cell carcinoma (BAC) appears responsive
to erlotinib (OSI-774, Tarceva)
in an ongoing phase II trial. Interim
findings also suggest that BAC might
be more common than previously believed
and perhaps behaves differently
in smokers than in nonsmokers.
Vincent Miller, MD, of Memorial
Sloan-Kettering Cancer Center in New
York City reported a 26% response
rate using erlotinib to treat BAC in 50
evaluable patients and a trend toward
higher response in nonsmokers (ASCO
abstract 2491). While 46% of patients
who never smoked responded to erlotinib,
only 19% of former or current
smokers did so.
"Erlotinib is an active drug in this
disease. We believe the duration of
response is encouraging, and the treatment
is certainly well tolerated," Dr.
Miller said in reporting interim results
from the ongoing study. Speaking for
co-investigators at his center and
Vanderbilt-Ingram Cancer Center in
Nashville, he said a phase III trial comparing
erotinib to platinum-based chemotherapy
BAC Component in NSCLC
As defined by World Health Organization
criteria, BAC accounts for only
3% of cases of non-small-cell lung
cancer (NSCLC). Dr. Miller suggest-
ed, however, that as many as 20% of
NSCLC cases might have a BAC component.
"Our previous work suggests
that pure BAC, BAC with focal invasion,
and adenocarcinoma with BAC
features have a similar clinical course,"
he said. Screening and monitoring of
patients for the current trial supported
that observation, he added.
From July 2002 to April 2003, a
reviewer at Memorial Sloan-Kettering
screened 98 patients whose prior pathology
and/or clinical presentation
suggested the possibility of a BAC diagnosis.
Dr. Miller said surgical pathology
material was reviewed for twothirds
of the patients and cytologic
material for the rest.
The review ruled out BAC in 27
patients. Among the remainder of
screened patients, 52 had adenocarcinoma
with BAC features, 2 had BAC
with focal invasion, and 17 had pure
BAC. Only one patient previously diagnosed
with BAC was ruled out. Conversely,
the review found BAC features
in 45 patients whose samples had
previously been classified as adenocarcinoma
"This is not a rare bird to find when
you start to look at your patients," Dr.
Miller advised. "So one of the messages
is, one can't accept a pathology
report that just says NSCLC. The physician
needs to ask his or her pathologist
for more information particularly
whether or not a BAC component
might be present."
Three-Quarters Were Smokers
Of 71 patients potentially eligible
for the trial, 55 consented for treatment
and 50 were evaluable for response.
Their median age was 66 with
a range of 33 to 85 years. Two-thirds of
the patients were women, and threequarters
were former or current smokers.
The majority, 38 patients, had
never received chemotherapy, while
12 patients had undergone one prior
The patients received 150 mg of
erlotinib daily. Erlotinib is a small
molecule inhibitor of the HER1/epidermal
growth factor receptor (HER1/
EGFR) tyrosine kinase. Little is known
about EGFR expression in BAC, Dr.
Miller said. Anecdotally, however, he
reported that BAC patients appeared
to have some of the most dramatic
responses to erlotinib and gefitinib
(ZD1839, Iressa), another EGFR inhibitor,
in phase I trials with advanced
Responses and Progression
Investigators noted partial responses
in 13 patients enrolled in the phase
II study and all but one has been confirmed.
One patient who responded
progressed after 3 months and another
patient after 7 months, but 11 responses
are ongoing. "The response
can be quite dramatic and long lasting,"
At 3 months, 48 of 55 patients originally
enrolled in the trial were still
alive, according to Dr. Miller. The
median duration of follow-up is 6
months, he said, and the median duration
of response had not yet been
While four deaths occurred on
study, Dr. Miller said two were due to
disease progression in the first month,
and a patient who died suddenly 9
days after starting treatment had appeared
better symptomatically. No
autopsy was performed.
Rash and diarrhea were dose limiting
in phase I. Only one responding
patient did not have a rash in phase II.
Four patients had grade 3 rash, and
two patients reported grade 2 rashes
to be intolerable, but none discontinued
because of rash, according to Dr.
In searching for clinical characteristics
that might identify the subset of
patients who were most likely to respond
to erlotinib, the investigators
found that females were only slightly
more likely to respond. The response
rate was also slightly higher in invasive
variants of BAC than in pure BAC, but
Dr. Miller said that both groups responded
Although the data did not reach
statistical significance, a history of never
smoking appeared to correlate with
being more sensitive to erlotinib. Dr.
Miller called the data provocative and
speculated that "lung cancer may have
a different biology in never smokers."
He said the investigators plan to
construct a tissue microarray comparing
erlotinib-sensitive and erlotinib-
resistant patients and to examine
the frequency of tobacco-related
mutations in both groups.