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

ROCHESTER, Minnesota-Determining adequate dosing ofepithelial growth factor receptor(EGFR) inhibitors and whether doserelatedside effects such as diarrheamight be useful markers of dose adequacyare issues that arose in severaltrials reported at ASCO. One studywas a phase II trial meant to addressthe question of whether treatment withgefitinib (Iressa) would improve outcomesof patients with newly diagnosedglioblastoma multiforme. Previoussmaller studies had suggested itwould.The primary study endpoint wasoverall survival and the secondary endpointwas progression-free survival(PFS), both in comparison to historicalcontrols from North Central CancerTreatment Group (NCCTG) studies."Amplification of EGFR is one ofthe most frequent gene alterations inglioblastoma, and our objective wasalso to correlate response with tumorEGFR status," said Joon H. Uhm,MD, of the Mayo Clinic.All Newly Diagnosed PatientsThe study accrued 98 patients, ofwhom 96 were evaluable for response.All were newly diagnosed, with noprior chemotherapy, were radiographicallystable or improved followingradiation treatment, and had begungefitinib within 5 weeks of completingradiation (abstract 1505).Tumor samples were evaluated forEGFR amplification or mutation byfluorescence in situ hybridization(FISH) and by immunohistochemistrywhen tissues were available.Gefitinib was given at 500 mg/d butwas increased to 1,000 mg/d for patientson dexamethasone and/or enzyme-inducing (CYP3A4) antiepilep-tic drugs (EIAEDs). Treatment cycleswere repeated at 4-week intervals.Tumor response was assessed bymagnetic resonance imaging (MRI)at 8-week intervals."Median overall survival was comparableto that seen in historical controls,about 11 months," Dr. Uhmsaid. Survival (calculated from time ofinitial surgery) at 1 year was 54.2%,which was not statistically differentfrom the 48.9% rate in three previousphase III NCCTG studies of newlydiagnosed glioblastoma multiformepatients. Progression-free status at 1year was also not statistically differenthistorical controls (13.3% vs 16.1%).Was Dose Too Low?"We looked at EGFR amplificationand found no apparent correlationbetween EGFR amplification statusand survival or progression-free survival,"Dr. Uhm said.A subgroup analysis to examinewhether systemic adverse events predictedbetter outcome revealed thatpatients with diarrhea of any gradehad significantly better overall survivalthan those who did not developdiarrhea (P = .003). However, EGFRstatus did not appear to influence outcomesin patients who had diarrhea."We wonder whether diarrheacould be a surrogate marker for adequatedosing," Dr. Uhm said. A participantin the discussion followingDr. Uhm's presentation suggestedthat there might be a genetic variationin this subgroup of patients thatinfluences response and would warrantadditional study.EGFR inhibitor therapy in combinationwith other treatments, such asconcurrent radiation, is being addressedin ongoing studies.