- Femara showed reduced risk of death by 13% (P=0.08), despite inclusion of patients crossing over from tamoxifen to Femara therapy
- In a separate censored analysis excluding patients after they crossed over to Femara, reduction in risk of death was 19%
- Long-term follow-up from major independent BIG 1-98 trial reinforces starting with Femara as the optimal treatment strategy versus tamoxifen
EAST HANOVER, N.J., Dec. 11 /PRNewswire/ -- New long-term data from a major international breast cancer study reports that postmenopausal woman with hormone receptor-positive early-stage breast cancer who took Femara(R) (letrozole tablets) for five years following surgery had a 13% (P=0.08) reduced risk of death, when compared with tamoxifen(1).
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These results are from a protocol-defined Intent-to-Treat (ITT) analysis (median follow-up of 76 months) of the Femara and tamoxifen monotherapy arms in the Breast International Group (BIG) 1-98 study. The suggested survival benefit from the ITT analysis is important considering that approximately 25% of patients in the tamoxifen arm selectively crossed over to Femara therapy after the tamoxifen arm was unblinded in 2005. While not statistically significant, these are the first data to suggest a survival benefit for an aromatase inhibitor versus tamoxifen in the monotherapy setting immediately following surgery.
To explore the impact of the selective crossover, an additional analysis was conducted censoring follow-up times at the date of crossover to letrozole. In this analysis, a 19% reduction in risk of death (HR=0.81, 95% CI: 0.69-0.94) was observed in favor of Femara.
The International Breast Cancer Study Group (IBCSG) presented these results from the BIG 1-98 trial today at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), an international scientific symposium for scientists and clinicians in breast cancer.
"These data represent an important milestone in the treatment of women with breast cancer. For the first time, we are seeing suggested survival benefit with aromatase inhibitor therapy for five years compared with tamoxifen for the same time period," said Henning T. Mouridsen, MD, PhD, Professor of Oncology,
BIG 1-98 is the only clinical trial designed to explore both a head-to-head comparison of an aromatase inhibitor with tamoxifen during the first five years following breast cancer surgery and the sequencing of both agents to determine the most effective approach to minimizing the risk of recurrence. In the initial adjuvant setting, Femara is the only aromatase inhibitor to have demonstrated an early significant reduction in distant metastases versus tamoxifen, at a median duration of follow-up of 26 months.
Beyond the potential survival benefit of 13% (P=0.08, HR=0.87, 95% CI: 0.75-1.02) reduction in risk of death for Femara patients seen in the ITT analysis, Femara demonstrated significant long-term benefit in reducing the risk of disease-free survival events by 12% (P=0.03, HR=0.88, 95% CI: 0.78-0.99) and reducing the risk of distant metastases by 15% (P=0.05, HR=0.85, 95% CI: 0.72-1.00) compared with tamoxifen.
"Femara has consistently demonstrated remarkable results and these data reaffirm the benefit of Femara for postmenopausal women with early-stage breast cancer," said Alessandro Riva, MD, Executive Vice President, Head of Global Development at Novartis Oncology. "The survival data shown may offer new promise for breast cancer patients."
Also presented at the meeting were results from the Sequential Treatment Analysis (STA) of BIG 1-98 that support the benefit of starting adjuvant treatment with five years of Femara after surgery. This analysis (from randomization) revealed that sequencing hormone therapy following surgery is not superior to five years of Femara alone.
The five-year disease-free survival rates for the three groups of patients in the STA were 87.9% for those patients receiving Femara only, 86.2% for those patients receiving two years of tamoxifen followed by three years of Femara and 87.6% for those patients receiving two years of Femara followed by three years of tamoxifen. The study investigators conclude that sequential treatment does not improve disease-free survival compared with Femara alone.
This Phase III, randomized, double-blind, controlled clinical trial enrolled postmenopausal women with early breast cancer, in 27 countries(1).
Patients were randomly assigned one of four treatment regimens: (1) five years of tamoxifen only; (2) five years of Femara only; (3) two years of tamoxifen followed by three years of Femara; (4) two years of Femara followed by three years of tamoxifen. In 1998 the first cohort began enrolling patients to receive either Femara or tamoxifen alone. In 1999, the second cohort (solely contributing to the Sequential Treatment Analysis) began enrolling patients to receive Femara or tamoxifen alone, tamoxifen followed by Femara or Femara followed by tamoxifen (n=6,182 patients). Combined, the monotherapy arms of the trial included 4,922 patients who were randomly assigned either Femara or tamoxifen treatment(1). The Primary Core Analysis, reported in 2005, included all 8,010 patients enrolled in the trial.
