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 approval.
A third Femara study of more than 500 women, which uses megestrol(Drug information on 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(Drug information on 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 States.
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 either study.
"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, she added.
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(Drug information on 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 the study.
"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 2 abstentions.
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."