synergy betw EGFR inhibitors and estrogen receptor inhibitors against breast cancer

synergy betw EGFR inhibitors and estrogen receptor inhibitors against breast cancer

Public release date: 16-May-2008
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Contact: Laura Sussman
lsussman@mdanderson.org
713-745-2457
University of Texas M. D. Anderson Cancer Center

Iressa shows promise for treatment of metastatic breast cancer when combined
with hormonal therapy

First positive findings in breast cancer for this class of drugs

HOUSTON - Gefitinib, the once-promising drug formerly approved as a second
line treatment for lung cancer, also known as Iressa, enhanced the
effectiveness of hormonal therapy for the treatment of specific types of
metastatic breast cancer, according to a Phase II clinical trial led by
researchers at The University of Texas M. D. Anderson Cancer Center.

These findings are surprising and represent the first positive study for
Iressa in breast cancer, as well as for the entire class of drugs known as
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, said
Massimo Cristofanilli, M.D., the study's principal investigator.

Cristofanilli will present the findings at the American Society for Clinical
Oncology's (ASCO) upcoming annual meeting as an oral presentation.

"We initiated this study in 2003 with hopes of reducing the resistance to
hormonal therapy," said Cristofanilli. "There was a lot of preclinical work
indicating that, in fact, resistance to hormonal therapy is strongly
associated with an activated EGFR pathway. Also, EGFR over-expression has
been associated with endocrine resistance. If there's a double blockage of
the EGFR and the estrogen receptor, you may achieve better control of the
disease."

The Phase II study enrolled 93 women from 30 centers across the United
States and Latin America, with M. D. Anderson enrolling 20 patients. All of
the women were newly diagnosed with metastatic breast cancer and were
hormone receptor positive and estrogen receptor HER-2 negative. Patients
were randomized to receive the aromatase inhibitor Arimidex (1 milligram)
and Iressa (250 milligram) daily or Arimidex and placebo. The primary
endpoint was progression-free survival.

When the study was unblinded, the researchers were surprised by the distinct
findings: in the women who received Arimidex and Iressa, progression-free
survival was 14.5 months, compared to 8.2 months in the women who did not
receive Iressa, representing a 45 percent reduction in risk.

Additionally, of the women taking the combination, 47 percent had stable
disease for more than 24 weeks and 49 percent had a clinical benefit. In
contrast, 22 percent of the women had taking Arimidex alone had stable
disease for more than 24 weeks and 34 percent had a clinical benefit.

Patients in the combination arm did have a higher rate of adverse events,
but Cristofanilli notes that overall Iressa was very well tolerated.

"To see such a difference in such a small subset of patients was
tremendously surprising," said Cristofanilli. "These findings show the
possibility of adding a targeted therapy such as Iressa or others in the
EGFR drug class to improve the benefit for hormonal therapy, giving another
option for women who are hormone receptor positive, Her-2 negative with
metastatic disease."

About 60 percent of women with breast cancer are hormone receptor positive
and Her-2 negative, said Cristofanilli.

Iressa, a once-daily, oral tablet, was the first in a new class of
anti-cancer drugs known as epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors, to become commercially available. Iressa received FDA
approval May 5, 2003 as a single agent treatment for patients whose advanced
lung cancer has continued to progress despite treatment with platinum-based
and docetaxel chemotherapy.

However, in 2005, after a large international study resulted in negative
findings and reported numerous negative side effects, the drug's labeling
was altered by the FDA. Only cancer patients who had already taken the
medicine and whose physician believed it was helping them were allowed to
receive the drug. No new lung cancer patients were given the drug after this
time.

During this period, Iressa was being tested in clinical trials in a number
of cancer types, including breast cancer. Other breast cancer trials
studying Iressa, either as a single agent or when combined with
chemotherapy, were mostly negative.

These negative findings impacted the accrual of the Arimidex-Iressa breast
cancer study, said Cristofanilli. The study fell well short of its accrual
goal of 174 women.

"Still, there's significant clinical relevance to our findings. Of course, I
would advise that physicians not rush to put metastatic breast cancer
patients who are hormone receptor positive and estrogen receptor negative on
other drugs in this class that are readily available," said Cristofanilli.
"Rather, this study should serve as a proof-of-concept. With our results,
there should be a renewed interest in this class of drugs and hopefully
follow-up studies in the adjuvant setting will be conducted."


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The study was funded by AstraZeneca. Updated data will be presented Sunday,
June 1 at 8:15 a.m. in the oral presentation, "Breast Cancer, Metastatic."