Novartis Femara Gets Priority Review; 1st-Line Use For AstraZeneca Arimidex

Novartis could see FDA action by January on its Femara sNDA for first-line treatment of advanced breast cancer in postmenopausal women. The application for the aromatase inhibitor was filed July 11 and received a priority review designation on Sept. 11, ten days after the approval of AstraZeneca’s AI Arimidex for the same indication.

Arimidex (anastrozole) cleared FDA Sept. 1 for "first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer." The agent was originally approved in 1996 for use after tamoxifen (AstraZeneca's Nolvadex ) failure.

Anastrozole is the first AI in the U.S. to receive the first-line breast cancer treatment indication. In addition to Femara (letrozole), the AI market includes Pharmacia's Aromasin (exemestane), which was approved October 1999 for second-line use.

Approval of the new Arimidex indication and the priority review designation for the Femara sNDA come at a time when Nolvadex is approaching the end of its patent. AstraZeneca will be looking to Arimidex to help maintain its position in the breast cancer market when its patent for tamoxifen expires, in August 2002.

Despite a recent challenge by Pharmachemie, AstraZeneca's patent was upheld on Sept. 11 by a Boston federal court ruling. However, the company is involved in another patent case with Mylan in Pittsburgh.

AstraZeneca submitted data from two pivotal trials to support the Arimidex first-line indication. In North American trial 030, anastrozole showed a statistically significant advantage over tamoxifen in time to tumor progression (TTP). Median TTP for Arimidex-treated patients was 11.1 months compared to 5.6 months for tamoxifen patients (p=0.006), according to labeling. The best objective response rate was 21.1% for Arimidex and 17% for tamoxifen, while the percentage of patients whose disease progressed was 67% vs. 76%, respectively.

In the European trial 027, TTP was 8.2 and 8.3 months for anastrozole- and tamoxifen-treated patients, respectively, suggesting that the AI was at least as effective as tamoxifen, according to labeling. This conclusion was mirrored in the percentage of patients whose disease progressed (73% with anastrozole; 75% with tamoxifen) as well as in best objective response rates (32.9% vs. 32.6%; p=0.920).

Both agents were well tolerated, labeling states. Thromboembolic disease events were lower, however, in anastrozole patients than in tamoxifen subjects (3.5% vs. 6.5%).

Approval of a first-line therapy indication for Femara "will represent a therapeutic advance in the treatment of advanced breast cancer," Novartis states. The sNDA for the first-line indication is supported by an international, multi-center study comparing 2.5 mg daily letrozole to 20 mg daily tamoxifen in 907 postmenopausal women with locally advanced or metastatic breast cancer.

Letrozole was shown to be "significantly superior" to tamoxifen on the primary endpoint of median TTP (41 weeks vs. 26 weeks, p=0.0001), according to a study abstract. Tumor assessment was conducted at baseline and every three months on the patients, who had either estrogen-receptor (ER) positive and/or progesterone-receptor (PgR) positive or ureceptor status.

Study results will be presented at the Chemotherapy Foundation Symposium in New York Nov. 8-11, the San Antonio Breast Cancer Symposium in San Antonio Dec. 6-12, and at European scientific conferences in September and October.

Pharmacia's Aromasin is also being evaluated in comparison to tamoxifen as first-line therapy for advanced breast cancer in a Phase II/III trial conducted by the European Organization for Research and Treatment of Cancer (EORTC).

Initial data from the Phase II segment of the trial, presented in May at the annual meeting of the American Society of Clinical Oncology, showed the median TTP was 8.9 months with 25 mg/daily Aromasin compared to 5.2 months with 20 mg/daily tamoxifen. Complete response rates were 10% and 3% for Aromasin and tamoxifen, while overall response rates were 42% and 16%, respectively.

In the Phase III segment of the EORTC study, exemestane is being tested against tamoxifen to assess progression-free survival in patients with locally recurrent or metastatic breast cancer. The trial should be completed in 2003. Pharmacia says that it is not planning to file for a first-line indication.

