of data from multiple phase II trials
with novel agents cetuximab(Drug information on 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)
(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). A recent journal
article also identified rash as a predictor
of response to gefitinib(Drug information on gefitinib)
(ZD1839, Iressa), a third agent that
targets EGFR (Cohen et al: J Clin Oncol
May 15; 21(10):1980-1987, 2003).
The big question is whether the
observation will prove clinically useful.
Both sets of researchers presenting
data speculated that the optimal dose
of HER1/EGFR inhibitors could be
linked to an optimal degree of rash in
each patient. They cautioned, however,
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; that some people may need more
drug and be able to tolerate more drug
in order to escalate to a degree of side
effect that will be commensurate with
a higher degree of activity," Leonard
B. Saltz, MD, of Memorial Sloan-Kettering
Cancer Center, told ONI.
"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(Drug information on tamoxifen) in the early 1980s. Some women asked to be taken off the new drug because of pain and vaginal dryness, but it turned out to be a sign the drug was working, Dr. Clark said. He is the lead investigator of the erlotinib analysis. "The question, of course, is can we do anything about this? Can we take advantage of it?" he said to ONI. "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 of Somerville, New Jersey, develop- er of cetuximab with Bristol-Myers Squibb Oncology, participated in the cetuximab study. Dr. Saltz reviewed trials evaluating cetuximab:
- with irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) in 120 patients with colorectal cancer;
- alone in 57 colorectal cancer patients;
- with cisplatin(Drug information on cisplatin) in 79 squamous cell cancer of the head and neck patients; and
- with gemcitabine(Drug information on gemcitabine) (Gemzar) in 41 pancreatic cancer patients.
- 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.