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Phase II study of ZD1839
in patients with newly diagnosed grade 4 astrocytoma
J. H. Uhm, K. V. Ballman, C. Giannini, J. C. Krauss, J. C. Buckner, D. James,
B. W. Scheithauer, J. R. O'Fallon, K. A. Jaeckle
Mayo Clinic, Rochester, MN; St Joseph Mercy Hospital, Ann Arbor,
MI
Background.
Amplification of the EGFR represents one of the most
frequent gene alterations in glioblastoma (GBM).
In the current study, our objectives were to evaluate
ZD1839 (Iressa), a potent EGFR inhibitor, in the treatment of adults with newly
diagnosed GBM, and to correlate response with tumor EGFR status.
Methods.
By the end of the study, 98 patients (96 evaluable) were
accrued.
All were newly diagnosed GBM patients who were
radiographically stable/improved following radiation treatment (enrollment
within in 5 weeks of radiation completion).
No prior chemotherapy was permitted.
EGFR amplification/mutation, as assessed by FISH and
immunohistochemistry, was not required for treatment with ZD1839 but was studied
when tissues were available.
ZD1839 was administered at 500mg QD; for patients
receiving dexamethasone and/or enzyme-inducing (CYP3A4) agents, dose was
escalated to a maximum of 1000mg QD.
Treatment cycles were repeated at 4-week intervals with
tumor response assessed by brain MRI at 8-week intervals.
Results.
Survival (calculated from time of initial surgery) at 1 year
(primary endpoint) with ZD1839 was 54.2%, which was not statistically different
compared to that of historical control population (48.9%, 3 previous phase III
NCCTG studies of newly diagnosed GBM patients).
Progression-free status at 1 year post-RT (13.3%) was also
not statistically different to that of historical controls (16.1%).
EGFR amplification, as assessed by FISH and
immunohistochemistry, was not associated with survival or progression-free
survival.
Fatigue (41%), rash (62%), and loose stools (58%)
constituted the most frequent adverse events, the majority of these being
limited to Grade 1/2.
Conclusions.
Modest activity of ZD1839 and other EGFR inhibitors have
been previously suggested in relatively smaller studies with recurrent
GBM.
In our current study of nearly one hundred patients with
newly diagnosed GBM, treatment with ZD1839 was not associated with significant
improvement in overall- nor progression-free survival.
Whether EGFR inhibitor therapy in combination with other
treatments, such as concurrent radiation, will show synergy is being addressed
in ongoing studies.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-00915,00.asp
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