# ![](media/image1.wmf){width="1.9479166666666667in" height="0.3125in"}FF Novartis Pharmaceuticals Corporation

East Hanover, NJ

# 

[Femara^^ Briefing Document November 9, 2000]{.underline}

# 

# Femara^^ (letrozole tablets)

**ONCOLOGIC DRUGS ADVISORY COMMITTEE**

**BRIEFING DOCUMENT**

## November 9, 2000

**NDA 20-726, Supplement \# 006**

## First-Line Breast Cancer Indication

Version: 11/9/00

Release date: November 9, 2000

**AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION.**

**Authors**

+-----------------------------------+-----------------------------------+
| # Interna                         | # Project Statistician            |
| tional Clinical Leader, Femara^®^ |                                   |
|                                   | Hilary Chaudri, MA (Hons) DEP     |
| Carolyn Brady, MSPH               |                                   |
|                                   | Clinical Research & Development   |
| Clinical Research & Development   |                                   |
|                                   | Novartis Pharma AG                |
| Novartis Pharmaceuticals          |                                   |
| Corporation                       | Basel, Switzerland                |
|                                   |                                   |
| East Hanover, New Jersey          |                                   |
+-----------------------------------+-----------------------------------+
|                                   |                                   |
+-----------------------------------+-----------------------------------+
| # Group Leader, Oncology          | # Clinical Trial Leader           |
|                                   |                                   |
| Margaret Dugan, MD                | Beatrix Staffler, PharmD          |
|                                   |                                   |
| Medical Advisor, Femara^®^        | Clinical Research & Development   |
|                                   |                                   |
| Clinical Research & Development   | Novartis Pharma AG                |
|                                   |                                   |
| Novartis Pharmaceuticals          | Basel, Switzerland                |
| Corporation                       |                                   |
|                                   |                                   |
| East Hanover, New Jersey          |                                   |
+-----------------------------------+-----------------------------------+
| #                                 | #                                 |
+-----------------------------------+-----------------------------------+
| #                                 | #                                 |
+-----------------------------------+-----------------------------------+

# List Of Studies

+------+---------------------+---------+-----------+------------------+
| **\  | **\                 | **\     | **T       | **\              |
| Stu  | Objective**         | Pat     | reatment\ | Treatments**     |
| dy** |                     | ients** | d         |                  |
|      |                     |         | uration** |                  |
+======+=====================+=========+===========+==================+
| **0  | Randomized, phase   | 939^1^  | Until     | Letrozole 2.5    |
| 25** | III, double-blind,  |         | pr        | mg/day\          |
|      | crossover;          |         | ogression | Tamoxifen 20     |
|      | first-line          |         | or        | mg/day\*         |
|      | treatment\          |         | w         |                  |
|      | (completed)         |         | ithdrawal |                  |
+------+---------------------+---------+-----------+------------------+
|      |                     |         |           |                  |
+------+---------------------+---------+-----------+------------------+
| **0  | Randomized, phase   | 337^3^  | 4 months  | Letrozole 2.5    |
| 24** | III, double-blind,  |         |           | mg/day\          |
|      | 2 parallel groups;  |         |           | Tamoxifen 20     |
|      | preoperative        |         |           | mg/day\*         |
|      | treatment\          |         |           |                  |
|      | (completed)         |         |           |                  |
+------+---------------------+---------+-----------+------------------+
|      |                     |         |           |                  |
+------+---------------------+---------+-----------+------------------+
| **0  | Randomized,         | 32^2^   | Until     | Letrozole 0.5    |
| 12** | double-blind, 3     |         | pr        | mg/day Letrozole |
|      | parallel groups;    |         | ogression | 2.5 mg/day\      |
|      | first-line          |         | or        | Tamoxifen 30     |
|      | treatment\          |         | w         | mg/day           |
|      | (completed)         |         | ithdrawal |                  |
+------+---------------------+---------+-----------+------------------+
|      |                     |         |           |                  |
+------+---------------------+---------+-----------+------------------+
| **0  | Randomized,         | 18^4^   | Until     | Letrozole 2.5    |
| 26** | open-label;         |         | disease   | mg/day Letrozole |
|      | first-line          |         | pr        | 2.5 mg plus      |
|      | treatment           |         | ogression | Tamoxifen 20     |
|      | (discontinued)      |         | or        | mg/day\*         |
|      |                     |         | w         |                  |
|      |                     |         | ithdrawal |                  |
|      |                     |         | from      |                  |
|      |                     |         | study     |                  |
+------+---------------------+---------+-----------+------------------+
|      |                     |         |           |                  |
+------+---------------------+---------+-----------+------------------+
| **01 | Bioequivalence,     | 36      | Si        | Tamoxifen        |
| 02** | double-blind,       |         | ngle-dose | (Nolvadex^®^)    |
|      | intrapatient        |         | in        | versus           |
|      | crossover;          |         | healthy   | Tamofen^®^       |
|      | single-dose study   |         | post-m    | (generic         |
|      |                     |         | enopausal | tamoxifen)       |
|      |                     |         | women     |                  |
+------+---------------------+---------+-----------+------------------+
| \    |                     |         |           |                  |
| *Tam |                     |         |           |                  |
| ofen |                     |         |           |                  |
| (gen |                     |         |           |                  |
| eric |                     |         |           |                  |
| ta   |                     |         |           |                  |
| moxi |                     |         |           |                  |
| fen) |                     |         |           |                  |
| was  |                     |         |           |                  |
| u    |                     |         |           |                  |
| sed. |                     |         |           |                  |
|      |                     |         |           |                  |
| ^    |                     |         |           |                  |
| 1^Le |                     |         |           |                  |
| troz |                     |         |           |                  |
| ole: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 458; |                     |         |           |                  |
| ta   |                     |         |           |                  |
| moxi |                     |         |           |                  |
| fen: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 458; |                     |         |           |                  |
| comb |                     |         |           |                  |
| inat |                     |         |           |                  |
| ion: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 23.  |                     |         |           |                  |
|      |                     |         |           |                  |
| ^2^  |                     |         |           |                  |
| L    |                     |         |           |                  |
| etro |                     |         |           |                  |
| zole |                     |         |           |                  |
| 0.5  |                     |         |           |                  |
| mg:  |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 10;  |                     |         |           |                  |
| Le   |                     |         |           |                  |
| troz |                     |         |           |                  |
| ole: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 12;  |                     |         |           |                  |
| t    |                     |         |           |                  |
| amox |                     |         |           |                  |
| ifen |                     |         |           |                  |
| 30   |                     |         |           |                  |
| mg:  |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 10.  |                     |         |           |                  |
|      |                     |         |           |                  |
| ^3^  |                     |         |           |                  |
| Le   |                     |         |           |                  |
| troz |                     |         |           |                  |
| ole: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 162; |                     |         |           |                  |
| ta   |                     |         |           |                  |
| moxi |                     |         |           |                  |
| fen: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 17   |                     |         |           |                  |
| 5^.^ |                     |         |           |                  |
|      |                     |         |           |                  |
| ^4^  |                     |         |           |                  |
| Le   |                     |         |           |                  |
| troz |                     |         |           |                  |
| ole: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 9;   |                     |         |           |                  |
| Let  |                     |         |           |                  |
| rozo |                     |         |           |                  |
| le + |                     |         |           |                  |
| ta   |                     |         |           |                  |
| moxi |                     |         |           |                  |
| fen: |                     |         |           |                  |
| n =  |                     |         |           |                  |
| 9.   |                     |         |           |                  |
+------+---------------------+---------+-----------+------------------+

**Executive Summary**

**Development History of Femara^®^ in Second-Line Therapy of Breast
Cancer**

Femara (letrozole, Novartis Pharmaceuticals Corporation, East Hanover,
NJ) is a potent, selective aromatase inhibitor that specifically blocks
estrogen biosynthesis. Femara is registered worldwide for the treatment
of advanced breast cancer in postmenopausal women with disease
progression following antiestrogen therapy.^1-4^

Two large, randomized, controlled, multinational clinical trials were
the basis of approval of Femara by the US FDA in 1997. In one trial,
patients were randomized to Femara (0.5 or 2.5 mg daily) or a comparator
(megestrol acetate \[160 mg daily\]), and aminoglutethimide (250 mg BID)
with corticosteroid supplementation in the other trial. In these trials,
Femara (2.5 mg) significantly reduced the relative risk of progression
compared with either megestrol acetate or aminoglutethimide. Femara was
also better tolerated with a superior safety profile than either
comparator. The results of an additional phase III trial (Study 02) that
compared the same 2 doses of Femara with megestrol acetate (160 mg
daily) demonstrated that both doses of Femara were at least as
efficacious as megestrol acetate and that the 0.5 mg dose improved time
to progression (TTP). A meta-analysis of these three trials support that
Femara 2.5 mg is effective and likely to produce good objective response
rates and longer disease control when used as second-line hormonal
therapy (data on file).

**Development History of Femara^®^ in First-Line Therapy of Breast
Cancer**

#### The efficacy and safety of Femara in the second-line treatment of advanced breast cancer in postmenopausal women, supported its development in first-line treatment. In November 1996, one large, double-blind, double-dummy, well-controlled, randomized, multinational, phase III study (Study 025) was initiated comparing Femara as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer against the current standard of care, tamoxifen. 