Combination use of exemestane and the selective estrogen receptor modulator raloxifene (Lilly's Evista ) is also being examined in a National Cancer Institute-sponsored trial in patients with a history of stage I, II or III breast cancer who have no clinical evidence of disease after completion of adjuvant therapy. Thirty patients will be taking the combination for one year. After one year, subjects can either continue raloxifene alone or receive combo therapy for up to five years.

Although the three AIs have been assessed for first-line use for advanced breast cancer treatment and Arimidex has been approved for the indication, healthcare information firm Decision Resources predicts that aromatase inhibitors "will never completely replace an antiestrogen such as tamoxifen as first-line hormonal therapy." The company believes that because AIs play a limited role in inhibition of estrogen, they may be more effective in combination therapy. Tamoxifen's low cost, high efficacy, and chemoprevention indication are the reasons that it should continue to be the gold-standard hormonal therapy, Decision Resources concludes in a July 2000 report (see p. 30 for summary of the Decision Resources analysis of the breast cancer market).

Nolvadex generated approximately $124.4 mil. in sales for the past twelve months ended in July, according to market research firm IMS Health. Arimidex was the leading aromatase inhibitor with $55 mil. in sales for the same time period, followed by Femara with $12.3 mil. Aromasin, launched in January, produced sales of $2.7 mil. for its first seven months on the market

Investigations of additional potential indications for the three AIs include an AstraZeneca study of Arimidex for neoadjuvant therapy. Trial results published in the June issue of Clinical Cancer Research showed that anastrozole, given in 1 mg or 10 mg daily doses for 12 weeks, produced median reductions of tumor volume of 80.5% and 69.6% in evaluable patients, respectively. Fifteen of 17 patients were found suitable for breast conservation after anastrozole treatment. Study subjects were postmenopausal women with newly diagnosed, estrogen receptor-rich, locally advanced or large (>3 cm) operable breast cancers. The company is considering filing for the neoadjuvant indication.

Femara was found to be "significantly superior to tamoxifen in tumor reduction which resulted in a superior rate of breast conserving surgery for...letrozole-treated patients" in a Phase IIb/III, European neoadjuvant therapy trial conducted by S. Paepke, University Clinic Charite, Berlin, Germany, et al. The study assessed 377 patients with ER-positive and/or PgR-positive breast cancer given either 2.5 mg daily letrozole or 20 mg daily tamoxifen.

According to a study abstract, the objective response as measured by clinical examination was 55% for letrozole compared to 36% for tamoxifen (p<0.001), while ultrasound evaluation yielded values of 35% vs. 25% (p=0.042) and mammography 34% vs. 17% (p<0.001), respectively. After four months of treatment, more letrozole-treated patients had breast conserving surgery vs. tamoxifen-treated patients (45% vs. 35%, p=0.022).

Novartis has filed for the neoadjuvant treatment indication in Europe, but says that it does not intend to submit an NDA for a neoadjuvant indication to FDA.

Studies examining the efficacy of Arimidex and Aromasin in breast cancer recurrence prevention are also underway. In AstraZeneca's ongoing ATAC (Arimidex, Tamoxifen, And Combination therapy) trial, treatment with Arimidex alone, tamoxifen alone, or the two agents in combination is being evaluated for prevention of recurrence in early breast cancer patients who have had surgery. Results from the five-year, 9,300-patient Phase III trial are expected in 2001.

The National Surgical Adjuvant Breast and Bowel Project is sponsoring a Phase III prevention of recurrence trial with Aromasin slated to start in October. The two-year study will compare exemestane to placebo in 3,000 disease-free stage I and II breast cancer patients who have previously had five years of tamoxifen therapy and will determine whether Aromasin treatment will prolong disease-free survival and overall survival.

Pharmacia is also planning to start four Aromasin chemoprevention trials by early next year that will test the product in high-risk patients. Both AstraZeneca and Novartis are considering chemoprevention trials with their agents.