Novartis Oncology recently announced that the US Food and Drug
Administration (FDA) has approved letrozole (Femara) tablets for the first-line
treatment of postmenopausal women with hormone-receptor-positive or
hormone-receptor-unknown locally advanced or metastatic breast cancer. Most
postmenopausal women with advanced breast cancer fall into these tumor-receptor
Approval of the new indication followed a priority review by the
FDA and a unanimous recommendation from the FDA’s Oncologic Drugs Advisory
Committee. The recommendation was based on data from the largest single study
ever to evaluate a hormonal therapy in this setting. The study found that
letrozole was significantly more effective than tamoxifen (Nolvadex) in multiple
efficacy end points. Tamoxifen has traditionally been the standard of therapy
for this indication.
"Femara shows great promise for becoming the new first-line
therapy of choice for postmenopausal women with advanced breast cancer,"
said Robert Smith, md, of South Carolina Oncology Associates and a lead
investigator in the study. "It is the first therapy to challenge tamoxifen
in multiple end points, including time to progression, response rates, and
overall clinical benefit."
The phase III trial on which the FDA based its decision was a
head-to-head, randomized, double-blind multicenter trial comparing the use of
letrozole vs tamoxifen in more than 900 postmenopausal women with locally
advanced (stage IIIB) disease, metastatic breast cancer, or recurrences not
amenable to treatment with surgery or radiotherapy.
The study demonstrated that letrozole delays progression of
advanced breast cancer for 9.4 months, as compared to 6.0 months for tamoxifen.
Results also indicated significant differences between letrozole and tamoxifen
with respect to overall tumor response rates (30% vs 20%), clinical benefit (49%
vs 38%), and time to treatment failure (9.1 vs 5.7 months, or 40 vs 25 weeks).
Letrozole and tamoxifen were equally well tolerated.
Supporting the filing was a phase III randomized, controlled
trial of 324 postmenopausal women with large localized or locally advanced
breast cancer tumors who were given letrozole or tamoxifen as preoperative
treatment to reduce tumor size before breast-conserving surgery. Clinical
responses after 4 months of preoperative therapy were significantly better for
letrozole than for tamoxifen (55% vs 36%).
Letrozole, an oral aromatase inhibitor, is a once-a-day oral
treatment that was first approved for marketing in 1997 for the treatment of
advanced breast cancer in postmenopausal women with disease progression
following antiestrogen therapy. In July 2000, Novartis submitted a supplemental
New Drug Application (sNDA) for first-line therapy in advanced breast cancer,
and, in August 2000, the sNDA received a priority review designation from the
In postmenopausal women, the primary source of estrogen is from
fat, liver, muscle, and breast tissue through a process that turns adrenal
androgens into estrogen, which stimulates the growth of certain
hormone-dependent cancer cells. A breast tumor itself also may generate
estrogen. Letrozole works by binding to the enzyme aromatase and blocking it
from converting adrenal androgens to estrogen in these tissues.
Letrozole is currently available in more than 75 countries
worldwide as a treatment for advanced breast cancer in postmenopausal women with
disease progression following antiestrogen therapy. Regulatory submissions for
the first-line indication have also been filed globally; the drug is also being
studied in the adjuvant setting.
Letrozole is generally well tolerated but is contraindicated in
patients with known hypersensitivity to the drug or any of its excipients. The
adverse reactions in the first-line study were generally mild to moderate and
were consistent with those seen in the second-line studies. The most commonly
reported adverse events for letrozole vs tamoxifen were bone pain (20% vs 18%),
hot flushes (18% vs 15%), back pain (17% vs 17%), nausea (15% vs 16%), dyspnea
or labored breathing (14% vs 15%), arthralgia (14% vs 13%), fatigue (11% vs
11%), and coughing (11% vs 10%).