Dosing Issues Raised in Study of Gefitinib in Newly Diagnosed Grade 4 Glioblastoma Multiforme

ROCHESTER, Minnesota- Determining adequate dosing of epithelial growth factor receptor (EGFR) inhibitors and whether doserelated side effects such as diarrhea might be useful markers of dose adequacy are issues that arose in several trials reported at ASCO. One study was a phase II trial meant to address the question of whether treatment with gefitinib(Drug information on gefitinib) (Iressa) would improve outcomes of patients with newly diagnosed glioblastoma multiforme. Previous smaller studies had suggested it would. The primary study endpoint was overall survival and the secondary endpoint was progression-free survival (PFS), both in comparison to historical controls from North Central Cancer Treatment Group (NCCTG) studies. "Amplification of EGFR is one of the most frequent gene alterations in glioblastoma, and our objective was also to correlate response with tumor EGFR status," said Joon H. Uhm, MD, of the Mayo Clinic. All Newly Diagnosed Patients The study accrued 98 patients, of whom 96 were evaluable for response. All were newly diagnosed, with no prior chemotherapy, were radiographically stable or improved following radiation treatment, and had begun gefitinib within 5 weeks of completing radiation (abstract 1505). Tumor samples were evaluated for EGFR amplification or mutation by fluorescence in situ hybridization (FISH) and by immunohistochemistry when tissues were available. Gefitinib was given at 500 mg/d but was increased to 1,000 mg/d for patients on dexamethasone(Drug information on dexamethasone) and/or enzyme- inducing (CYP3A4) antiepilep- tic drugs (EIAEDs). Treatment cycles were repeated at 4-week intervals. Tumor response was assessed by magnetic resonance imaging (MRI) at 8-week intervals. "Median overall survival was comparable to that seen in historical controls, about 11 months," Dr. Uhm said. Survival (calculated from time of initial surgery) at 1 year was 54.2%, which was not statistically different from the 48.9% rate in three previous phase III NCCTG studies of newly diagnosed glioblastoma multiforme patients. Progression-free status at 1 year was also not statistically different historical controls (13.3% vs 16.1%). Was Dose Too Low? "We looked at EGFR amplification and found no apparent correlation between EGFR amplification status and survival or progression-free survival," Dr. Uhm said. A subgroup analysis to examine whether systemic adverse events predicted better outcome revealed that patients with diarrhea of any grade had significantly better overall survival than those who did not develop diarrhea (P = .003). However, EGFR status did not appear to influence outcomes in patients who had diarrhea. "We wonder whether diarrhea could be a surrogate marker for adequate dosing," Dr. Uhm said. A participant in the discussion following Dr. Uhm's presentation suggested that there might be a genetic variation in this subgroup of patients that influences response and would warrant additional study. EGFR inhibitor therapy in combination with other treatments, such as concurrent radiation, is being addressed in ongoing studies.