#### In addition, 2 small, pilot studies (Studies 012 and 026) in first-line treatment of advanced breast cancer in postmenopausal women were also conducted. Study 012 was initiated prior to the pivotal trial, Study 025. Study 012 used the same comparator, tamoxifen, as Study 025 and randomized patients to 0.5 and 2.5 mg daily doses of Femara and 30 mg of tamoxifen. This trial was initiated before the second-line studies were completed and was discontinued early, after 32 patients were enrolled, when the 2.5 mg dose was approved as second-line treatment. Study 026 was initiated in November 1996 and was a phase II, open-label study that compared Femara at 2.5 mg daily doses to Femara at 2.5 mg in combination with 20 mg tamoxifen. This study was discontinued after 18 patients were enrolled when the results of a pharmacokinetic interaction study indicated that adding tamoxifen to Femara reduced mean Femara blood levels (AUC) by 38%.^5^ 

Study 024, initiated in March 1998, was a double-blind, double-dummy,
well-controlled, randomized, multinational phase II/III study comparing
Femara or tamoxifen for 4 months prior to surgery in postmenopausal
patients with ER and/or PgR positive, stage II/III primary breast
cancer. Study 024 was supportive of the pivotal Study 025 in that it
preselected a group of breast cancer patients who would most likely
respond to endocrine therapy (postmenopausal women with ER and/or PgR
positive tumors) and who were more importantly never exposed to either
endocrine or other forms of therapy. Therefore, these truly
therapy-naive patients represented an appropriate group of patients in
whom to evaluate differences between two endocrine therapies.

**Pivotal Study 025**

*Study Design*

Study 025 was a double-blind, double-dummy, randomized, multinational,
phase III trial comparing Femara versus tamoxifen as first-line therapy
in postmenopausal women with locally advanced or metastatic breast
cancer. The original protocol was designed as a comparison of 3 arms:
2.5 mg Femara, 20 mg tamoxifen, and the combination of 2.5 mg Femara
plus 20 mg tamoxifen; however, preliminary data from a pharmacokinetic
study indicated that adding tamoxifen to Femara reduced Femara blood
levels (AUC) by 38% on average.^5^ Therefore, the combination therapy
arm was dropped. The protocol was amended to demonstrate superiority of
Femara over tamoxifen using time to progression as the primary endpoint.
Patients were randomized to initial double-blind therapy with Femara
(2.5 mg daily) or tamoxifen (20 mg) until progression or discontinuation
of initial treatment. At such time patients were allowed to cross over
to the alternative therapy still under double-blind conditions if they
still qualified for further endocrine therapy. All patients were
followed for survival. Secondary endpoints included rate and duration of
overall tumor response (CR + PR), rate and duration of clinical benefit
(CR + PR + SD ≥ 6 months), time to treatment failure (TTF), overall
survival, and safety.

A total of 916 patients were randomly assigned treatment on the
monotherapy arms in 29 countries from 201 centers. The intent-to-treat
(ITT) population included a total of 907 patients, 453 on Femara and 454
on tamoxifen. The results presented here on the ITT population represent
the primary analysis of all efficacy endpoints (excluding survival and
safety) from the initial treatment phase (ie, first-line therapy). Data
are current until March 8, 2000. The efficacy results of the "ITT" and
"all randomized patients" populations are nearly identical. A subsequent
supplementary analysis that will report the results of the crossover
treatment and also include the final analysis of survival for the ITT
population, is anticipated in the fourth quarter of 2001. This study
represents the largest randomized phase III study of endocrine therapy
in postmenopausal women with advanced breast cancer.

*Patient Demographic and Efficacy Results*

Important patient characteristics and major efficacy results are shown
in Table 1.

Femara was superior to tamoxifen in prolonging time to progression and
time to treatment failure, and in the rates of overall objective
response and clinical benefit. There were no significant differences
between treatments in duration of overall tumor response or in duration
of clinical benefit.

+---------------------+-------------------+----------------------------+
| **Table 1. Study    |                   |                            |
| 025 Summary of      |                   |                            |
| Demographic         |                   |                            |
| Characteristics and |                   |                            |
| Efficacy Results**  |                   |                            |
+---------------------+-------------------+----------------------------+
| **\                 | **Femara^®^\      | **Tamoxifen\               |
| **                  | (N = 453), n      | (N = 454), n (%)**         |
|                     | (%)**             |                            |
+---------------------+-------------------+----------------------------+
| **Patient           |                   |                            |
| Demographics**      |                   |                            |
+---------------------+-------------------+----------------------------+
| > **Median Age,     | 65 (31 -- 96)     | 64 (31 -- 93)              |
| > years (range)**   |                   |                            |
+---------------------+-------------------+----------------------------+
| > **WHO Performance |                   |                            |
| > Status**          |                   |                            |
+---------------------+-------------------+----------------------------+
| **0**               | 253 (56)          | 264 (58)                   |
+---------------------+-------------------+----------------------------+
| **1**               | 170 (38)          | 150 (33)                   |
+---------------------+-------------------+----------------------------+
| **2**               | 30 (7)            | 39 (9)                     |
+---------------------+-------------------+----------------------------+
| > **Receptor        |                   |                            |
| > Status**          |                   |                            |
+---------------------+-------------------+----------------------------+
| > **ER and/or PgR   | 294 (64)          | 305 (67)                   |
| > positive**        |                   |                            |
+---------------------+-------------------+----------------------------+
| > **Both Unknown**  | 156 (35)          | 149 (33)                   |
+---------------------+-------------------+----------------------------+
| > **Disease Stage** | 25 (6)            | 32 (7)                     |
| >                   |                   |                            |
| > **III B**         | 422 (93)          | 419 (92)                   |
| >                   |                   |                            |
| > **Metastatic      |                   |                            |
| > disease**         |                   |                            |
+---------------------+-------------------+----------------------------+
| **Efficacy          |                   |                            |
| results**           |                   |                            |
+---------------------+-------------------+----------------------------+
| > **Median time to  | 9.4               | 6.0                        |
| > progression\*,    |                   |                            |
| > months**          |                   |                            |
+---------------------+-------------------+----------------------------+
|                     | *P* = .0001       |                            |
+---------------------+-------------------+----------------------------+
| > **Median time to  | 9.1               | 5.7                        |
| > treatment         |                   |                            |
| > failure\*,        |                   |                            |
| > months**          |                   |                            |
+---------------------+-------------------+----------------------------+
|                     | *P* = .0001       |                            |
+---------------------+-------------------+----------------------------+
| > **Confirmed       | 137 (30)          | 92 (20)                    |
| > response rate\*\* |                   |                            |
| > (CR + PR), %**    |                   |                            |
+---------------------+-------------------+----------------------------+
|                     | *P* = .0006       |                            |
+---------------------+-------------------+----------------------------+
| > **Clinical        | 221 (49)          | 173 (38)                   |
| > benefit rate\*\*  |                   |                            |
| > (CR + PR + SD ≥ 6 |                   |                            |
| > months), %**      |                   |                            |
+---------------------+-------------------+----------------------------+
|                     | *P* = .001        |                            |
+---------------------+-------------------+----------------------------+
| CI = Confidence     |                   |                            |
| interval; CR =      |                   |                            |
| Complete response;  |                   |                            |
| PR = Partial        |                   |                            |
| response; SD =      |                   |                            |
| Stable disease.     |                   |                            |
|                     |                   |                            |
| WHO = World Health  |                   |                            |
| Organization, ER =  |                   |                            |
| Estrogen receptor,  |                   |                            |
| PgR = Progesterone  |                   |                            |
| receptor            |                   |                            |
|                     |                   |                            |
| \* Cox regression   |                   |                            |
| analysis, \*\*      |                   |                            |
| Logistic regression |                   |                            |
| analysis            |                   |                            |
+---------------------+-------------------+----------------------------+

A full survival analysis was initially planned to be conducted at the
end of year 2001 at the time of completion of the supplementary
analysis. The protocol was subsequently amended to include two interim
analyses. The primary analysis indicated that Femara was superior to
tamoxifen in all main endpoints (ie, TTP, TTF, and rates of objective
response and clinical benefit). As became obvious, the
protocol-specified evaluation of the number of deaths in each treatment
arm differed from expectation, and it might be advisable to constitute a
group of experts to consider whether there were any issues that would
warrant a modification of the trial or analysis plan. In order to
maintain the integrity of the survival analysis, Novartis convened an
independent, external Data Monitoring Committee (DMC) under the
chairmanship of Dr. Thomas Fleming, University of Washington, Seattle.
The DMC recommended that a formal group sequential analysis plan be
implemented for overall survival with O'Brien-Fleming type boundaries
and Lan-DeMets alpha spending function to maintain an overall two-sided
significance level of *P* = .05 with a maximum of 3 looks at the data.
The results of the survival data at the time of the primary analysis
constitute the first interim look. The second look would be 6-9 months
later. These decisions were made prior to the DMC's learning the results
of the formal survival analysis. The recommendation of the DMC with
regard to the first interim analysis was that no results be disclosed.
The results of the second interim analysis may or may not be presented
at the ODAC meeting pending the recommendations of the DMC.

#### Safety

Discontinuations due to adverse events were reported in 2% of
Femara-treated patients and in 3% of tamoxifen-treated patients. The
nature and frequency of adverse events irrespective of study drug
relationship were similar for Femara-treated patients and
tamoxifen-treated patients. The most frequently reported adverse events
were bone pain, hot flashes, back pain, and nausea. Thromboembolic
events were reported in 6 (1%) patients in the Femara group and in 11
(2%) patients in the tamoxifen group. Pulmonary embolus was reported in
2 patients, 1 in each treatment group.

Overall, Femara was safe and very well tolerated.

####### 

####### **Supportive Study 024**

######## *Study Design*

Study 024 was a double-blind, double-dummy, randomized, multinational,
Phase II/III study comparing once-daily doses of Femara (2.5 mg) or
tamoxifen (20 mg) for 4 months prior to surgery in postmenopausal
patients with ER and/or PgR positive, stage II/III primary breast
cancer. Response rate (CR + PR) was the primary endpoint as assessed by
clinical palpation (the primary endpoint) and by ultrasound and
mammography. In addition, the rate of breast conserving surgery was to
be compared. In total, 337 patients were enrolled at 55 centers in 16
countries. The intent-to-treat population included 154 patients on
Femara and 170 on tamoxifen.

*Efficacy and Safety Results*

The important demographic characteristics and efficacy results of Study
024 are shown in Table 2.

