Femara First-Line Breast Cancer Label Includes Tamoxifen Superiority Claim

Novartis' Femara (letrozole) first-line breast cancer approval Jan. 10 is based on superiority over tamoxifen (AstraZeneca's Nolvadex and Barr's generic).

"Femara was superior to tamoxifen in [median time-to-tumor progression] and rate of objective tumor response" in a Phase III trial, labeling states. The 916-patient study showed that the primary endpoint of TTP was 9.4 months for patients on letrozole and 6 months for patients on tamoxifen.

The pivotal Phase III trial compared letrozole 2.5 mg and tamoxifen 20 mg in patients with locally advanced or metastatic breast cancer.

The objective tumor response rate (complete response plus partial response) was 30% (137 patients) for Femara versus 20% (92 patients) for tamoxifen. Complete response was also greater for Femara: 8% (34 patients) versus 3% (13 patients) for tamoxifen.

"Results from the prospectively defined secondary endpoint of time to treatment failure and clinical benefit were supportive of the results of the primary efficacy endpoint," labeling states.

TTF was 9.1 months for Femara and 5.7 months for tamoxifen, while clinical benefit was 49% versus 38%, respectively, the company's Jan. 10 release announcing the approval notes.

Overall survival data, another secondary endpoint, will be evaluated in November according to the trial's protocol (¹ ). The company said that survival data is not yet conclusive.

In a subgroup analysis of participants who received prior antiestrogen therapy, time-to-tumor progression was 8.8 months for the 84 patients on Femara compared to 5.9 months for the 83 tamoxifen patients. The objective response rate was 29% for Femara versus 8% for tamoxifen.

Novartis noted that "Femara was significantly more effective than tamoxifen in multiple efficacy endpoints," with tamoxifen being the standard of therapy for this indication.

At an FDA advisory panel meeting Dec. 13, members expressed support for Femara in part due to the aromatase inhibitor's role in combating resistance to hormonal therapies. The Oncologic Drugs Advisory Committee unanimously recommended letrozole for approval.

Letrozole was approved as a first-line treatment for postmenopausal women with hormone receptor unknown, advanced or metastatic breast cancer.

A first-line indication for AstraZeneca's aromatase inhibitor Arimidex (anastrozole) was granted Sept. 1, 2000 (² (Also see "AstraZeneca Arimidex" - Pink Sheet, 4 Sep, 2000.)).

"Femara was generally well-tolerated across all studies as first-line and second-line treatment for breast cancer and adverse reaction rates were similar in both settings," labeling states.

The most common adverse events for Femara versus tamoxifen were bone pain (20% vs. 18%), hot flushes (18% vs. 15%), back pain (17% vs. 17%), nausea (15% vs. 16%), dyspnea (14% vs. 15%), arthralgia (14% vs. 13%), fatigue (11% vs. 11%) and coughing (11% vs. 10%).

"Discontinuations for adverse experiences other than progression of tumor occurred in 10/455 (2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen," labeling states.

Novartis has two ongoing studies with letrozole related to the first-line indication, the company said.

An adjuvant trial in postmenopausal estrogen/progesterone receptor positive patients is completing enrollment and data should be available in two years, the company said.

Femara is also being tested in postmenopausal patients who have been disease free after five years of adjuvant tamoxifen, according to the company.

Novartis has not announced marketing plans to promote the new indication. The company has 100 reps in its oncology group to detail Femara.

The sNDA, submitted July 11, 2000, received priority review status. Femara has been approved for second-line treatment of advanced breast cancer in postmenopausal women since 1997.