of data from multiple phase II
trials with novel agents cetuximab (Erbitux)
and erlotinib (OSI-774, Tarceva)
have concluded that patients who
developed an acne-like rash lived longer
than those who did not, and that patients with more severe rash lived
longer than patients with mild rash
In presenting their analyses at the
39th Annual Meeting of the American
Society of Clinical Oncology (ASCO)
(abstracts 786 and 817), the investigators
suggested that rash could be a
biomarker for response to HER1/
epidermal growth factor receptor inhibitors
(HER1/EGFR). Rash also was
identified as a predictor of response to
gefitinib (ZD1839, Iressa), a third
agent that targets EGFR (J ClinOncol
The big question is whether the
observation will prove clinically useful.
Both groups of researchers speculated
that the optimal dose of HER1/
EGFR inhibitors could be linked to an
optimal degree of rash in each patient,
but they cautioned that the rash might
be a surrogate for another factor involved
in the response.
"It could mean that a strategy for
improving the effectiveness of the drug
could be to dose to a certain level of
rash... in order to escalate to a degree
of side effect that will be commensurate
with a higher degree of activity,"
said Leonard B. Saltz, MD, associate
attending physician, Memorial Sloan-
Kettering Cancer Center.
"An alternative hypothesis would
be that patients have particular polymorphisms
of the epidermal growth
factor receptor that make them more
vulnerable to toxicity and their tumors
more vulnerable to the attack by
this particular drug," Dr. Saltz continued.
"We really don't know if this
observation will have a therapeutic
meaning or not," Dr. Saltz said.
Gary M. Clark, PhD, senior director
of biostatistics and data management
of OSI Pharmaceuticals, Inc.,
compared the rash to tumor flares experienced
by breast cancer patients treated with tamoxifen in the early
1980s. Some women asked to be taken
off the then-new drug because of pain
and vaginal dryness, but it turned out
to be a sign the drug was working, said
Dr. Clark, lead investigator of the
"The question, of course, is can we
do anything about this? Can we take
advantage of it?" Dr. Clark said. "Is it
possible to increase the dose in some
patients and achieve a better clinical
outcome?" He said that OSI has already
started a dose-to-rash study.
Review of Previous Trials
Dr. Saltz and Dr. Clark each mined
data from previously reported phase
II trials. ImClone Systems Incorporated,
Somerville, New Jersey, developer
of cetuximab with Bristol-Myers
Squibb Oncology, participated in the
Dr. Saltz reviewed trials evaluating
- with irinotecan (CPT-11,
Camptosar) in 120 patients with colorectal
- alone in 57 colorectal cancer patients;
- with gemcitabine (Gemzar) in
41 pancreatic cancer patients.
with cisplatin in 79 patients with
squamous cell cancer of the head and
About 75% of patients developed a
rash. In all four studies, patients with
no rash had the shortest median survival,
while patients with grade 3 rash
lived longest (see Figure 1). In patients
with pancreatic cancer, for example,
the range for length of survival went
from 2.3 months with no rash to 13.9
months with grade 3 rash.
So far the rash has been treatable as
well as controllable with dose adjustment,
Dr. Saltz said. He voiced a concern,
however, that the finding "implies
a relatively modest therapeutic
window whereby we're going to have
to accept the skin toxicity to get what
we want out of the drug."
Relationship to Outcome
Dr. Clark reviewed three erlotinib
- Among 57 patients with refractory
non-small-cell lung cancer
(NSCLC), 75% developed rash.
- Among 115 patients with advanced
squamous cell cancer of the
head and neck, 70% developed rash.
- Among 34 patients with advanced
ovarian cancer, 82% developed rash.
No patient without a rash responded
to therapy. Pooled data from all
three studies showed median survival
of 44 days without rash, 67 days with
grade 1 rash, and 95 days with grades
"I looked at every possible pretreatment
characteristic I could find. Some of them correlated with outcomes,
but none of them changed the relationship
between rash and outcomes,"
Dr. Clark said.
A coauthor of the erlotinib analysis,
Roman Perez-Soler, MD, of Montefiore
Medical Center, Albert Einstein
College of Medicine, Bronx, New
York, raised the rash issue at "Targeting
Critical Pathways in Oncology," a
post-ASCO, industry-sponsored satellite
symposium. Nine studies with
several hundred patients have shown
a strong relationship between rash and
survival with agents targeting HER1/
EGFR, according to Dr. Perez-Soler.
And there is a consistant trend between
higher grades of rash and longer
survival. (Also see the report on Dr.
Perez-Soler's presentation at the 10th
World Conference on Lung Cancer,
on pages 23 and 24 of this issue.)
"Should we adjust doses to grade
1/2 rash?" Dr. Perez-Soler asked rhetorically.
"We don't have the answer
today; but obviously we should pay
attention to this."