Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074.
OBJECTIVE
Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM.


METHODS
Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals.


RESULTS
Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS.


CONCLUSIONS
In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.
Division of Neuro-Oncology, Department of Neurology, Mayo Clinic Rochester, Rochester, MN 55905, USA. uhm.joon@mayo.edu
Joon H
JH
Uhm
Karla V
KV
Ballman
Wenting
W
Wu
Caterina
C
Giannini
J C
JC
Krauss
Jan C
JC
Buckner
C D
CD
James
Bernd W
BW
Scheithauer
Robert J
RJ
Behrens
Patrick J
PJ
Flynn
Paul L
PL
Schaefer
Shaker R
SR
Dakhill
Kurt A
KA
Jaeckle
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003907:Dexamethasone / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D020536:Enzyme Activators / Q000008:administration & dosage; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification / Q000235:genetics; D018773:Genes, erbB-1 / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
D000970:Antineoplastic Agents; D020536:Enzyme Activators; D011799:Quinazolines; D003907:Dexamethasone; D066246:ErbB Receptors; D000077156:Gefitinib