The primary endpoint of the study was disease-free survival (DFS), defined as the time from randomization to the first of one of the following events: recurrence at local, regional, or distant sites; a new invasive cancer in the contralateral breast; any second, non-breast cancer; or death without a prior cancer event, which is similar but not identical to the endpoint definitions used in other AI adjuvant trials. Other endpoints included time to breast cancer recurrence [including invasive contralateral breast cancer, ignoring second (non-breast) malignancies, and censoring deaths prior to cancer event], time to distant breast cancer recurrence (time to breast cancer recurrence but ignoring local, regional and contralateral breast events), and overall survival.
In 2005, following initial results showing superiority of Femara monotherapy over tamoxifen monotherapy in improving disease-free survival and reducing the risk of recurrence, the tamoxifen-only treatment arm was unblinded and approximately one quarter of those patients selectively crossed over to Femara treatment. The other three treatment arms remained blinded. Subsequent analyses were designed to estimate the extent to which the crossover affected the comparative benefit of Femara(1).
With the long-term follow-up in the analysis conducted more than 10 years after the start of the study, adverse events for Femara and tamoxifen were found to be consistent with the known safety profiles of both drugs. Patients will be monitored for the rest of their lives to track disease status, safety and overall survival(1).
Femara(R) (letrozole tablets) is approved for the adjuvant (following surgery) treatment of postmenopausal women with hormone receptor-positive early stage breast cancer. The benefits of Femara in clinical trials are based on 24 months of treatment. Further follow-up will be needed to determine long-term results, safety and efficacy.
Femara is also approved for the extended adjuvant treatment of early stage breast cancer in postmenopausal women who are within three months of completion of five years of tamoxifen therapy. The benefits of Femara in clinical trial are based on 24 months of treatment. Further follow-up will be needed to determine long-term results, including side effects.
In addition, Femara is approved for the treatment of postmenopausal women with estrogen receptor-positive or estrogen receptor-unknown breast cancer that has spread to another part of the body (metastatic cancer).
Important Safety Information
You should not take Femara if you are premenopausal. Your doctor should discuss the need for adequate birth control if you have the potential to become pregnant, if you are not sure of your postmenopausal status, or if you recently became postmenopausal. Femara is only indicated in postmenopausal women. Talk to your doctor if you're allergic to Femara or any of its ingredients. You should not take Femara if you are pregnant as it may cause fetal harm. Some women reported fatigue and dizziness with Femara. Until you know how it affects you, use caution before driving or operating machinery. Some patients taking Femara had an increase in cholesterol. Additional follow-up is needed to determine the risk of bone fracture associated with long-term use of Femara.
In the adjuvant setting, commonly reported side effects are generally mild to moderate. The most common side effects seen with Femara include hot flashes, joint pain, night sweats, weight gain, nausea, tiredness, other heart-related events and bone fractures. Other less commonly reported side effects include vaginal bleeding, blood clots, other cancers, osteoporosis, stroke, heart attack and endometrial cancer.
In the extended adjuvant setting, commonly reported side effects are generally mild to moderate. Commonly reported side effects for Femara include hot flashes, fatigue, joint pain, headache, increase in sweating, swelling due to fluid retention, increase in cholesterol, dizziness, constipation, nausea, cardiovascular ischemic events, muscle pain, osteoporosis, arthritis and bone fracture.
In the metastatic cancer setting, commonly reported side effects are generally mild to moderate and may include bone pain, hot flashes, back pain, nausea, joint pain, shortness of breath, tiredness, coughing, constipation, limb pain, chest pain and headache.
The foregoing release contains forward-looking statements that can be identified by terminology such as "risk," "suggested," "suggest," "potential," "may," "explore," "promise," "estimate," "will," or similar expressions, or by express or implied discussions regarding potential new indications or labelling for Femara or regarding potential future revenues from Femara. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Femara to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Femara will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that Femara will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Femara could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
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Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, GI and respiratory areas. The Company's mission is to improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 97,000 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.
1. Mouridsen H for the BIG 1-98 Collaborative Group, Letrozole Alone or in Sequence with Tamoxifen for Postmenopausal Women with Early Breast Cancer. Presented at: the 31st Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, 31st Annual Meeting, December 11, 2008. Abstract No. 13.
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