+--------------------+---+------------------------+---+---------------------+---+---+
| #### **T           |   |                        |   |                     |   |   |
| able 2. Study 024  |   |                        |   |                     |   |   |
| Summary of Demogra |   |                        |   |                     |   |   |
| phic Characteristi |   |                        |   |                     |   |   |
| cs and Efficacy**  |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| ####               |   | ####                   |   |                     |   |   |
|                    |   |  **Patients, no. (%)** |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| #                  |   | **Femara^®^ (2.5 mg)\  |   | **Tamoxifen (20     |   |   |
|                    |   | (N =154)**             |   | mg)\                |   |   |
|                    |   |                        |   | (N =170)**          |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| ###                |   |                        |   |                     |   |   |
| # **Demographics** |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| #                  |   |                        |   |                     |   |   |
| ### **Age, years** |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > Median (range)   |   | 68 (44 - 91)           |   | 67 (48 - 89)        |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > **Receptor       |   |                        |   |                     |   |   |
| > status**         |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > ER+ and PgR+     |   | 90 (58)                |   | 91 (54)             |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > ER+ or PgR+      |   | 64 (42)                |   | 76 (45)             |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| ###                |   |                        |   |                     |   |   |
| ## **Tumor stage** |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > T2               |   | 77 (50)                |   | 91 (54)             |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > T3               |   | 42 (27)                |   | 31 (18)             |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > T4               |   | 35 (23)                |   | 48 (28)             |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| **Efficacy         |   |                        |   |                     |   |   |
| results\***        |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > **Clinical       | 8 |                        | 6 |                     |   |   |
| > response**       | 5 |                        | 1 |                     |   |   |
|                    | ( |                        | ( |                     |   |   |
|                    | 5 |                        | 3 |                     |   |   |
|                    | 5 |                        | 6 |                     |   |   |
|                    | ) |                        | ) |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
|                    | ( |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | P |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | \ |                        |   |                     |   |   |
|                    | < |                        |   |                     |   |   |
|                    | . |                        |   |                     |   |   |
|                    | 0 |                        |   |                     |   |   |
|                    | 0 |                        |   |                     |   |   |
|                    | 1 |                        |   |                     |   |   |
|                    | ) |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > **Ultrasound     | 5 |                        | 4 |                     |   |   |
| > response**       | 4 |                        | 3 |                     |   |   |
|                    | ( |                        | ( |                     |   |   |
|                    | 3 |                        | 2 |                     |   |   |
|                    | 5 |                        | 5 |                     |   |   |
|                    | ) |                        | ) |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
|                    | ( |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | P |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | = |                        |   |                     |   |   |
|                    | . |                        |   |                     |   |   |
|                    | 0 |                        |   |                     |   |   |
|                    | 4 |                        |   |                     |   |   |
|                    | 2 |                        |   |                     |   |   |
|                    | ) |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > **Mammographic   | 5 |                        | 2 |                     |   |   |
| > response**       | 3 |                        | 8 |                     |   |   |
|                    | ( |                        | ( |                     |   |   |
|                    | 3 |                        | 1 |                     |   |   |
|                    | 4 |                        | 7 |                     |   |   |
|                    | ) |                        | ) |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
|                    | ( |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | P |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | \ |                        |   |                     |   |   |
|                    | < |                        |   |                     |   |   |
|                    | . |                        |   |                     |   |   |
|                    | 0 |                        |   |                     |   |   |
|                    | 0 |                        |   |                     |   |   |
|                    | 1 |                        |   |                     |   |   |
|                    | ) |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| > *                | 6 |                        | 5 |                     |   |   |
| *Breast-conserving | 9 |                        | 9 |                     |   |   |
| > surgery**        | ( |                        | ( |                     |   |   |
|                    | 4 |                        | 3 |                     |   |   |
|                    | 5 |                        | 5 |                     |   |   |
|                    | ) |                        | ) |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
|                    | ( |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | P |                        |   |                     |   |   |
|                    | * |                        |   |                     |   |   |
|                    | = |                        |   |                     |   |   |
|                    | . |                        |   |                     |   |   |
|                    | 0 |                        |   |                     |   |   |
|                    | 2 |                        |   |                     |   |   |
|                    | 2 |                        |   |                     |   |   |
|                    | ) |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+
| ER = Estrogen      |   |                        |   |                     |   |   |
| receptor; PgR =    |   |                        |   |                     |   |   |
| Progesterone       |   |                        |   |                     |   |   |
| receptor.          |   |                        |   |                     |   |   |
|                    |   |                        |   |                     |   |   |
| \* Stratified      |   |                        |   |                     |   |   |
| Mantel Haenszel    |   |                        |   |                     |   |   |
| test               |   |                        |   |                     |   |   |
+--------------------+---+------------------------+---+---------------------+---+---+

Both treatment groups were well-balanced with regard to demographic and
baseline disease characteristics. The median age of the study population
was 67 years (range, 44-91 years). All but 3 patients were ER and/or PgR
receptor positive. Regardless of the method of evaluation, the response
rate was significantly higher in the Femara group compared with the
tamoxifen group. In addition, a significantly greater proportion of
patients treated with Femara were able to undergo breast-conserving
surgery. In Study 024, Femara was equally safe and well tolerated
compared with tamoxifen.

####### 

####### **Overall Conclusions**

The results of the pivotal Study 025 demonstrate that Femara is superior
to tamoxifen in time to progression, objective tumor response rate,
clinical benefit rate and time to treatment failure in first-line
therapy of postmenopausal women with advanced breast cancer. Study 024
confirmed the superiority of Femara compared with tamoxifen in overall
response rate as assessed by clinical palpation, ultrasound,
mammography, and rate of breast-conserving surgery in a selected group
of postmenopausal patients with primary hormone-sensitive breast cancer
in whom potential bias due to previous treatment with tamoxifen or other
therapies was eliminated. The safety results of both studies demonstrate
that Femara is equally well tolerated compared with tamoxifen and is
safe.

These data support our first-line study 025 results comparing Femara to
tamoxifen and further demonstrate that treatment with Femara is
associated with:

-   Significantly longer time to progression

-   Significantly higher objective tumor response rate

-   Significantly higher clinical benefit rate

-   Significantly longer time to treatment failure

-   Consistently superior results in all subgroup analyses

Given the consistently superior results demonstrated in these trials,
Novartis is seeking expanded label indication *for first-line therapy in
postmenopausal women with advanced breast cancer*.

