Gefitinib Shows Modest Activity Against Recurrent Glioblastoma

DURHAM, North Carolina- Gefitinib(Drug information on gefitinib) (ZD1839, Iressa) was well tolerated and showed modest activity against glioblastoma in preliminary results from a phase II trial presented by David A. Reardon, MD, of Duke University Medical Center (ASCO abstract 396). Dr. Reardon, clinical director for medical research at the Brain Tumor Center at Duke, reported that 1 of 52 evaluable patients sustained a partial response through nine cycles of treat- ment. Another 22 patients had stable disease, including 8 still on therapy with a mean follow-up of 5.3 months. One patient has been on study for 16 months. "He's enjoying 100% performance status and excellent quality of life at this point," Dr. Reardon said. HER1/EGFR Correlations
Gefitinib inhibits the HER1/epidermal growth factor receptor (HER1/ EGFR) tyrosine kinase. Approved for treatment of advanced non-small-cell lung cancer, gefitinib is being tested in glioblastomas because disruption of the EGFR pathway occurs in most of these brain tumors. Dr. Reardon said that 40% to 50% of patients in the study had amplified wild-type EGFR, and about 50% had mutated EGFR, according to immunohistochemistry of their tumors. The investigators are correlating response to tumor EGFR levels, but results were not ready for release at the time of Dr. Reardon's report. "That analysis is ongoing. It's obviously a critical factor," Dr. Reardon said. "We've got an awful lot to learn about how these drugs are working. We're just scratching the surface." Main Toxicity Was Rash
Among the patients with radiographically stable disease, two were removed from the trial because of toxicity and three because of clinical decline. Dr. Reardon reported the main toxicity was rash followed by diarrhea. About half the glioblastoma patients had grade 1 or 2 rash, he said, and 15% had grade 3 or 4. Two other presentations reported that severity of rash appeared to correlate with response to two other novel agents targeting the EGFR pathway: cetuximab(Drug information on cetuximab) (Erbitux) and erlotinib (OSI-774, Tarceva). (See article in this supplement on page 1.) Rash also was the leading side effect in a phase I trial testing erlotinib in glioma patients (see previous report on page 11.) Probably Underdosing
All patients in the ongoing trial, 57 to date, entered with first-relapse glioblastoma, histologically confirmed after surgery. If patients are on dexamethasone(Drug information on dexamethasone) and/or enzyme-inducing (CYP3A4) agents, the base dose of 500 mg of gefitinib daily can be escalated to 1,000 mg. Treatment cycles last 4 weeks, and tumor response is assessed by magnetic resonance imaging (MRI) every 8 weeks. Gefitinib may have more activity than the early results indicate. Dr. Reardon concurred with neurosurgeon Abhijit Guha, MD, of the University of Toronto, who suggested the appropriate biological dose might be higher than the trial dose. Dr. Guha discussed two studies targeting EGFR inhibitors in brain tumors, praising them for exploring pharmokinetics and calling for greater tissue accrual in future trials. Dr. Reardon told ONI the investigators used a conservative dosing schedule because they had little experience with the class of agents that includes gefitinib and were concerned about the potential for toxicity. "We subsequently learned that although we did see very encouraging responses in a subset of patients, we were probably significantly underdosing due to the intense metabolism that occurs in these patients due to the use of enzymeinducing, anticonvulsant drugs," he said. Future trials will address the issue. "With more effective dosing regimens, I think we will see enhanced activity in this group of patients," Dr. Reardon predicted. Defining Optimal Dose
"Our next step will be to define the optimal biological dose, the safest dose to use, and then look very carefully and quickly at other agents that can also affect tumor cells," Dr. Reardon said. The investigators are interested in whether a combination of therapies, conventional chemotherapy agents as well as targeted therapeutics, might be more effective against the complex web of signaling pathways in tumor cells. "There's a lot of redundancy, and I think it's naive to expect that one agent is going to be able to eliminate or affect all of those different signaling pathways," he said. "We're probably going to have agents that are impacting different points at different levels in the signaling cascade before we see the true benefit," Dr. Reardon concluded.