NovartisNewly published data in The New England Journal of Medicine affirm five-year upfront use of Femara® (letrozole) following surgery as an optimal treatment approach versus tamoxifen for postmenopausal women with early stage breast cancer (hormone-receptor positive).

The data include an analysis from the Breast International Group (BIG) 1-98 trial that evaluated patients taking either a sequence of Femara and tamoxifen for five years or Femara alone (as monotherapy) for five years. Also included is the update of the Monotherapy Arms Analysis (MAA) conducted 10 years after initiation of the study, comparing five years of Femara alone versus five years of tamoxifen alone following surgery (adjuvant setting). The BIG 1-98 trial was conducted by the International Breast Cancer Study Group (IBCSG).

Results from the Sequential Treatments Analysis (STA) concluded that sequential treatment with tamoxifen and Femara in the first five years after breast cancer surgery did not improve disease-free survival compared with Femara alone for the same duration after surgery. In the 10-year MAA analysis, Femara monotherapy demonstrated significant long-term improvement of disease-free survival (P=0.03) and significant long-term reduction in risk of distant disease spread (metastasis) (P=0.05) compared with tamoxifen. In patients treated with Femara monotherapy, a non-statistically significant relative reduction in the risk of death of 13% versus tamoxifen (P=0.08) was observed.

"The BIG 1-98 study results suggest survival benefit with five years of letrozole therapy after surgery compared to tamoxifen for the same time period following surgery, confirming the benefit of initial use of letrozole in the adjuvant breast cancer setting," said Henning T. Mouridsen, MD, PhD, Professor of Oncology, Copenhagen University Hospital and BIG 1-98 investigator. "Letrozole is the only aromatase inhibitor versus tamoxifen to demonstrate early and significant reduction in the risk of distant metastases, significant improvement in disease-free survival and this suggestion in overall survival benefit in primary breast cancer patients."

Sequential Treatments Analysis (STA)
Results of the STA (median follow-up of 71 months) concluded that sequential treatment with tamoxifen did not improve disease-free survival compared with Femara alone. In the study, patients either received sequential treatment with Femara and tamoxifen (two years of Femara followed by three years of tamoxifen or two years of tamoxifen followed by three years of Femara) or five years of Femara alone. 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 tamoxifen followed by Femara and 87.6% for those patients receiving Femara followed by tamoxifen.

Monotherapy Arms Analysis (MAA)
Updated results from the MAA (median follow-up of 76 months) confirm the significant long-term benefit of Femara. The data demonstrated that patients who took Femara alone for five years following surgery experienced a significant reduction in the risk of distant metastases (15%, P=0.05) with a corresponding reduction in risk of disease-free survival events (12%, P=0.03) compared with patients treated with tamoxifen alone for the same duration.

The analysis also revealed a non-significant trend towards an overall survival benefit with five years of Femara therapy following surgery (13% reduced risk of death, P=0.08) versus tamoxifen for five years following surgery. This occurred even though approximately 25% of patients in the tamoxifen arm selectively crossed over to Femara therapy after the tamoxifen arm was unblinded in 2005 due to the superiority of Femara over tamoxifen[1]. This crossover confounds the evaluation of the true differences between letrozole and tamoxifen. The study group therefore, conducted a retrospective censored analysis that was not protocol-defined and in which observation times were censored at the date of crossover. Time and events beyond the crossover were ignored in patients who selectively crossed over to Femara. In this censored analysis, there was an improved survival benefit for patients receiving five years of Femara versus tamoxifen (19%; HR 0.81; 95% CI: 0.68, 0.96). According to the authors, these censored results may be an overestimate of the Femara benefit since women who had recurrent disease were not candidates for the crossover. It is likely that the most accurate assessment of the survival benefit with Femara is between these two analyses - 13-19% reduction in the relative risk of death compared with tamoxifen[2].

BIG 1-98 is the only clinical trial designed to explore both a head-to-head comparison of an aromatase inhibitor versus tamoxifen monotherapy, as well as sequencing of an aromatase inhibitor and tamoxifen therapy in the first five years following breast cancer surgery, in order to determine the most effective way to minimize breast cancer recurrence. In the initial adjuvant setting, Femara is the only aromatase inhibitor to have consistently demonstrated an early significant reduction in distant metastases versus tamoxifen at a median follow-up of 26, 51 and 76 months.

"Femara is the only aromatase inhibitor to demonstrate consistent, early and significant reduction in risk of distant metastases," said Alessandro Riva, MD, Global Head Oncology Development, Novartis Oncology. "Based on these results, starting with Femara monotherapy for five years in the adjuvant setting instead of tamoxifen may offer breast cancer patients the opportunity for a better outcome."

Study details
This Phase III, randomized, double-blind, controlled clinical trial enrolled more than 8,000 postmenopausal women with early breast cancer in 27 countries[2].

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.

The primary endpoint of the study was disease-free survival, defined as the time from randomization to the first of any 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 previous cancer event. Other endpoints included time to breast cancer recurrence, time to distant breast cancer recurrence 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.

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. The long-term BIG 1-98 findings add to the large body of clinical evidence regarding the established safety profile of Femara.

About Femara
Femara is a leading once-daily oral aromatase inhibitor available in more than 100 countries, including the US, major European countries and Japan. It is approved for a number of indications:

  • Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer*
  • Extended adjuvant treatment of hormone-dependent early breast cancer in postmenopausal women who have had prior standard adjuvant tamoxifen therapy for five years**
  • First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer
  • Advanced breast cancer in women with natural or artificially induced postmenopausal status after relapse or disease progression who have been treated with antiestrogens
  • Pre-operative therapy in postmenopausal women with localized hormone receptor-positive breast cancer which allows subsequent breast-conserving surgery in patients not originally considered suitable for this type of surgery.

* Femara is also approved as neo-adjuvant (pre-operative) therapy in Japan, and in some countries for patients with metastatic disease.
** Not all indications are approved in every country.

About Novartis
Novartis 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 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

[1] Thürlimann B et al. A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer. N Engl J Med. 2005 Dec 29; 353(26); 2807-9.
[2] Mouridsen H for the BIG 1-98 Collaborative Group. Letrozole Alone or in Sequence with Tamoxifen for Postmenopausal Women with Breast Cancer. N Engl J Med. 2009 Aug 20; 361(8); 22-32.