**Table of Contents**

+--------------------------------------------------------------+---+-----+
|                                                              | # |     |
|                                                              | # |     |
|                                                              | # |     |
|                                                              | # |     |
|                                                              |   |     |
|                                                              | * |     |
|                                                              | * |     |
|                                                              | S |     |
|                                                              | e |     |
|                                                              | c |     |
|                                                              | t |     |
|                                                              | i |     |
|                                                              | o |     |
|                                                              | n |     |
|                                                              | * |     |
|                                                              | * |     |
+--------------------------------------------------------------+---+-----+
| BACKGROUND                                                   |   | 1.0 |
+--------------------------------------------------------------+---+-----+
| Existing Therapies for Postmenopausal Women With Advanced    |   | 1.1 |
| Breast Cancer                                                |   |     |
+--------------------------------------------------------------+---+-----+
| Overview of Femara^®^                                        |   | 1.2 |
+--------------------------------------------------------------+---+-----+
| Pharmacology                                                 |   | 1.  |
|                                                              |   | 2.1 |
+--------------------------------------------------------------+---+-----+
| Human Pharmacokinetics and Metabolism                        |   | 1.  |
|                                                              |   | 2.2 |
+--------------------------------------------------------------+---+-----+
| Efficacy and Safety of Femara^®^ in Second-Line Therapy      |   | 1.3 |
+--------------------------------------------------------------+---+-----+
| Efficacy                                                     |   | 1.  |
|                                                              |   | 3.1 |
+--------------------------------------------------------------+---+-----+
| Safety Profile                                               |   | 1.  |
|                                                              |   | 3.2 |
+--------------------------------------------------------------+---+-----+
| PHASE II/III TRIALS                                          |   | 2.0 |
+--------------------------------------------------------------+---+-----+
| Phase II Trials of Femara^®^ in First-Line Therapy           |   | 2.1 |
+--------------------------------------------------------------+---+-----+
| Randomized Phase II Trial (Study 012)                        |   | 2.  |
|                                                              |   | 1.1 |
+--------------------------------------------------------------+---+-----+
| Study Design                                                 |   | A   |
+--------------------------------------------------------------+---+-----+
| Results                                                      |   | B   |
+--------------------------------------------------------------+---+-----+
| Randomized Phase II Trial (Study 026)                        |   | 2.  |
|                                                              |   | 1.2 |
+--------------------------------------------------------------+---+-----+
| PIVOTAL PHASE III STUDY 025                                  |   | 3.0 |
+--------------------------------------------------------------+---+-----+
| Study Design                                                 |   | 3.1 |
+--------------------------------------------------------------+---+-----+
| Entry Criteria                                               |   | 3.  |
|                                                              |   | 1.1 |
+--------------------------------------------------------------+---+-----+
| Randomization Procedures: Treatment Assignment and Blinding  |   | 3.  |
|                                                              |   | 1.2 |
+--------------------------------------------------------------+---+-----+
| Treatment Administration: Study Drug                         |   | 3.  |
|                                                              |   | 1.3 |
+--------------------------------------------------------------+---+-----+
| Types and Timing of Assessments                              |   | 3.  |
|                                                              |   | 1.4 |
+--------------------------------------------------------------+---+-----+
| Efficacy Assessments                                         |   | A   |
+--------------------------------------------------------------+---+-----+
| Safety Assessments                                           |   | B   |
+--------------------------------------------------------------+---+-----+
| Statistical Analysis                                         |   | 3.  |
|                                                              |   | 1.5 |
+--------------------------------------------------------------+---+-----+
| Endpoints                                                    |   | A   |
+--------------------------------------------------------------+---+-----+
| Core and Extension Phase                                     |   | B   |
+--------------------------------------------------------------+---+-----+
| Survival Analyses                                            |   | C   |
+--------------------------------------------------------------+---+-----+
| Populations                                                  |   | D   |
+--------------------------------------------------------------+---+-----+
| Sample Size and Power Considerations                         |   | 3.  |
|                                                              |   | 1.6 |
+--------------------------------------------------------------+---+-----+
| Patient Enrollment                                           |   | 3.  |
|                                                              |   | 1.7 |
+--------------------------------------------------------------+---+-----+
| Patient Characteristics                                      |   | 3.  |
|                                                              |   | 1.8 |
+--------------------------------------------------------------+---+-----+
| Baseline and Disease Characteristics in US Patients          |   | A   |
+--------------------------------------------------------------+---+-----+
| Baseline Laboratory Criteria (CTC Grade ≥ 1)                 |   | B   |
+--------------------------------------------------------------+---+-----+
| Efficacy                                                     |   | 3.2 |
+--------------------------------------------------------------+---+-----+
| Time to Progression                                          |   | 3.  |
|                                                              |   | 2.1 |
+--------------------------------------------------------------+---+-----+
| Supportive Analysis                                          |   | A   |
+--------------------------------------------------------------+---+-----+
| Overall Tumor Response                                       |   | 3.  |
|                                                              |   | 2.2 |
+--------------------------------------------------------------+---+-----+
| Supportive Analysis                                          |   | A   |
+--------------------------------------------------------------+---+-----+
| Exploratory Analysis                                         |   | B   |
+--------------------------------------------------------------+---+-----+
| Number of Deaths                                             |   | 3.  |
|                                                              |   | 2.3 |
+--------------------------------------------------------------+---+-----+
| Other Analyses                                               |   | 3.  |
|                                                              |   | 2.4 |
+--------------------------------------------------------------+---+-----+
| Time to Worsening Performance Status                         |   | A   |
+--------------------------------------------------------------+---+-----+
| Summary                                                      |   | 3.  |
|                                                              |   | 2.5 |
+--------------------------------------------------------------+---+-----+
| SUPPORTIVE PHASE IIB/III STUDY 024                           |   | 4.0 |
+--------------------------------------------------------------+---+-----+
| Study Design                                                 |   | 4.1 |
+--------------------------------------------------------------+---+-----+
| Entry Criteria                                               |   | 4.  |
|                                                              |   | 1.1 |
+--------------------------------------------------------------+---+-----+
| Randomization Procedures                                     |   | 4.  |
|                                                              |   | 1.2 |
+--------------------------------------------------------------+---+-----+
| Treatment Administration                                     |   | 4.  |
|                                                              |   | 1.3 |
+--------------------------------------------------------------+---+-----+
| Study Endpoints                                              |   | 4.  |
|                                                              |   | 1.4 |
+--------------------------------------------------------------+---+-----+
| Efficacy Assessments                                         |   | A   |
+--------------------------------------------------------------+---+-----+
| Safety Assessments                                           |   | B   |
+--------------------------------------------------------------+---+-----+
| Statistical Analysis                                         |   | 4.  |
|                                                              |   | 1.5 |
+--------------------------------------------------------------+---+-----+
| Primary Endpoint                                             |   | A   |
+--------------------------------------------------------------+---+-----+
| Secondary Endpoints                                          |   | B   |
+--------------------------------------------------------------+---+-----+
| Sample Size and Power Considerations                         |   | 4.  |
|                                                              |   | 1.6 |
+--------------------------------------------------------------+---+-----+
| Patient Demographics                                         |   | 4.2 |
+--------------------------------------------------------------+---+-----+
| Patient Enrollment                                           |   | 4.  |
|                                                              |   | 2.1 |
+--------------------------------------------------------------+---+-----+
| Patient Characteristics                                      |   | 4.  |
|                                                              |   | 2.2 |
+--------------------------------------------------------------+---+-----+
| Efficacy                                                     |   | 4.3 |
+--------------------------------------------------------------+---+-----+
| Summary of Results                                           |   | 4.  |
|                                                              |   | 3.1 |
+--------------------------------------------------------------+---+-----+

  ---------------------------------------------------------------- ------
  SAFETY IN PHASE III STUDIES                                      5.0

  Study 025 Safety Results                                         5.1

  Study 024 Safety Results                                         5.2

  BENEFIT/RISK ASSESSMENT                                          6.0

  OVERALL CONCLUSIONS                                              7.0

  REFERENCES                                                       8.0

  ATTACHMENT: COMPOSITION OF DATA MONITORING COMMITTEE (DMC)       

  ATTACHMENT: CURRENT FEMARA APPROVED LABELING                     
  ---------------------------------------------------------------- ------

**List of Tables**

+--------+-----------------------------------------------------+---+-----+
|        |                                                     | # |     |
|        |                                                     | # |     |
|        |                                                     | # |     |
|        |                                                     | # |     |
|        |                                                     |   |     |
|        |                                                     | * |     |
|        |                                                     | * |     |
|        |                                                     | S |     |
|        |                                                     | e |     |
|        |                                                     | c |     |
|        |                                                     | t |     |
|        |                                                     | i |     |
|        |                                                     | o |     |
|        |                                                     | n |     |
|        |                                                     | * |     |
|        |                                                     | * |     |
+--------+-----------------------------------------------------+---+-----+
| Table  | Study 025 Summary of Demographic Characteristics    |   | Ex  |
| 1.     | and Efficacy Results (Intent-to-Treat Population)   |   | ec. |
+--------+-----------------------------------------------------+---+-----+
| Table  | Study 024 Summary of Demographic Characteristics    |   | Ex  |
| 2.     | and Efficacy Results (Intent-to-Treat Population)   |   | ec. |
+--------+-----------------------------------------------------+---+-----+
| Table  | Patient Demographic and Disease Characteristics by  |   | 3.  |
| 3.     | Treatment Group                                     |   | 1.8 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Baseline and Disease Characteristics (US and        |   | 3.  |
| 4.     | Canadian Patients)                                  |   | 1.8 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Baseline Laboratory Criteria (CTC Grade ≥ 1)        |   | 3.  |
| 5.     |                                                     |   | 1.8 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Study 025 Summary of Efficacy Results               |   | 3.  |
| 6.     | (Intent-to-Treat Population)                        |   | 2.1 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Stratified Analysis of TTP by Baseline Covariates   |   | 3.  |
| 7.     | (Supportive Analysis)                               |   | 2.1 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Stratified Analysis of TTP by Baseline Covariates   |   | 3.  |
| 8.     | (Exploratory Analysis)                              |   | 2.1 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Stratified Analysis of Objective Overall Tumor      |   | 3.  |
| 9.     | Response by Baseline Covariates (Supportive         |   | 2.2 |
|        | Analysis)                                           |   |     |
+--------+-----------------------------------------------------+---+-----+
| Table  | Stratified Analysis of Objective Overall Tumor      |   | 3.  |
| 10.    | Response by Baseline Covariates (Exploratory        |   | 2.2 |
|        | Analysis)                                           |   |     |
+--------+-----------------------------------------------------+---+-----+
| Table  | Patient Demographic and Disease Characteristics by  |   | 4.  |
| 11.    | Treatment Group                                     |   | 2.2 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Summary of Responses                                |   | 4.  |
| 12.    |                                                     |   | 3.1 |
+--------+-----------------------------------------------------+---+-----+
| Table  | Number of Patients With Most Frequent Adverse       |   | 5.1 |
| 13.    | Events Regardless of Study Drug Relationship (≥ 10% |   |     |
|        | in Either Group) by Preferred Term                  |   |     |
+--------+-----------------------------------------------------+---+-----+

**List of Figures**

+--------+-----------------------------------------------------+---+-----+
|        |                                                     | # |     |
|        |                                                     | # |     |
|        |                                                     | # |     |
|        |                                                     | # |     |
|        |                                                     |   |     |
|        |                                                     | * |     |
|        |                                                     | * |     |
|        |                                                     | S |     |
|        |                                                     | e |     |
|        |                                                     | c |     |
|        |                                                     | t |     |
|        |                                                     | i |     |
|        |                                                     | o |     |
|        |                                                     | n |     |
|        |                                                     | * |     |
|        |                                                     | * |     |
+--------+-----------------------------------------------------+---+-----+
| Figure | Molecular structure of Femara                       |   | 1.2 |
| 1.     |                                                     |   |     |
+--------+-----------------------------------------------------+---+-----+
| Figure | Kaplan-Meier estimate of time to progression        |   | 3.  |
| 2.     |                                                     |   | 2.1 |
+--------+-----------------------------------------------------+---+-----+
| Figure | Hazard ratios and 95% confidence intervals for time |   | 3.  |
| 3.     | to progression within strata for each baseline      |   | 2.1 |
|        | covariate                                           |   |     |
+--------+-----------------------------------------------------+---+-----+
| Figure | # Exploratory                                       |   | 3.  |
| 4.     |  analysis of time to progression by geographic area |   | 2.1 |
+--------+-----------------------------------------------------+---+-----+
| Figure | Kaplan-Meier estimates of duration of overall tumor |   | 3.  |
| 5.     | response and duration of clinical benefit           |   | 2.2 |
+--------+-----------------------------------------------------+---+-----+
| Figure | Odds ratios and 95% confidence intervals for        |   | 3.  |
| 6.     | objective response within strata for each baseline  |   | 2.2 |
|        | covariate                                           |   |     |
+--------+-----------------------------------------------------+---+-----+

**Glossary of Abbreviations and Definition of Terms**

  ----------------- -----------------------------------------------------
  AE                Adverse event

  AUC               Area under the curve

  BID               Twice daily

  CI                Confidence interval

  CNS               Central nervous system

  COSTART           Coding symbols for a thesaurus of adverse reaction
                    terms

