BETHESDA, MdSeconding the advice of a Food and Drug
Administration review team, the Oncologic Drugs Advisory Committee (ODAC) has
recommended that the FDA approve Femara tablets (letrozole, Novartis) as
first-line therapy in postmenopausal women with advanced breast cancer.
The unanimous vote followed the company’s presentation of a
study that found letrozole significantly more effective than tamoxifen
(Nolvadex) in this setting and a highly favorable review of the drug by the FDA’s
panel of experts. "The FDA analysis did not differ significantly from the
sponsor’s," said FDA reviewer Martin Cohen, MD.
Letrozole is a nonsteroidal aromatase inhibitor that is given
at 2.5 mg daily to block estrogen synthesis. The FDA approved the drug for
second-line breast cancer therapy in 1997.
Novartis presented data from two prospective, double-blind,
multicenter, randomized phase III trials. Its pivotal study, designated 025,
compared letrozole 2.5 mg with tamoxifen 20 mg in 916 womenequally divided
between the two drugstreated at 201 centers in 29 countries worldwide.
The company’s supportive study involved 324 women (154 on
letrozole and 170 on tamoxifen) treated at 55 centers in 16 countries with the
The pivotal study’s primary endpoint was time to progression,
which proved to be 9.4 months for letrozole and 6.0 months for tamoxifen.
"The median time to progression was prolonged with use of
Femara by 56%," said Margaret Dugan, MD, group leader for oncology
clinical development and research at Novartis. "Femara was statistically
significantly superior to tamoxifen in time to progression, reducing the risk
of progression by 30%. These treatment differences favoring Femara are
clinically important to patients."
Letrozole had a time to treatment failure of 9.1 months vs 5.7
months for tam-oxifen, and a significantly higher overall rate of confirmed
objective tumor response. The letrozole response rate was 30% (34 complete
responders, 103 partial), compared with 20% (13 complete, 79 partial) for
The finding represents "a 71% higher odds of responding to
Femara than tamoxifen," Dr. Dugan said. Dr. Cohen called the difference in
the two response rates "highly significant."
The FDA analysis of response was even more positive than that
of the company; the agency reported a response rate of 32% for letrozole and
21% for tamoxifen. However, the FDA’s analysis of the response duration was
different from the company’s findings. Novartis reported 17 months for
letrozole and 16.5 months for tamoxifen; the FDA put the response duration at
11.5 months for letrozole and 10.3 months for tamoxifen.
Adverse events were similar in the two groups, according to the
FDA. They included peripheral thromboembolic events (2% in each group);
cardiovascular events (2% for letrozole and 1% for tamoxifen); cerebrovascular
events (1% for letrozole vs 2% for tamoxifen); fractures (5% vs 4%); and ocular
toxicity (2% vs 1%). Hot flashes occurred in 18% of the letrozole patients and
in 16% of those taking tamoxifen. One case of endometrial cancer occurred in
the tamoxifen group.
Although study 025 has not progressed yet to the point of
yielding valid survival data, the FDA agreed that this information was not
needed, in light of the clinical and safety data from the trial.