Results in The New England Journal of Medicine confirm Novartis drug Femara® is superior to tamoxifen after breast cancer surgery

Wednesday, 19. August 2009 23:00
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* Data validate Femara alone for five years following
hormone-receptor positive breast cancer surgery as an optimal
first treatment vs. tamoxifen in postmenopausal women

* Results show long-term superiority of Femara in improving
disease-free survival (P=0.03) and reducing risk of distant
metastases (P=0.05) compared with tamoxifen

* Femara for five years following surgery is first aromatase
inhibitor to suggest survival benefit versus tamoxifen; 13%
reduction in risk of death (P=0.08, non-significant)

Basel, August 19, 2009 - Newly 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.

Important Safety Information
Femara should not be taken by women who have previously had any
unusual or allergic reactions to letrozole or any of its ingredients.
Femara should not be taken by women who are pregnant or
breastfeeding. Only women who are of postmenopausal endocrine status
should take Femara. Patients with severe liver impairment should be
monitored closely. The use of Femara in patients with significantly
impaired kidney function warrants careful consideration.

The most frequent adverse reactions of Femara are hot flushes,
nausea, fatigue and arthralgia. Other common side effects are
anorexia, appetite increase, peripheral oedema, headache, dizziness,
malaise, vomiting, dyspepsia, constipation, diarrhea, alopecia,
increased sweating, rash, myalgia, bone pain, osteoporosis, bone
fractures, weight increase, hypercholesterolemia and depression.
Other rare, but potentially serious adverse events include
leukopenia, cataract, cerebrovascular accident or infarction,
thrombophlebitis, pulmonary embolism, arterial thrombosis, general
edema, ischemic cardiovascular disease, angioedema, anaphylactic
reaction, hepatitis, toxic epidermal necrolysis and erythema
multiforme.

This press release is not intended for UK media.

Disclaimer
The foregoing release contains forward-looking statements that can be
identified by terminology such as "long-term," "risk," "suggest,"
"suggestion," "will," "may," "likely," "designed to explore," or
similar expressions, or by express or implied discussions regarding
potential new indications or labeling 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, the company's ability to obtain or maintain
patent or other proprietary intellectual property protection;
competition in general; unexpected regulatory actions or delays or
government regulation generally; unexpected clinical trial results,
including unexpected new clinical data and unexpected additional
analysis of existing clinical data; 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.

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.

References
[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.

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