Novartis Oncology recently announced that the US Food and Drug Administration (FDA) has approved letrozole(Drug information on letrozole) (Femara) tablets for the first-line treatment of postmenopausal women with hormone-receptor-positive or hormone-receptor-unknown locally advanced or metastatic breast cancer. Most postmenopausal women with advanced breast cancer fall into these tumor-receptor categories.
Approval of the new indication followed a priority review by the FDA and a unanimous recommendation from the FDA’s Oncologic Drugs Advisory Committee. The recommendation was based on data from the largest single study ever to evaluate a hormonal therapy in this setting. The study found that letrozole was significantly more effective than tamoxifen(Drug information on tamoxifen) (Nolvadex) in multiple efficacy end points. Tamoxifen has traditionally been the standard of therapy for this indication.
"Femara shows great promise for becoming the new first-line therapy of choice for postmenopausal women with advanced breast cancer," said Robert Smith, md, of South Carolina Oncology Associates and a lead investigator in the study. "It is the first therapy to challenge tamoxifen in multiple end points, including time to progression, response rates, and overall clinical benefit."
The phase III trial on which the FDA based its decision was a head-to-head, randomized, double-blind multicenter trial comparing the use of letrozole vs tamoxifen in more than 900 postmenopausal women with locally advanced (stage IIIB) disease, metastatic breast cancer, or recurrences not amenable to treatment with surgery or radiotherapy.
The study demonstrated that letrozole delays progression of advanced breast cancer for 9.4 months, as compared to 6.0 months for tamoxifen. Results also indicated significant differences between letrozole and tamoxifen with 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, controlled trial of 324 postmenopausal women with large localized or locally advanced breast cancer tumors who were given letrozole or tamoxifen as preoperative treatment to reduce tumor size before breast-conserving surgery. Clinical responses after 4 months of preoperative therapy were significantly better for letrozole than for tamoxifen (55% vs 36%).
Letrozole, an oral aromatase inhibitor, is a once-a-day oral treatment that was first approved for marketing in 1997 for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. In July 2000, Novartis submitted a supplemental New Drug Application (sNDA) for first-line therapy in advanced breast cancer, and, in August 2000, the sNDA received a priority review designation from the FDA.
In postmenopausal women, the primary source of estrogen is from fat, liver, muscle, and breast tissue through a process that turns adrenal androgens into estrogen, which stimulates the growth of certain hormone-dependent cancer cells. A breast tumor itself also may generate estrogen. Letrozole works by binding to the enzyme aromatase and blocking it from converting adrenal androgens to estrogen in these tissues.
Letrozole is currently available in more than 75 countries worldwide as a treatment for advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Regulatory submissions for the first-line indication have also been filed globally; the drug is also being studied in the adjuvant setting.
Letrozole is generally well tolerated but is contraindicated in patients with known hypersensitivity to the drug or any of its excipients. The adverse reactions in the first-line study were generally mild to moderate and were consistent with those seen in the second-line studies. The most commonly reported 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%), dyspnea or labored breathing (14% vs 15%), arthralgia (14% vs 13%), fatigue (11% vs 11%), and coughing (11% vs 10%).