  CR                Complete response

  CRF               Case report form

  CT                Computed tomography

  CTC               Common Toxicity Criteria

  DMC               Data Monitoring Committee

  ECG               Electrocardiogram

  ER                Estrogen receptor

  FDA               US Food and Drug Administration

  FPFV              First patient, first visit

  FSH               Follicle-stimulating hormone

  GCP               Good Clinical Practice

  HIV               Human immunodeficiency virus

  HRT               Hormone replacement therapy

  IU                International Units

  ITT               Intent to treat

  K~i~              Inhibitory constant

  KPS               Karnofsky performance status

  LH                Luteinizing hormone

  NA                Not applicable

  NA/NE             Not assessable/not evaluable

  NCI               National Cancer Institute

  NDA               New Drug Application

  NOS               Not otherwise specified

  NSAIDs            Nonsteroidal anti-inflammatory drugs

  ODAC              Oncologic Drugs Advisory Committee

  ORR               Objective response rate

  PD                Progression of disease

  PK                Pharmacokinetics

  PgR               Progesterone receptor

  PR                Partial response

  SAE               Serious adverse events

  SAERS             Serious Adverse Event Reporting System

  SD                Stable disease

  TTF               Time to treatment failure

  TTP               Time to tumor progression

  TTR               Time to response

  TSH               Thyroid-stimulating hormone

  UICC              International Union Against Cancer

  US                United States

  WHO               World Health Organization

                    
  ----------------- -----------------------------------------------------

**1.0 Background**

**1.1 Existing Therapies for Postmenopausal Women With Advanced Breast
Cancer**

Breast cancer is an estrogen-dependent tumor and, therefore, inhibition
of estrogen action or production provides an effective therapy for
patients with hormone-dependent breast cancer.^6,7^ In postmenopausal
women, the major source of estrogens is from the conversion of adrenal
androgens to estrogens by the aromatase enzyme present in peripheral
tissues (eg, adipose tissue). Selective aromatase inhibition results in
suppression of estrogen production without influencing adrenal
steroidogenesis. This deprives the tumor cells of their growth stimulus.
Another approach that deprives tumor cells of their growth stimulus is
to block the ER with an antiestrogen (eg, tamoxifen). The goals of
hormonal therapy are to induce tumor regression or stabilization, delay
progression, and prolong survival, with minimal impact on the patient's
quality of life.

Approximately 60 - 75% of postmenopausal women with breast cancer will
be ER positive, with ER status highly dependent on age.^7,8^ It has been
hypothesized that similar percentages of postmenopausal women with
unknown hormone receptor status would be ER and/or PgR positive.
Currently, tamoxifen is the standard of care as first-line therapy in
postmenopausal women with endocrine sensitive advanced breast cancer.
Although this agent is generally well tolerated, its adverse effects
(eg, increased incidence of endometrial cancer) are related to its
estrogenic effects in certain tissues. The use of tamoxifen has also
been reported to increase the incidence of uterine carcinoma and
thromboembolic events. Although these events occur infrequently, they
are of important clinical consequence to the patient. Thus, there is a
need for more well-tolerated alternative hormonal therapies for
postmenopausal women with advanced breast cancer.

**1.2 Overview of Femara^®^**

Femara tablets for oral administration contain 2.5 mg of letrozole, a
nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It
is chemically described as 4,4\'-(1H-1,2,4-Triazol-1-ylmethylene)
dibenzonitrile, and its structural formula is shown in Figure 1.

![](media/image2.png)

#### 

**Figure 1.---**Molecular structure of Femara.

#### **1.2.1 Pharmacology**

Letrozole is a potent and selective inhibitor of estrogen biosynthesis.
It is a nonsteroidal inhibitor of the aromatase enzyme system that
inhibits the conversion of androgens to estrogens by competitively
binding to the heme of the cytochrome P450 subunit of the enzyme.

Pharmacodynamic in vitro studies demonstrated that letrozole
competitively inhibits the human placental microsomal aromatase enzyme
and is about 150- to 250-fold more potent than aminoglutethimide.^9,10^
Similarly, letrozole was approximately 650 times more potent than
aminoglutethimide in inhibiting estrogen production and, unlike
aminoglutethimide, letrozole did not inhibit adrenal steroidogenesis in
vitro.^11,12^ In vivo studies have also demonstrated that letrozole is
\> 10,000-fold more potent than aminoglutethimide with respect to
inhibition of aromatase enzyme activity.^9-11^ In adult female animals,
letrozole is as effective as ovariectomy in reducing uterine weight,
elevating serum luteinizing hormone (LH) level, and causing the
regression of estrogen-dependent tumors. In contrast with ovariectomy,
treatment with letrozole does not lead to an increase in serum
follicle-stimulating hormone (FSH) level. letrozole selectively inhibits
gonadal steroidogenesis but has no significant effect on adrenal
mineralocorticoid or glucocorticoid synthesis. In a model that is more
appropriate to human breast cancer, the effects of long-term
administration of letrozole on spontaneously occurring rat mammary
tumors was examined. In this long-term study, 2 years of letrozole
treatment completely blocked the spontaneous appearance of both benign
and malignant mammary tumors. Furthermore, treatment of aromatase
transgenic mice with letrozole (5 µg/day) resulted in complete reduction
or disappearance of breast hyperplasia and other preneoplastic and
neoplastic changes that were induced as a consequence of the
overexpression of aromatase in the mammary gland.

In humans, the activity of letrozole has been demonstrated by measuring
the suppression of circulating estrogen (estrone and estradiol) levels
in healthy volunteers and patients with breast cancer, as well as by
assessing the inhibition of in vivo aromatization of radiolabeled
androstenedione into estrone. Other hormones, including cortisol,
aldosterone, testosterone, androstenedione, 17-α-OH-progesterone, LH,
FSH, TSH, or renin, were not affected to any clinically significant
level by treatment with letrozole. In postmenopausal women with
metastatic breast cancer, letrozole suppressed estrone and estrone
sulfate levels significantly better than anastrozole.^13^

Supply of estrogens to the tumor is, however, not only from the
circulation, but also from biosynthesis within the tumor. Letrozole has
been shown not only to substantially reduce intratumoral aromatization,
but also the total estrogen burden of the tumors through inhibition of
peripheral estrogen synthesis.^14^

The results of these pharmacodynamic studies demonstrated that letrozole
is a very potent and highly selective inhibitor of aromatase in both in
vitro and in vivo experimental models and in humans.

## *1.2.2 Human Pharmacokinetics and Metabolism* 

Letrozole is rapidly absorbed and completely bioavailable after oral
administration, and food has no effect on the bioavailability.^15,16^
The plasma PK profile of letrozole in humans is characterized by a
dominant terminal elimination phase, with a half-life of approximately 2
days in healthy volunteers. The clearance of letrozole is mainly via
metabolism to its major carbinol metabolite, CGP44645, which has no
pharmacologic activity. Renal clearance of the parent compound
represents only approximately 5% of total clearance. The glucuronidated
carbinol metabolite is excreted by the kidneys. Approximately 60% of
letrozole is bound to plasma proteins, mainly to albumin.^17^

In vitro experiments suggested that the cytochrome P450 isoenzymes 3A4
and 2A6 (CYP3A4, CYP2A6) mediate the metabolic clearance of
letrozole.^18^ The affinity of CYP3A4 for letrozole appears to be low,
and saturation of the enzyme could not be achieved at concentrations far
exceeding physiologic levels. The affinity of CYP2A6 for letrozole could
not be well defined, but the experiments suggested that it is high, and
saturation may occur in the low micromolar range. Letrozole was also
shown to be a very strong inhibitor of CYP2A6, with a K~i~ = 0.12 µM.
This suggested that the PK of letrozole might show some nonlinearity due
to autoinhibition/saturation of CYP2A6.

In clinical studies, slight deviations from linearity were observed at
steady state. Systemic exposure increased proportionally to doses up to
1 mg/day, but steady-state plasma concentrations were higher than
predicted at doses ≥ 2.5 mg/day, although patients achieved steady state
at all doses. At a dose of 10 mg/day plasma levels increased
approximately proportionally to those observed at 5 mg/day, indicating
no further or only minimal deviation from linearity between these 2
doses. Thus, nonlinearity appears to be observed in the dose range of
2.5 to 5 mg/day. This is consistent with the hypothesis that
nonlinearity in the PK of letrozole is a result of partial inhibition of
its metabolic clearance due to an autoinhibition/saturation of CYP2A6,
whereas clearance may be dose-independent (although lower) at higher
doses and at concentrations at which CYP3A4 becomes the dominant
metabolizing enzyme.

No dose adjustment is needed in elderly patients or in patients with
renal creatine clearance ≥ 10 mL/min or moderate hepatic insufficiency,
because the PK of letrozole was not markedly changed in these
populations. Patients with severe hepatic impairment (Child-Pugh score
C) are expected to be exposed to considerably higher levels of
letrozole, corresponding to a daily dose of about 5 mg. However, given
that normal patients who received daily doses of\
5 or 10 mg/day did not show an increased toxicity compared with normal
patients who received 2.5 mg/day, no dose adjustment is warranted in
patients with severe hepatic dysfunction, although such patients should
be kept under close supervision and carefully monitored for adverse
events. Prolonged exposure to letrozole in patients with significant
liver damage, as indicated by markedly elevated transaminases,
bilirubin, or alkaline phosphatase (grade 3 or 4 according to NCI common
toxicity criteria), showed mean plasma letrozole levels within the
normal range. Thus, no dose adjustment is needed for breast cancer
patients with evidence of liver damage.

