Panel Advises FDA To OK Letrozole for Advanced Breast Cancer

January 1, 1997

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.

ROCKVILLE, Md--The Food and Drug Administration's Oncologic Drugs AdvisoryCommittee (ODAC) voted, with one abstention, to recommend the approvalof Femara Tablets (letrozole, Ciba-Geigy Corp.) for the treatment of advancedbreast cancer in postmenopausal women who suffer a relapse or disease progressionafter antiestrogen therapy.

Femara, a nonsteroidal aromatase inhibitor, attenuates the productionof estrogen by cells. Ciba-Geigy presented two international studies involving1,106 patients, about 30% of them age 70 or older, in support of the drug'sapproval.

A third Femara study of more than 500 women, which uses megestrol acetate(Megace) as the control, has completed its enrollment, and data shouldbecome available in about 1 year.

The protocols for the two studies described at the ODAC meeting wereessentially the same. The women had to be estrogen-receptor and/or progesterone-receptorpositive or of unknown status for both receptors.

Each study included a treatment period and a 6-month follow-up. Neithercalled for a washout period between a patient's last hormonal treatmentand entry into the study. This raised questions from the FDA whether thismight have made the studies' findings appear a little more positive.

In the first protocol, AR/BC2, 551 women at 91 centers in 10 countrieswere treated in a randomized, double-blind trial whose three arms consistedof 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 UnitedStates.

The second study, AR/BC3, enrolled 555 patients at 86 centers in 11countries. 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/BC2and the treatment phase of AR/BC3. Follow-up data from the second phaseof the AR/BC3 trial is now being analyzed and will be submitted to theFDA shortly, the company said.

According to the data presented by Franzanne Vreeland, MD, directorof clinical research at Ciba Pharmaceuticals, 24% of the women in AR/BC2responded to 2.5 mg of Femara and 18% in AR/BC3. This was a significantlyhigher number than found in either the 0.5 mg Femara or control group ineither study.

"A low percentage of patients on either dose of Femara discontinuedfor 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, shesaid. Other problems included arthralgia, nausea, fatigue, rash, and hypertension.Researchers found a slight increase in leukopenia, but "this was transientand of no apparent clinical effect," Dr. Vreeland told the panel."There appears to be no problem with hepatic function or with renalfunction," she added.

The FDA Review

Dr. Genevieve Schechter of the FDA said that a staff review found thatthe median time to treatment failure in AR/BC2 favored megestrol, but thatthe median time to progression in AR/BC3 was very close, 102 in both Femaragroups and 102 for Cytadren patients.

However, Dr. Schechter noted, the FDA found that the Femara 2.5 mg groupshad 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 receivingmegestrol also had a significantly increased incidence of thromboembolisms,she added.

For reasons still unknown, different counties, in both studies, showedmarkedly different, sometimes opposite response rates to the drugs. However,after an examination of how the centers carried out the studies, the FDAhas 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 ODACmembers agreed, with three abstentions, that a low rate of tamoxifen (Nolvadex)withdrawal likely influenced the studies' positive findings. They alsoagreed, 11 to 0, that the failure to require a washout period before patientsenrolled did not bias the findings of the two studies.

Nonetheless, in a very split decision, the committee recommended 6 to5 that the FDA require that future studies of second-line hormonal therapyof advanced breast cancer have an interval of a least 1 month between thelast dose of the prior hormonal treatment and the baseline evaluation forthe 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 superiorto the control drug, and only AR/BC2 found it to be as effective.

In discussing the recommended daily dose, several ODAC members notedthat the two studies had not yielded definitive evidence that one of thetwo doses used was more effective than the other. Given that knowledgegap, the panel recommended 2.5 mg over 0.5 mg by a vote of 9 in favor and2 abstentions.

Derek Raghavan, MD, PhD, of Roswell Park Cancer Institute, seemed tovoice the committee's consensus when he said: "We are probably safermaking it 2.5 and talking again when the third study is completed."