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 (Iressa) would improve outcomes
of patients with newly diagnosed
glioblastoma multiforme. Previous
smaller studies had suggested it
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 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
EGFR inhibitor therapy in combination
with other treatments, such as
concurrent radiation, is being addressed
in ongoing studies.