Letrozole showed no interaction with warfarin or cimetidine, and a
review of the data from the phase III trials, as well as in vitro
studies of cytochrome P450 enzymes, indicated that letrozole has a low
potential for drug interactions. However, concomitant administration of
letrozole (2.5 mg/day) and tamoxifen (20 mg/day) resulted in decreased
steady-state levels of letrozole; the AUC was reduced by 38% on
average.^5^ The mechanism of this interaction is not known, but
induction of CYP3A4 by tamoxifen was considered to be a likely
explanation. The clinical relevance of this finding has not been
investigated. Letrozole appears to have no effect on plasma levels of
tamoxifen in combination therapy.^19^

## 

**1.3 Efficacy and Safety of Femara^®^ in Second-Line Therapy**

Two large, randomized, controlled, multinational clinical trials were
the basis of approval of Femara by the US FDA in 1997 in the treatment
of advanced breast cancer in postmenopausal women with disease
progression following antiestrogen therapy.^1-3^ In the first trial,
patients were randomized to Femara (0.5 or 2.5 mg daily) versus
megestrol acetate (160 mg daily); in the second trial, patients were
randomized to Femara (0.5 or 2.5 mg daily) versus aminoglutethimide (250
mg bid) with corticosteroid supplementation. In each trial \> 60% of the
patients had received therapeutic antiestrogens, and approximately 20%
of patients had an objective tumor response. The megestrol
acetate-controlled trial was double-blind; the
aminoglutethimide-controlled trial was open-label. Objective tumor
response was the primary endpoint of both trials.

***1.3.1 Efficacy***

In the first trial comparing Femara with megestrol acetate (N = 552),
2.5 mg Femara produced a 24% objective response rate compared with 16%
in the megestrol acetate group (odds ratio = 1.58; 95% CI = 0.94 to
2.66; *P* = .08).^1^ With a minimum follow-up of 15 months, the risk of
progression was significantly reduced in patients treated with 2.5 mg
Femara compared with megestrol acetate (hazard ratio = 0.77, 95% CI =
0.60 to 0.98; *P* = .03).

In the trial comparing Femara with aminoglutethimide (N = 557), 2.5 mg
Femara produced an 18% objective response rate compared with 12% in the
aminoglutethimide group (odds ratio = 1.61; 95% CI = 0.90 to 2.87; *P*
=*0.11*).^3^ With a minimum follow-up of 9 months, Femara (2.5 mg)
demonstrated a statistically significant reduction in the risk of
progression compared with aminoglutethimide (hazard ratio = 0.74; 95% CI
= 0.57 to 0.94; *P* = .02). Overall survival was statistically
significantly improved compared with aminoglutethimide, with a reduction
of approximately 30% in the risk of death with Femara (hazard ratio =
0.69; 95% CI = 0.53 to 0.91; *P* \< .05).^1^

***1.3.2 Safety Profile***

Femara was safe and well tolerated in both of these trials and was
better tolerated than either megestrol acetate or aminoglutethimide. The
most commonly reported adverse events irrespective of study drug
relationship in patients treated with 2.5 mg Femara were musculoskeletal
pain (includes musculoskeletal pain, skeletal pain, back pain, arm pain,
and leg pain) (21%), nausea (13%), headache (9%), arthralgia (8%),
fatigue (8%), vomiting (7%), and dyspnea (7%). No adverse event appeared
to be dose related. There were fewer thromboembolic events at both
Femara doses than on the megestrol acetate arm (\<1% vs. 5%). There was
also less vaginal bleeding (0.3% vs. 3%) on Femara than on megestrol
acetate. In addition, patients treated with megestrol acetate had a
higher incidence of weight gain, 9% vs. 2% Femara and dyspnea 16% vs. 7%
Femara.

**2.0 PhASE ii/iii TRIALS (First-Line)**

Generic tamoxifen (Tamofen^®^, Leiras OY, Finland) was used as the
comparator in the international studies 026, 025 and 024. Because this
generic tamoxifen is not commercially available in the United States, a
bioequivalence study was conducted, to determine if the generic
tamoxifen approved and marketed in Europe had equivalent biologic
activity to Nolvadex^®^ available in the United States. The results
confirmed the bioequivalence and equivalent pharmacokinetics of generic
tamoxifen and Nolvadex.

**2.1 Phase II Trials of Femara^®^ in First-Line Therapy**

***2.1.1 Randomized Phase II Trial (Study 012)***

**A. Study Design**

A phase II, randomized, double-blind, 3-arm study was conducted to
determine the antitumor effects of Femara at doses of 0.5 and 2.5 mg
daily compared with tamoxifen (30 mg daily) in the first-line treatment
of postmenopausal women with advanced breast cancer. This pilot study
was initiated before the second-line studies were completed and was
discontinued early because of the worldwide approval of Femara at the
2.5 mg dose. A total of 75 patients was planned, but accrual was stopped
after 32 patients had been enrolled. Ten patients were randomly assigned
Femara (0.5 mg), 12 Femara (2.5 mg), and 10 tamoxifen (30 mg). Patients
were treated until disease progression or withdrawal from the study for
other reasons. The efficacy data for the Femara groups were pooled for
analysis.

**B. Results**

The overall response rate (CR + PR) was 55% (12/22) for Femara and 20%
(2/10) for tamoxifen. Complete response was observed in 3 (14%) patients
treated on Femara and in none on tamoxifen; clinical benefit rate (CR +
PR + SD ≥ 6 months) was 68% (15/22) on Femara and 30% (3/10) on
tamoxifen. The median TTP was 17 months (95% CI = 6 to 30 months) on
Femara and 3 months on tamoxifen (95% CI = 3 to 18 months). The
responses were demonstrated at both 0.5 mg and 2.5 mg. The duration of
objective tumor response (CR + PR) ranged from 10 to 37+ months in the
Femara group. In the tamoxifen group, the duration of response in the 2
patients with PR was 18 months and 34+ months. Reported adverse events
were consistent with the known toxicity profiles associated with Femara
and tamoxifen. Although the study was stopped prematurely and the
numbers of patients are too small to be conclusive, the efficacy results
(time to progression, overall objective tumor response, duration of
treatment, and patient population) are consistent with the pivotal Study
025.

#### **2.1.2 Randomized Phase II Trial (Study 026)**

A randomized, open-label, phase II trial was conducted to compare the
efficacy of\
2.5 mg Femara daily with the combination of 2.5 mg Femara plus 20 mg
tamoxifen daily. This trial was discontinued after enrolling only 18
patients because preliminary data from a pharmacokinetic study indicated
that adding tamoxifen to Femara reduced Femara blood levels (AUC) by 38%
on average.^5^ The objectives of this study were primarily for safety
and no efficacy data were analyzed. Reported adverse events were
consistent with the known safety profile associated with Femara.

**3.0 Pivotal Phase III Study 025**

**3.1 Study Design**

Pivotal Study 025 was a double-blind, double-dummy, randomized,
multinational, phase III trial comparing Femara (2.5 mg) versus
tamoxifen (20 mg) daily as first-line therapy in postmenopausal women
with locally advanced or metastatic breast cancer. The original protocol
was designed as a comparison of 3 groups: 2.5 mg Femara, 20 mg
tamoxifen, and the combination of 2.5 mg Femara plus 20 mg tamoxifen;
however, preliminary data from a pharmacokinetic study^5^ indicated that
adding tamoxifen to Femara reduced Femara blood levels (AUC) by 38% on
average. Therefore, the study was amended to drop the combination group
and the sample size considerations were based on demonstration of
superiority of one treatment over the other for time to progression. All
efficacy and safety analyses were based on the 2 monotherapy groups and
these results are presented.

Initial study treatment was administered until progression of disease or
until some other reason necessitated discontinuation from the initial
treatment. If at progression the patient remained suitable for further
endocrine treatment, she could be switched to the alternative treatment
(ie, crossover) still under double-blind conditions or if not suitable,
could discontinue treatment. Patients were followed for overall survival
at discontinuation of study treatment(s) and every 6 months thereafter.

The dose of 2.5 mg of Femara once daily is the approved dose for
treatment of advanced breast cancer in postmenopausal patients with
disease progression following antiestrogen therapy. A daily dose of
Femara 2.5 mg was therefore selected for the current study as first-line
treatment of patients with advanced breast cancer. Manufacturer\'s
recommendations for tamoxifen in the treatment of patients with advanced
breast cancer refer to a daily dose of 20 to 40 mg of tamoxifen. The 20
mg dose of tamoxifen is commonly employed in clinical practice in the
United States and Europe, and was therefore chosen as the comparator in
this study.

***3.1.1 Entry Criteria***

Postmenopausal women with histologically or cytologically confirmed
stage IIIB locally advanced or locoregional recurrence not amenable to
treatment by surgery or radiotherapy, or with metastatic breast cancer,
met the eligibility criteria for entry into this study. Eligible
patients had either ER and/or PgR positive tumors or with both receptors
unknown; Karnofsky Performance Status of ≥ 50; and measurable or
evaluable disease. However patients with only blastic bone lesions were
allowed and these lesions were considered as nonevaluable lesions.
Patients previously treated for metastatic disease (only one previous
regimen of chemotherapy) were to have objective evidence of progression
and no prior systemic endocrine treatment for metastatic disease was
allowed. Patients with CNS metastases, or diffuse involvement of the
lung and liver or inflammatory breast cancer, were not eligible.
Patients with a recurrence of breast cancer on adjuvant tamoxifen
therapy or recurrence within 12 months of completing adjuvant tamoxifen
therapy were also ineligible. Concomitant bisphosphonate treatment was
permitted at randomization for the treatment of bone metastases only.

***3.1.2 Randomization Procedures: Treatment Assignment and Blinding***

The two treatments were randomly assigned according to a predetermined,
computer-generated randomization list using permuted blocks of a fixed
size. The double-dummy technique was used to ensure that study
treatments were blinded. The treatments were unblinded for the
preparation of the Clinical Study Report and regulatory submissions when
statistical analysis of the core phase was performed, although
investigators and patients remained blinded. Emergency code breaks
occurred in 16 patients (11 on Femara**,** 5 on tamoxifen). These were
not due to real emergencies, but to determine further treatment of the
patients after termination. No true emergency code breaks occurred in
this study. There was no stratification for any demographic variables;
however, randomization and packaging were stratified according to
linguistic group. Investigators were instructed to take the next lowest
number pack available for each subsequent patient enrolled.

***3.1.3 Treatment Administration: Study Drug***

Study drug was dispensed by center. Femara was provided as 2.5 mg
film-coated tablets for daily oral administration. Tamoxifen was
provided as 20 mg tablets for daily oral administration. Patients
failing first-line treatment with tamoxifen switched to blinded
treatment with Femara and vice versa. Supply of either core or crossover
study medication was continued as long as a patient was responding (CR,
PR, or SD) to treatment. A double-dummy technique was used to ensure
blinding.

