Novartis Submits Applications in U.S. and Europe for Femara as Adjuvant Treatment for Postmenopausal Women with Early Breast Cancer
Applications based on data from large head-to-head trial showing Femara is more effective than tamoxifen in helping these women stay cancer free
EAST HANOVER, N.J., July 11, 2005 -- Novartis has submitted marketing authorization applications in the United States and Europe for the use of Femara (letrozole tablets) in the adjuvant (post-surgery) treatment of postmenopausal women with hormone receptor-positive early breast cancer.
Once approved for this indication, Femara will become the only breast cancer treatment available to significantly reduce the risk of recurrence in the adjuvant setting as well as in extended adjuvant treatment following tamoxifen.
"Femara represents an important advance to help increase a woman's chance of staying cancer free after initial treatment for early breast cancer," said Diane Young, MD, vice president and global head, Clinical Development, Novartis Oncology. "The data filed today add to the already substantial body of evidence supporting the use of Femara in breast cancer."
The submissions are 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 vs. 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% (p=0.002)[*] over the reduction offered by tamoxifen. Women who were treated with Femara experienced a 27% reduction in the risk that their cancer would spread to other parts of the body (distant metastases) 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% reduction in the risk of death, although this did not reach statistical significance (p=0.155).
In two separate pre-planned subset analyses, Femara also reduced the risk of cancer returning by 29% among patients whose initial cancer had already spread to the lymph nodes at the time of diagnosis (node-positive breast cancer) and by 30% in those who had received chemotherapy, two groups that are at increased risk of recurrence. Additionally, in node-positive patients and in patients who received adjuvant chemotherapy, the risk of distant metastases was reduced by more than 30% with Femara compared to tamoxifen.
About BIG 1-98
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. Results from the ongoing arms of the study, which are expected to determine whether monotherapy or sequential therapy is more effective, and if sequential therapy, which sequence is more effective, are expected in 2008.
BIG 1-98 was conducted by the International Breast Cancer Study Group (IBCSG), with participation of the Danish Breast Cancer Group, the French FNCLCC group, the Yorkshire Group and many independent centers. The study was supported by Novartis.
The data upon which the submissions are based were initially presented at the Primary Therapy of Early Breast Cancer 9th International Conference in St. Gallen, Switzerland in January 2005. Updated data from this analysis, presented in May at the annual meeting of the American Society for Clinical Oncology (ASCO) in Orlando, Florida, clarified the safety of Femara as compared with that of tamoxifen.
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 profile in the two treatment arms was similar. Only arthralgia/arthritis, bone fractures and osteoporosis were significantly more common in the Femara arm as compared to tamoxifen. Hot flashes/flushes, night sweats, vaginal bleeding and thromboembolic events in turn were significantly more frequent in the tamoxifen group.
Overall, more deaths were reported on tamoxifen (n=192) than on Femara (n=166). More patients on tamoxifen (n=135) died from breast cancer than Femara (n=100). In patients whose breast cancer did not recur, more deaths due to cardiac causes were reported in Femara-treated patients than tamoxifen- treated patients.
The frequency of bone fractures and osteoporosis on both treatments was low but the numbers were higher in the Femara arm (6.4%) compared to tamoxifen (4.8%). Endometrial hyperplasia or cancer was reported more often for tamoxifen (2.1%) than for Femara (0.4%).
In the trial, the number of all cardiovascular events was overall lower in the Femara arm than in the tamoxifen arm (9.7% vs. 10.5%). Irrespective of causality, the following adverse events occurred in the Femara and tamoxifen groups respectively: thromboembolic events (1.2% vs. 2.8%), angina pectoris (0.7% vs. 0.6%), myocardial infarction (0.6% vs. 0.4%) and cardiac failure (0.9% vs. 0.4%). Tamoxifen slightly decreased the cholesterol values, whereas Femara treatment resulted in no relevant overall changes over time in serum total cholesterol.
Femara is a leading once-a-day oral aromatase inhibitor currently available in more than 90 countries worldwide. Femara is approved for extended adjuvant treatment of early breast cancer in postmenopausal women who have completed standard adjuvant tamoxifen therapy in 57 countries worldwide, now including member countries of the EU as well as the United States. In addition, it is indicated for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer and for the treatment of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. Not all indications are available in every country.
Contraindications, warnings and adverse events
You should not take Femara if you are pregnant as it may cause fetal harm. You must be postmenopausal to take Femara.
Commonly reported side effects are generally mild to moderate. Those seen more often with Femara versus placebo were hot flashes (50% vs. 43%), joint pain (22% vs. 18%) and muscle pain (7% vs. 5%). Other side effects, which were comparable to placebo, include fatigue (34% vs. 32%), swelling due to fluid retention (18% vs. 16%), headache (20% vs. 20%), increase in sweating (24% vs. 22%) and increase in cholesterol (16% vs. 16%).
Longer follow up is needed to determine the risk of fracture associated with long-term use of Femara. The percentage of patients on Femara versus placebo reporting a fracture was 5.9% vs. 5.5%. The percentage of patients reporting osteoporosis was 6.9% vs. 5.5%. Bisphosphonates, drugs that increase bone strength, were given to 21.1% of Femara patients and 18.7% of placebo patients.
[*] 19% (p=0.003) in European filing due to slightly different definition of disease-free survival by European health authorities.
Posted: July 2005
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