Antitumor Activity Seen in Trial of Erlotinib for Glioblastoma Multiforme in First Relapse

HOUSTON-"Interesting antitumoractivity" was seen in the firststage of a phase II trial of erlotinib(Tarceva) for glioblastoma multiformein first relapse, according to W.K. AlfredYung, MD, of The University ofTexas M.D. Anderson Cancer Center,Houston (abstract 1555). There appearedto be a slightly higher responserate in patients whose tumors overexpressedthe epithelial growth factorreceptor (EGFR) by fluorescence insitu hybridization (FISH+), but responsewas not limited to those patients,he reported."FISH-negative patients should notbe excluded from future studies untilthis relationship is studied more carefully,"Dr. Yung said.Erlotinib has documented clinicalactivity in glioblastoma multiforme,and Dr. Yung noted that this tumor isan interesting target for EGFR inhibitorsbecause it typically has a high rateof EGFR gene amplification and ofactivating mutations in EGFR, such asEGFRvIII.Dr. Yung reported a multi-institutionalphase II clinical trial of the singleagent erlotinib that was initiated inAugust 2003 for glioblastoma multiformepatients with measurable diseasein first relapse.Higher Starting Dose"Erlotinib is metabolized byCYP3A4. Therefore, to ensure adequateexposure, patients receivingenzyme-inducing antiepileptic drugs(EIAED group) receive a higher startingdose (300 mg/d). Otherwise, thestandard dose of 150 mg/d was given(non-EIAED group)," Dr. Yung said.Individual dose titration until dose-limiting toxicity (diarrhea, rash, other)was allowed. This ranged from 150to 200 mg in the non-EIAED groupand from 300 to 500 mg in the EIAEDgroup.The primary study objectives wereto estimate the objective response ratesin glioblastoma multiforme patients,irrespective of tumor EGFR amplificationand with tumors positive forHER1/EGFR amplification. An additionalobjective was investigating thesafety and tolerability of single-agenterlotinib.The study had a two-stage enrollmentthat was based on the number ofresponses in the first 47 patients andwhether responses occurred in patientswith or without HER1/EGFR geneamplification.Radiography was repeated every 8weeks, and responding patients hadconfirmatory scans at 4 weeks andreview by an independent radiologicfacility.Rash, DiarrheaMost CommonForty-eight subjects were enrolled(19 female, 29 male), with a medianage of 50 years (range 37-70). Onepatient did not receive the study drug,so Dr. Yung reported data on 47 patients.Of these, 20 were on EIAEDand 27 were not. In the EIAED group,10 (50%) were FISH-positive. In theno-EIAED group, 13 (54%) wereFISH-positive. All had previous radiationtherapy, and 75% had one previouschemotherapy regimen. Medianfollow-up was 6.25 months.Dr. Yung reported that 57% of patientshad grade 3 or higher adverseevents, most commonly rash (19%)and diarrhea (4%). One patient discontinuedtherapy due to grade 3 rash.Forty-five patients were evaluablefor response. "Three patients responded:two partial responses (PR), onecomplete response (CR)," Dr. Yungsaid. The complete responder, however,did not have the required level ofmeasurable disease at entry (> 1 cmtumor), and independent radiologyreview confirmed only one of the twopartial responses. "The patient remainson study at month 7 with an ongoingPR based on an investigator-determinedresponse," Dr. Yung said.Gene amplification, as determinedby FISH, has been seen in 16 of 30subjects tested. Clinical benefit (CR,PR, or stable disease) was observed in57% of patients with high HER1/EGFRexpression and in 35% of FISHnegativepatients."Additional analyses will investigatethe relationship between response andmolecular correlates. Ongoing workwill explore whether EGFRvIII aloneor in combination with FISH statusimproves the ability to predict responseto erlotinib," Dr. Yung told OncologyNews International.