ROCKVILLE, Md--The Food and Drug Administration's Oncologic Drugs Advisory
Committee (ODAC) voted, with one abstention, to recommend the approval
of Femara Tablets (letrozole, Ciba-Geigy Corp.) for the treatment of advanced
breast cancer in postmenopausal women who suffer a relapse or disease progression
after antiestrogen therapy.
Femara, a nonsteroidal aromatase inhibitor, attenuates the production
of estrogen by cells. Ciba-Geigy presented two international studies involving
1,106 patients, about 30% of them age 70 or older, in support of the drug's
A third Femara study of more than 500 women, which uses megestrol acetate
(Megace) as the control, has completed its enrollment, and data should
become available in about 1 year.
The protocols for the two studies described at the ODAC meeting were
essentially the same. The women had to be estrogen-receptor and/or progesterone-receptor
positive or of unknown status for both receptors.
Each study included a treatment period and a 6-month follow-up. Neither
called for a washout period between a patient's last hormonal treatment
and entry into the study. This raised questions from the FDA whether this
might have made the studies' findings appear a little more positive.
In the first protocol, AR/BC2, 551 women at 91 centers in 10 countries
were treated in a randomized, double-blind trial whose three arms consisted
of two different levels of Femara, 0.5 mg and 2.5 mg, and megestrol acetate,
currently regarded as the standard second-line hormone therapy in the United
The second study, AR/BC3, enrolled 555 patients at 86 centers in 11
countries. It compared the same two doses of Fem-ara with Orimeten/Cytadren,
a second-line hormonal agent used in Europe.
The Ciba-Geigy presentation covered an analysis of both phases of AR/BC2
and the treatment phase of AR/BC3. Follow-up data from the second phase
of the AR/BC3 trial is now being analyzed and will be submitted to the
FDA shortly, the company said.
According to the data presented by Franzanne Vreeland, MD, director
of clinical research at Ciba Pharmaceuticals, 24% of the women in AR/BC2
responded to 2.5 mg of Femara and 18% in AR/BC3. This was a significantly
higher number than found in either the 0.5 mg Femara or control group in
"A low percentage of patients on either dose of Femara discontinued
for any reason," she said. "We have shown that Femara, 2.5 mg,
is well tolerated."
Muscle pain topped the list of adverse effects noted with Femara, she
said. Other problems included arthralgia, nausea, fatigue, rash, and hypertension.
Researchers found a slight increase in leukopenia, but "this was transient
and of no apparent clinical effect," Dr. Vreeland told the panel.
"There appears to be no problem with hepatic function or with renal
function," she added.
The FDA Review
Dr. Genevieve Schechter of the FDA said that a staff review found that
the median time to treatment failure in AR/BC2 favored megestrol, but that
the median time to progression in AR/BC3 was very close, 102 in both Femara
groups and 102 for Cytadren patients.
However, Dr. Schechter noted, the FDA found that the Femara 2.5 mg groups
had a better median survival than either control drug--740 days in AR/BC2
(633 days for 0.5 mg Femara; 659 days for megestrol) and 793 days in AR/BC3
(637 days for 0.5 mg Femara; 593 days for Cytadren). Patients receiving
megestrol also had a significantly increased incidence of thromboembolisms,
For reasons still unknown, different counties, in both studies, showed
markedly different, sometimes opposite response rates to the drugs. However,
after an examination of how the centers carried out the studies, the FDA
has concluded that "there is no reason to doubt any of the results,"
Dr. Schechter said.
The ODAC Vote
After reviewing the data presented by Ciba-Geigy and the FDA, the ODAC
members agreed, with three abstentions, that a low rate of tamoxifen (Nolvadex)
withdrawal likely influenced the studies' positive findings. They also
agreed, 11 to 0, that the failure to require a washout period before patients
enrolled did not bias the findings of the two studies.
Nonetheless, in a very split decision, the committee recommended 6 to
5 that the FDA require that future studies of second-line hormonal therapy
of advanced breast cancer have an interval of a least 1 month between the
last dose of the prior hormonal treatment and the baseline evaluation for
"I think that vote pretty much summarizes the discussion,"
ODAC chairman Janice Dutcher, MD, of the Montefiore Medical Center, NY,
said of the very narrow split decision.
The committee recommended Fema-ra's approval with 10 "yes"
votes. Committee member David H. Johnson, MD, director of medical oncology,
Vanderbilt Medical School, abstained. During a previous discussion period,
Dr. Johnson had argued that neither study showed Femara to be superior
to the control drug, and only AR/BC2 found it to be as effective.
In discussing the recommended daily dose, several ODAC members noted
that the two studies had not yielded definitive evidence that one of the
two doses used was more effective than the other. Given that knowledge
gap, the panel recommended 2.5 mg over 0.5 mg by a vote of 9 in favor and
Derek Raghavan, MD, PhD, of Roswell Park Cancer Institute, seemed to
voice the committee's consensus when he said: "We are probably safer
making it 2.5 and talking again when the third study is completed."