib and temozolomide. "Clearly use of EIAEDs reduces response to the agent," Dr. Prados said, noting that 500 mg is almost four times the recommended dose. Rash was the primary dose-limiting toxicity, according to Dr. Prados. At a later ASCO session, Gary M. Clark, PhD, of OSI Pharmaceuticals presented an analysis that found rash correlated with response and survival in prior erlotinib trials. (See article in this supplement, page 1.) At the post- ASCO symposium, Dr. Prados said grades 1 and 2 rashes were common in the glioma study, but his group has not yet done a correlation. Survival Data Pending
As the phase I trial continues to enroll patients, Dr. Prados said estimation of progression-free survival is still pending. Meanwhile, he announced plans for phase II trials of erlotinib in combination with radiation therapy in new glioma patients and by itself in relapsed patients. "There's going to have to be some combination strategy," Dr. Prados concluded. "It's a well-tolerated oral drug that has exciting, early, objective biological activity."

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