***3.1.4 Types and Timing of Assessments***

### A. Efficacy Assessments

**Tumor measurement and response.---**Evaluations of tumor response were
performed according to UICC criteria 3 months after the start of
treatment and every 3 months thereafter, or when the patient
discontinued treatment, with modifications to include liver, lung, or
soft tissue lesions of a minimal size and all involved sites rather than
a representative indicator lesion. An external peer review on all tumor
imaging was to be performed to determine response and the date and site
of progression for the core phase of the study. Experience from
Novartis' second-line studies showed no important difference in the
overall conclusions when external peer review assessments were compared
to the assessments by investigators. Therefore, the first-line protocol
was amended to replace the external peer review with a blinded internal
review of all patients' data by a committee of Novartis personnel.
Overall tumor response and in particular, progression of disease, were
reviewed internally against the investigator's reported response.
Discrepancies were resolved with the investigator.

In each institution all images of all patients were to be reviewed by
the same professional ("center-specific radiologist"). Depending on the
institution, the "central radiologist" could have been one person or
several specialists each assigned to a specific technique (eg,
ultrasound, CT scan, nuclear medicine scan). The purpose of the central
radiologist's review was to allow uniformity in the assessment of tumor
response.

### B. Safety Assessments 

Safety assessments consisted of monitoring and recording all adverse
events and serious adverse events (with their severity classified
according to the NCI Common Toxicity Criteria (Version 1.3) and
relationship to study drug), the regular monitoring of hematology and
blood chemistry, and the performance of physical examinations.
Hematologic and blood chemistry tests including hemoglobin, hematocrit,
and liver and kidney function were performed.

***3.1.5 Statistical Analysis***

**A. Endpoints**

The primary efficacy endpoint was time to progression. Additional
efficacy variables included overall objective tumor response rate (CR +
PR), duration of overall objective tumor response, clinical benefit rate
(CR + PR + SD ≥ 6 months), duration of clinical benefit, time to
treatment failure, number of deaths, and overall survival. Safety was
characterized in terms of the incidence of adverse events, laboratory
abnormalities, discontinuations due to adverse events, and deaths.

**B. Core and Extension Phase**

The core phase was defined as the interval from first patient
randomization until 632 patients had reached the primary endpoint of
progressive disease. The crossover (second-line) treatment period of a
patient was defined as the time at which a patient was switched to
crossover treatment until further progression of disease or until
discontinuation for any other reason, whichever occurred earlier. The
extension phase was defined as the interval from the end of the core
phase until approximately 18 months later, or sooner if all patients
discontinued second-line study treatment (ie, crossover treatment)
earlier for any reason. It is expected that at this time point the
majority of patients on crossover treatment will have progressed and
that approximately 72% of patients will have died.

The results of the core phase (ie, first-line treatment, primary
analysis) are presented here. A supplementary analysis is planned at the
time of analysis of the extension phase to report cross-over data and to
conduct the final analysis of overall survival (time to death).

**Primary analysis.---**Time to progression and time to treatment
failure were analyzed by Cox regression (proportional hazards model)
estimating the hazard ratio of the risk of progression with Femara
compared with the risk of progression with tamoxifen (standard),
unadjusted for any baseline covariate. Kaplan-Meier curves were
provided.

Overall tumor response (confirmed CR + PR) and rate of clinical benefit
(defined as CR + PR + SD ≥ 6 months) were analyzed by a logistic
regression procedure, unadjusted for any baseline covariate.

Duration of overall objective tumor response and duration of clinical
benefit were calculated by two methods: 1) from date of randomization to
earliest date of progression in patients who achieved an objective
response or clinical benefit and 2) from onset date of response to
earliest date of progression in patients who achieved an objective
response or clinical benefit.

**Supportive analysis.---**A supportive, prospective multivariate
analysis (Cox regression for TTP, logistic regression for ORR) was
performed adjusting the treatment comparison for the key baseline
covariates of receptor status (ER and/or PgR positive/otherwise), prior
adjuvant treatment with antiestrogens (yes/no) and dominant site of
disease (soft tissue/bone/viscera). The multivariate analysis examined
the influence on TTP of each baseline covariate in the presence of all
the other baseline covariates. Dominant site was defined as soft tissue
if only soft-tissue disease was present (at baseline); as bone if
skeletal metastases were present (regardless of coexistent soft-tissue
disease) without involvement of visceral sites; and as viscera if
visceral metastases were present (irrespective of soft-tissue or bone
involvement).

**Exploratory analysis.---**Two types of prospective exploratory
analyses were conducted: multivariate (Cox regression for TTP, logistic
regression for ORR) adjusting the treatment comparison for all
covariates in the model and stratified analyses (logrank for TTP,
Mantel-Haenszel for ORR) examining each baseline covariate
("stratification factors") one covariate at a time, providing a
treatment comparison adjusted across the strata of the covariate. These
covariates included the 3 key baseline covariates (mentioned previously)
as well as other baseline covariates of interest: duration of adjuvant
antiestrogen treatment, treatment-free interval, geographic area, age,
body mass index, and use of bisphosphonates

**C. Survival Analyses**

The protocol specified that a comparison of overall survival as assessed
by log-rank analysis was to be performed as part of the supplementary
analysis at the completion of the extension phase of the study,
approximately 18 months following the primary analysis (end of 2001),
and that at the time of the primary analysis for TTP the number of
deaths during core treatment or within 6 weeks of stopping core
treatment would be tabulated by treatment.

The primary analysis indicated that Femara was superior to tamoxifen in
all main endpoints (TTP, TTF and rates of objective response and
clinical benefit). As became obvious, the number of deaths in each
treatment arm was different from expectation and it might be advisable
to constitute a group of experts to consider whether there were any
issues that would warrant a modification of the trial or analysis. In
order to maintain the integrity of the survival analysis, Novartis
convened an independent, external Data Monitoring Committee (DMC) under
the chairmanship of Dr. Thomas Fleming, University of Washington,
Seattle.

The DMC convened on May 9, 2000 to review the survival data, as well as
the results of the primary analysis. The DMC recommended that a formal
group sequential analysis plan be implemented for overall survival with
O'Brien-Fleming type boundaries and Lan-DeMets alpha spending function
to maintain an overall two-sided significance level of 0.05 with a
maximum of 3 looks at the data. The results of the survival data at the
time of the primary analysis constitute the first interim look. The
second look would be 6-9 months later. These decisions were made prior
to the DMC's learning of the formal survival analysis (for listing of
committee members, see Appendix 1).

The recommendation of the DMC with regard to the first-line interim
analysis was that no results be disclosed. The results of the second
interim analysis are currently under review by the DMC and may or may
not be presented at the ODAC meeting, pending the recommendation of the
DMC.

### D. Populations {#d.-populations .unnumbered}

All efficacy analyses, inferential or exploratory, were based on
patients in the intent-to-treat population, who were randomly assigned
study treatment with monotherapy and had advanced breast cancer at study
entry, excluding patients at the one GCP-noncompliant center. Novartis
took the decision to exclude these 5 patients from all analyses and all
tabulations (including demographic characteristics). Efficacy analysis
of TTP, rate and duration of overall response, and rate and duration of
clinical benefit were performed for all randomized patients (N = 916)
and for the protocol-specified ITT population of all randomized patients
with active breast cancer at randomization (N = 911) and the results
were almost identical to the ITT analysis presented here (N = 907).

The safety population excludes 6 patients from the monotherapy arms, 4
from the one GCP-noncompliant center (2 on each arm) and 2 who never
received study medication (1 on each arm). Twenty-two of 23 patients
assigned to combination treatment were included in the safety
population. One patient was enrolled at the GCP non-compliant center.

## *3.1.6 Sample Size and Power Considerations* {#sample-size-and-power-considerations .unnumbered}

In the amended protocol, sample size was calculated on the primary
endpoint, time to progression. Sample size was calculated assuming
enrollment over 2 years, an exponential distribution, a reduction in the
risk of progression under Femara of 20% compared with tamoxifen (i.e.
hazard ratio of 0.80), minimum follow-up of around 14 months after
enrollment of the last patient, two-sided significance at the 5% level,
and 80% power. It was estimated that 632 events of progression should be
observed (monotherapy). The calculated sample size was 900 patients. The
same sample size allowed the detection of a 10% absolute difference in
overall objective tumor response at the 5% significance level with 80%
power, assuming an overall response rate of around 35% with tamoxifen.

***3.1.7 Patient Enrollment***

From November, 1996, through January, 1999, a total of 916 patients were
randomized, 458 patients on each arm; from 201 centers in 29
participating countries (589 \[64%\] patients in Europe, 100 \[11%\]
patients in North America and 227 \[25%\] in the Rest of the World). An
additional 23 patients were randomly assigned the combination treatment.

The intent-to-treat population for the monotherapy arm excludes 9
patients: 5 who were randomly assigned study treatment (3 Femara, 2
tamoxifen) but were subsequently found not to have active breast cancer
at study entry, and 4 patients from the one GCP-noncompliant center (2
on each arm). Efficacy analyses were based on the ITT population of the
core phase of the study.

At the time of this analysis 43% of patients in both monotherapy groups
received crossover treatment. In the Femara group, 111 patients remain
on core treatment without evidence of progression compared with 67 in
the tamoxifen group. All of these patients are in the ITT population.
The median follow-up for the ITT population was approximately 18 months.
The results that are to be presented here will be for the ITT population
unless otherwise specified.

***3.1.8 Patient Characteristics***

# The Femara and tamoxifen treatment groups were well balanced with respect to baseline demographic and disease characteristics (Table 3). 

