Letrozole gets priority FDA review
Novartis seeking approval for use in the adjuvant treatment of hormone-receptor-positive early breast cancer
BASEL, Switzerland
The United States Food and Drug Administration (FDA) has granted priority review to letrozole (Femara) in the adjuvant (postsurgery) treatment of postmenopausal women with hormone-receptor-positive early breast cancer.
If approved for this new indication, Femara will become the only breast-cancer treatment in the US to significantly reduce the risk of recurrence for both the adjuvant setting and in extended adjuvant treatment following standard tamoxifen therapy. The supplemental new-drug application for use of Femara in the adjuvant setting was submitted by Novartis in June 2005.
The FDA grants priority review to products that could potentially offer a significant improvement compared with marketed products in the treatment, diagnosis, or prevention of a disease.
Novartis asked for priority review based on enhanced efficacy in high-risk subgroups for which existing therapies have not demonstrated benefit. In studies, Femara showed significantly improved efficacy compared with tamoxifen in women with node-positive disease and those who received chemotherapy treatment. It has also demonstrated a significantly reduced risk of distant metastases compared with tamoxifen.
"This priority review acknowledges the potential for Femara to represent a significant advance in treating postmenopausal women with early breast cancer immediately following surgery," said Dr. Diane Young, vice president and global head of clinical development at Novartis Oncology.
The submission was based on data from the Breast International Group (BIG) 1-98 study, a phase-III, randomized, double-blind study that compared the safety and efficacy of adjuvant Femara v. tamoxifen in more than 8,000 postmenopausal women with hormone receptor-positive early breast cancer.
The overall results of BIG 1-98 demonstrated that at a median follow-up of 26 months, Femara prolonged disease-free survival by reducing risk of recurrence by an additional 21 percent (p = 0.002) over the reduction offered by tamoxifen. Women who were treated with Femara experienced a 27-percent reduction in the risk that their cancer would spread to other parts of the body compared with tamoxifen (p = 0.001), a clinically relevant finding since women who develop distant metastases may be at greater risk of dying from their disease. Femara also provided a 14-percent reduction in the risk of death, although this did not reach statistical significance (p = 0.155).
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In two separate preplanned subset analyses, Femara also reduced the risk of recurrence by 29 percent among patients whose initial cancer had already spread to the lymph nodes at the time of diagnosis, and by 30 percent in those who had received chemotherapy. Additionally, in node-positive patients and those who received adjuvant chemotherapy, the risk of distant metastases was reduced by more than 30 percent with Femara.
BIG 1-98 is the only clinical trial designed to incorporate both a head-to-head comparison of Femara with tamoxifen during the first five years following breast-cancer surgery and a sequencing of both agents to determine the most effective approach to minimizing the risk of recurrence. Patients were randomized to the following arms: tamoxifen for five years, Femara for five years, tamoxifen for two years followed by Femara for three years, and Femara for two years followed by tamoxifen for three years. BIG1-98 was conducted by the International Breast Cancer Study Group (IBCSG) through several independent centers and with the support of Novartis.
The adverse events in the BIG 1-98 study were consistent with published data on both Femara and tamoxifen. In the BIG 1-98 study, the two treatments were generally well tolerated and the safety profiles overall were similar. Arthralgia/arthritis, bone fractures and osteoporosis were significantly more common with Femara treatment than with tamoxifen. Hot flashes, night sweats, vaginal bleeding, thromboembolic events, and endometrial proliferative disorders were significantly more frequent in the tamoxifen arm.
Overall, more deaths were reported with tamoxifen (192) than with Femara (166). More patients on tamoxifen (154) than on Femara (111) died after a recurrence from cancer- and noncancer-related causes. Among patients whose breast cancer did not recur, more deaths due to cardiac causes were reported in the Femara arm than in the tamoxifen arm. The number of all cardiovascular events was lower in the Femara arm (9.7 percent) than in the tamoxifen arm (10.5 percent).
The frequency of bone fractures and osteoporosis in both treatment arms was low, but the numbers were higher in the Femara arm (fractures: 5.7 percent; osteoporosis 2.0 percent) compared with tamoxifen (fractures 4.0 percent; osteoporosis: 1.1 percent). Endometrial proliferative disorders were reported more often with tamoxifen (1.8 percent) than with Femara (0.3 percent).
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