Panel Gives Nod to Ellence for Adjuvant Use in Breast Cancer

SILVER SPRING, Md—The Oncologic Drugs Advisory Committee (ODAC) has recommended that the FDA approve Ellence (epirubicin hydrochloride for injection, Pharmacia & Upjohn) for use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer (stage II and III).

The 9-to-0 recommendation followed the company’s presentation of seven phase III multicenter studies. “The FDA, however, did not include three of the studies in its analysis because it did not receive primary data from the trials,” said FDA reviewer Susan Honig, MD.

Ellence, marketed outside the United States as Farmorubicin, is an anthra-cycline that was first approved in France in 1982 and is currently used in more than 80 countries to treat a variety of cancers. The drug “has been given to millions of people worldwide” and “the short- and long-term efficacy and safety of epirubicin have now been thoroughly characterized,” Langdon L. Miller, MD, vice president for clinical development oncology, told ODAC members.

The advisory committee considered two studies that addressed Ellence’s use in early-stage breast cancer, MA-5 and GFEA-05, and two that dealt with its use in metastatic breast cancer, HEPI/013 and HEPI/010.

MA-5 involved 716 premenopausal women enrolled at 37 Canadian centers between 1989 and 1993; 356 received cyclophosphamide, epirubicin, and fluorouracil (5-FU) (CEF) and 360 got cyclophosphamide, methotrexate, and 5-FU (CMF). The primary endpoint was relapse-free survival, with overall survival as a secondary endpoint. The hypothesis of the study was that “CEF would be associated with a 10% absolute improvement in 5-year relapse-free survival,” Dr. Miller said.

The GFEA-05 study was conducted in France at 20 centers and enrolled 565 women between 1990 and 1993. All women received CEF, with the only difference being in the starting dose of epirubicin. In one arm, 276 women began treatment with 100 mg/m²; the other 289 women received 50 mg/m² of epirubicin. “The actual delivered dose intensity in both trials was about 100 mg/m² per cycle,” the FDA said.

In the MA-5 study, the epirubicin arm had a 62% 5-year relapse-free survival rate and a 77% overall survival rate, compared with 53% and 70%, respectively, in the control arm. In GFEA-05, the women starting with 100 mg/m² had a relapse-free survival of 65% and an overall survival of 76% vs 52% and 65%, respectively, in the lower starting-dose arm.

Epirubicin patients in MA-5 tended to have more adverse events, as did the high-dose patients in GFEA-05. Febrile neutropenia occurred in 9% of the CEF patients vs 1% of the CMF group. “Nausea and vomiting was fairly significant, but I would point out that serotonin-specific antiemetic therapies were not available when these studies were done,” Dr. Honig added.

There were four deaths in the two trials, none of which were attributed to the drug. However, there were five cases of leukemia in the CEF arm of MA-5 vs one in the CMF arm, and one leukemia in each of the two arms of GFEA-05. Cardiotoxicity was 3% in the CEF arm of MA-5 and 5% in the high-dose epirubicin arm of GFEA-05 vs 1% and 3%, respectively, in the control arms.

The panel members found Ellence’s benefits worth its risks for use as an adjuvant in women with axillary node involvement. “I think these differences in survival in adjuvant situations are as good as we’ve seen with any individual trial and better, actually,” said Robert Ozols, MD, PhD, of Fox Chase Cancer Center.

ODAC members voted 6 to 3 that the two studies presented that tested Ellence as a first-line treatment for metastatic breast cancer did not support its approval. In study HEPI/013, for example, the 233 women in the epirubicin arm had a median survival rate of 20.1 months vs 18.2 months among the 237 women in the methotrexate arm. The epirubicin arm had a cardiotoxicity rate of 13% vs 4% in the methotrexate group.