Letrozole Approved as First-Line Treatment for Advanced Breast Cancer in Postmenopausal Women

February 1, 2001

Novartis Oncology recently announced that the US Food and Drug Administration (FDA) has approved letrozole (Femara) tablets for the first-line treatment of postmenopausal women with hormone-receptor-positive or hormone-receptor-unknown

Novartis Oncology recently announced that the US Food and DrugAdministration (FDA) has approved letrozole (Femara) tablets for the first-linetreatment of postmenopausal women with hormone-receptor-positive orhormone-receptor-unknown locally advanced or metastatic breast cancer. Mostpostmenopausal women with advanced breast cancer fall into these tumor-receptorcategories.

Approval of the new indication followed a priority review by theFDA and a unanimous recommendation from the FDA’s Oncologic Drugs AdvisoryCommittee. The recommendation was based on data from the largest single studyever to evaluate a hormonal therapy in this setting. The study found thatletrozole was significantly more effective than tamoxifen (Nolvadex) in multipleefficacy end points. Tamoxifen has traditionally been the standard of therapyfor this indication.

"Femara shows great promise for becoming the new first-linetherapy of choice for postmenopausal women with advanced breast cancer,"said Robert Smith, md, of South Carolina Oncology Associates and a leadinvestigator in the study. "It is the first therapy to challenge tamoxifenin multiple end points, including time to progression, response rates, andoverall clinical benefit."

Study Details

The phase III trial on which the FDA based its decision was ahead-to-head, randomized, double-blind multicenter trial comparing the use ofletrozole vs tamoxifen in more than 900 postmenopausal women with locallyadvanced (stage IIIB) disease, metastatic breast cancer, or recurrences notamenable to treatment with surgery or radiotherapy.

The study demonstrated that letrozole delays progression ofadvanced breast cancer for 9.4 months, as compared to 6.0 months for tamoxifen.Results also indicated significant differences between letrozole and tamoxifenwith respect to overall tumor response rates (30% vs 20%), clinical benefit (49%vs 38%), and time to treatment failure (9.1 vs 5.7 months, or 40 vs 25 weeks).Letrozole and tamoxifen were equally well tolerated.

Supporting the filing was a phase III randomized, controlledtrial of 324 postmenopausal women with large localized or locally advancedbreast cancer tumors who were given letrozole or tamoxifen as preoperativetreatment to reduce tumor size before breast-conserving surgery. Clinicalresponses after 4 months of preoperative therapy were significantly better forletrozole than for tamoxifen (55% vs 36%).

Letrozole Background

Letrozole, an oral aromatase inhibitor, is a once-a-day oraltreatment that was first approved for marketing in 1997 for the treatment ofadvanced breast cancer in postmenopausal women with disease progressionfollowing antiestrogen therapy. In July 2000, Novartis submitted a supplementalNew Drug Application (sNDA) for first-line therapy in advanced breast cancer,and, in August 2000, the sNDA received a priority review designation from theFDA.

In postmenopausal women, the primary source of estrogen is fromfat, liver, muscle, and breast tissue through a process that turns adrenalandrogens into estrogen, which stimulates the growth of certainhormone-dependent cancer cells. A breast tumor itself also may generateestrogen. Letrozole works by binding to the enzyme aromatase and blocking itfrom converting adrenal androgens to estrogen in these tissues.

Letrozole is currently available in more than 75 countriesworldwide as a treatment for advanced breast cancer in postmenopausal women withdisease progression following antiestrogen therapy. Regulatory submissions forthe first-line indication have also been filed globally; the drug is also beingstudied in the adjuvant setting.

Letrozole is generally well tolerated but is contraindicated inpatients with known hypersensitivity to the drug or any of its excipients. Theadverse reactions in the first-line study were generally mild to moderate andwere consistent with those seen in the second-line studies. The most commonlyreported adverse events for letrozole vs tamoxifen were bone pain (20% vs 18%),hot flushes (18% vs 15%), back pain (17% vs 17%), nausea (15% vs 16%), dyspneaor labored breathing (14% vs 15%), arthralgia (14% vs 13%), fatigue (11% vs11%), and coughing (11% vs 10%).