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FDA Approval for Letrozole

 Brand name(s): Femara®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

 Initial Adjuvant Therapy
 

On December 28, 2005, the U.S. Food and Drug Administration approved letrozole tablets (Femara®, made by Novartis Pharmaceuticals Corp.) for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. The effectiveness of letrozole in early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months and followed for a median of 26 months. Follow-up analyses will determine long-term outcomes for both safety and efficacy.

A multicenter, double-blind clinical trial randomized over 8,000 postmenopausal women with resected (surgically removed) receptor-positive early breast cancer to one of the following arms:

  • Arm A: tamoxifen for five years
  • Arm B: letrozole for five years
  • Arm C: tamoxifen for two years followed by letrozole for three years
  • Arm D: letrozole for two years followed by tamoxifen for three years

The analysis includes data from the arms A and B together with data truncated 30 days after the change in treatment in the two sequential treatments (arms C and D). The comparison of monotherapy to sequential endocrine treatments will be conducted when the necessary number of events has been achieved.

Disease-free survival was defined as the time from randomization to the earliest occurrence of invasive loco-regional recurrence, distant metastases, invasive contralateral breast cancer, or death from any cause. Significantly fewer disease-free survival events in patients treated with letrozole [hazard ratio 0.79 (95 percent CI: 0.68, 0.92) p=0.002] were observed.

Systemic disease-free survival was defined as time from randomization to invasive regional recurrence, distant metastases, or death from any cause. There were significantly fewer systemic disease-free survival events in patients treated with letrozole [hazard ratio 0.83 (95 percent CI: 0.70, 0.97) p=0.022].

Time-to-distant metastases was defined as time from randomization to distant metastases (death not included); significantly fewer events in patients letrozole-treated were noted [hazard ratio 0.73 (95 percent CI: 0.60, 0.88) p=0.001]. Survival was not significantly different between patients receiving letrozole and those receiving tamoxifen [hazard ratio 0.86 (95 percent CI: 0.70, 1.06) p=0.155].

The most common adverse events reported for letrozole compared to tamoxifen were hot flashes/flushes (33.7 percent vs. 38 percent), arthralgia/arthritis (21.1 percent vs. 13.4 percent), night sweats (14.1 percent vs. 16.4 percent), weight increase (10.7 percent vs. 12.9 percent), and nausea (9.5 percent vs. 10.4 percent).

Other adverse events of importance included fractures (5.7 percent vs. 4 percent), myocardial infarction (0.6 percent vs. 0.4 percent), endometrial cancer (0.2 percent vs. 0.4 percent), second malignancies (1.9 percent vs. 2.4 percent), and thromboembolic events (1.2 percent vs. 2.8 percent).

The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals. In the adjuvant setting, the optimal treatment duration with letrozole is unknown. The planned treatment duration in the study is five years. However, at the time of analysis, the median treatment duration was 24 months, the median follow-up duration was 26 months, and 16 percent of the patients were treated for five years.

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 Extended Adjuvant Therapy
 

On October 29, 2004, the U.S. Food and Drug Administration granted accelerated approval for letrozole tablets (Femara®, a trademark of Novartis Pharmaceuticals Corp.) for the extended adjuvant treatment of early breast cancer in postmenopausal women who had received five years of adjuvant tamoxifen therapy. Approval was granted under accelerated approval regulations that require the sponsor to provide long-term outcome analyses.

Safety and efficacy were evaluated in a double-blind, multicenter, international clinical study in postmenopausal women with hormone receptor positive early stage breast cancer who had received five years of adjuvant therapy with tamoxifen. A total of 5,187 women who were within three months of completion of adjuvant tamoxifen were randomly assigned to receive five years of either letrozole or placebo.

Patients were stratified by hormone receptor status, lymph node status and prior adjuvant chemotherapy. Assessment of both safety and efficacy is limited because of short follow-up. The median duration of follow-up was 28 months; 30 percent of patients completed three or more years of follow-up and less than 1 percent were followed for five years or greater.

Approval was based on an analysis of disease free survival (DFS), defined as the time from randomization to the earliest event of time-to-loco-regional or distant recurrence of the primary disease, development of contralateral breast cancer, or death. At the time of analysis, the frequency of DFS events was 4.7 percent in patients receiving letrozole compared to 7.5 percent in patients receiving placebo (HR=0.62, 95 percent CI: 0.49, 0.78; p=0.00003). The risk of distant metastases was also significantly lower for letrozole than placebo (HR 0.61, 95 percent CI: 0.44, 0.84; p=0.003). Data on survival were not mature enough for analysis.

The long term risks of letrozole have not been fully evaluated. With short follow-up, the incidences of clinical fractures were comparable between patients who received letrozole (5.9 percent) and those receiving placebo (5.5 percent). The incidence of self-reported osteoporosis was higher in patients who received letrozole (6.9 percent) than in patients who received placebo (5.5 percent).

Preliminary results (20 month median follow-up) from a bone sub-study demonstrated that the mean decrease in hip bone mineral density (BMD) compared to baseline at two years was 3 percent versus 0.4 percent for letrozole versus placebo, respectively (p=0.048). The mean decrease in BMD from baseline for the lumbar spine at two years was 4.6 percent decrease and 2.2 percent for letrozole and placebo, respectively (p=0.069).

The incidence of cardiovascular ischemic events (lack of blood flow and oxygen to the heart) from the core randomized study was comparable between patients receiving letrozole (6.8 percent) and placebo (6.5 percent).

In the extended adjuvant setting, the optimal treatment duration with letrozole is unknown. In the randomized trial the median treatment duration was 24 months, with only 25 percent of patients treated for at least three years and less than 1 percent of patients treated for five years (the planned treatment duration). Treatment should be discontinued at tumor relapse.

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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: July 3, 2013