Median age was 65 years (range 31 to 96 years) for the study population.
The majority (82%) of patients were WHO performance status 0 or 1
(Karnofsky 70 or better). Two-thirds of the patients were ER and/or PgR
positive with the remainder of unknown receptor status. Ninety-three
percent of the patients had metastatic disease at the time of
randomization. Forty-four percent of the patients had disease in the
viscera. Thirty-six percent of patients had only one organ involvement
with tumor. The majority of patients had not received prior adjuvant
chemotherapy (72%), prior adjuvant antiestrogen therapy (82%), or prior
chemotherapy for advanced disease (90%).

+----------------------------+--------------------+-------------------+
| **Table 3. Patient         |                    |                   |
| Characteristics by         |                    |                   |
| Treatment Group**          |                    |                   |
+----------------------------+--------------------+-------------------+
| **\                        | **Femara^®^\       | **Tamoxifen\      |
| Characteristic**           | (N = 453), n (%)** | (N = 454), n      |
|                            |                    | (%)**             |
+----------------------------+--------------------+-------------------+
| > **Median age, years      | 65 (31 - 96)       | 64 (31 - 93)      |
| > (range)**                |                    |                   |
+----------------------------+--------------------+-------------------+
| > **WHO performance        |                    |                   |
| > status**                 |                    |                   |
+----------------------------+--------------------+-------------------+
| > 0                        | 253 (56)           | 264 (58)          |
+----------------------------+--------------------+-------------------+
| > 1                        | 170 (38)           | 150 (33)          |
+----------------------------+--------------------+-------------------+
| > 2                        | 30 (7)             | 39 (9)            |
+----------------------------+--------------------+-------------------+
| > **Race, no. patients**   |                    |                   |
+----------------------------+--------------------+-------------------+
| > White/Caucasian          | 385 (85)           | 393 (87)          |
+----------------------------+--------------------+-------------------+
| > Black                    | 12 (3)             | 13 (3)            |
+----------------------------+--------------------+-------------------+
| > Oriental                 | 28 (6)             | 25 (6)            |
+----------------------------+--------------------+-------------------+
| > Other                    | 28 (6)             | 23 (5)            |
+----------------------------+--------------------+-------------------+
| > **Disease stage**        |                    |                   |
+----------------------------+--------------------+-------------------+
| > IIIB                     | 25 (6)             | 32 (7)            |
+----------------------------+--------------------+-------------------+
| > Metastatic               | 422 (93)           | 419 (92)          |
+----------------------------+--------------------+-------------------+
| > **Disease-free           |                    |                   |
| > interval\***             |                    |                   |
+----------------------------+--------------------+-------------------+
| > \< 1 month               | 145 (32)           | 146 (32)          |
+----------------------------+--------------------+-------------------+
| > ≥ 1 month to \< 24       | 57 (13)            | 63 (14)           |
| > months                   |                    |                   |
+----------------------------+--------------------+-------------------+
| > ≥ 24 months              | 251 (55)           | 245 (54)          |
+----------------------------+--------------------+-------------------+
| > **Receptor status**      |                    |                   |
+----------------------------+--------------------+-------------------+
| > ER+ and PgR+             | 174 (38)           | 186 (41)          |
+----------------------------+--------------------+-------------------+
| > ER+ or PgR+              | 120 (26)           | 119 (26)          |
+----------------------------+--------------------+-------------------+
| > Both unknown             | 156 (34)           | 149 (33)          |
+----------------------------+--------------------+-------------------+
| > Other                    | 3 (1)              | 0                 |
+----------------------------+--------------------+-------------------+
| > **Dominant site of       |                    |                   |
| > disease**                |                    |                   |
+----------------------------+--------------------+-------------------+
| > Soft tissue only         | 113 (25)           | 116 (25)          |
+----------------------------+--------------------+-------------------+
| > Bone ± soft tissue       | 146 (32)           | 130 (29)          |
+----------------------------+--------------------+-------------------+
| > Visceral ± bone ± soft   | 194 (43)           | 208 (46)          |
| > tissue                   |                    |                   |
+----------------------------+--------------------+-------------------+
| > **Number of organ sites  |                    |                   |
| > involved**               |                    |                   |
+----------------------------+--------------------+-------------------+
| > 1                        | 159 (35)           | 170 (37)          |
+----------------------------+--------------------+-------------------+
| > 2                        | 156 (34)           | 158 (35)          |
+----------------------------+--------------------+-------------------+
| > ≥ 3                      | 138 (30)           | 126 (28)          |
+----------------------------+--------------------+-------------------+
| > **Prior therapy\***      |                    |                   |
+----------------------------+--------------------+-------------------+
| > Prior adjuvant           | > 93 (21)          | > 105 (23)        |
| > chemotherapy             |                    |                   |
+----------------------------+--------------------+-------------------+
| > Prior adjuvant tamoxifen | > 84 (19)          | > 83 (18)         |
+----------------------------+--------------------+-------------------+
| > Prior chemotherapy for   | > 40 (9)           | > 48 (11)         |
| > advanced disease         |                    |                   |
+----------------------------+--------------------+-------------------+
| \*Includes patients with   |                    |                   |
| stage IV or earlier stage  |                    |                   |
| of disease at time of      |                    |                   |
| study entry.               |                    |                   |
|                            |                    |                   |
| WHO = World Health         |                    |                   |
| Organization; ER =         |                    |                   |
| Estrogen receptor; PgR =   |                    |                   |
| Progesterone receptor.     |                    |                   |
+----------------------------+--------------------+-------------------+

### A. Baseline and Disease Characteristics in US Patients {#a.-baseline-and-disease-characteristics-in-us-patients .unnumbered}

Baseline demographic and disease characteristics for the US patients are
summarized in Table 4.

+---------------------------------+------------------+----------------+
| **Table 4. Baseline and Disease |                  |                |
| Characteristics (US and         |                  |                |
| Canadian Patients)**            |                  |                |
+---------------------------------+------------------+----------------+
| **Characteristic by geographic  | **Femara^®\ ^**  | # Tamoxifen    |
| area (North America)**          |                  |                |
|                                 | ## N=49          | ## N=51        |
+---------------------------------+------------------+----------------+
| Median age, years               | 67               | 70             |
+---------------------------------+------------------+----------------+
| Race, %                         |                  |                |
+---------------------------------+------------------+----------------+
| White/Caucasian                 | 82               | 84             |
+---------------------------------+------------------+----------------+
| Black                           | 12               | 10             |
+---------------------------------+------------------+----------------+
| Oriental                        | 2                | 2              |
+---------------------------------+------------------+----------------+
| Other                           | 4                | 4              |
+---------------------------------+------------------+----------------+
| Estrogen receptor status        | 98               | 94             |
| positive, %                     |                  |                |
+---------------------------------+------------------+----------------+
| Prior adjuvant tamoxifen, %     | 33               | 28             |
+---------------------------------+------------------+----------------+
| Prior chemotherapy, %           | 27               | 22             |
|                                 |                  |                |
| -   adjuvant                    | 6                | 4              |
|                                 |                  |                |
| -   advanced                    |                  |                |
+---------------------------------+------------------+----------------+

###  {#section-15 .unnumbered}

### B. Baseline Laboratory Criteria (CTC Grade ≥ 1): {#b.-baseline-laboratory-criteria-ctc-grade-1 .unnumbered}

There were no baseline entry criteria for hematologic, renal, or liver
function tests. The baseline values for a number of important laboratory
criteria of CTC grade 1 or greater are summarized in Table 5.

+------------------------------+-------------------+-------------------+
| # Table 5. Baseline Laborat  |                   |                   |
| ory Criteria (CTC Grade ≥ 1) |                   |                   |
+------------------------------+-------------------+-------------------+
| **Baseline laboratory        | # Femara^®^       | **Tamoxifen**     |
| criterion**                  |                   |                   |
+------------------------------+-------------------+-------------------+
| Alkaline phosphatase         | 167 / 427 (39%)   | 148 / 423 (35%)   |
+------------------------------+-------------------+-------------------+
| Hemoglobin\*                 | 38 / 452 (8%)     | 27 / 448 (6%)     |
+------------------------------+-------------------+-------------------+
| Creatinine                   | 25 / 452 (6%)     | 24 / 449 (5%)     |
+------------------------------+-------------------+-------------------+
| Gamma glutamyltransferase    | 196 / 427 (46%)   | 201 / 423 (48%)   |
+------------------------------+-------------------+-------------------+
| Aspartate aminotransferase   | 113 / 452 (25%)   | 103 / 449 (23%)   |
+------------------------------+-------------------+-------------------+
| Alanine aminotransferase     | 106 / 452 (23%)   | 86 / 449 (19%)    |
+------------------------------+-------------------+-------------------+
| Bilirubin                    | 27 / 452 (6%)     | 22 / 449 (5%)     |
+------------------------------+-------------------+-------------------+
| \*CTC grade ≥ 2.             |                   |                   |
+------------------------------+-------------------+-------------------+

**3.2 Efficacy**

Remarkable consistency across major key efficacy endpoints (TTP, TTF,
ORR, and clinical benefit rate) favoring treatment with Femara was
demonstrated in this large, double-blind, phase III, randomized,
multinational study. In addition, the robustness of the data favoring
treatment with Femara was clearly demonstrated in all protocol-specified
subgroup analyses of the primary endpoint of TTP and for most subgroup
analyses of secondary endpoints.

***3.2.1 Time to Progression***

Femara was superior to tamoxifen in time to progression (Table 6; Figure
2), reducing the risk of progression by 30% compared with tamoxifen and
prolonging median TTP by over 50% (hazard ratio = 0.70, 95% CI = 0.61 to
0.82, *P* = .0001). Fewer patients progressed on Femara (68%) than on
tamoxifen (77%) during core treatment.

Because both treatments are relatively safe and TTF is closely
correlated with TTP, Femara was significantly superior to tamoxifen in
TTF (hazard ratio = 0.71; 95% CI = 0.61 to 0.82, *P* = .0001). Treatment
failure occurred in 75% of patients in the Femara group and in 85% of
patients in the tamoxifen group. Median TTF was 9.1 months for Femara
and 5.7 months for tamoxifen.

+------------------------+--------------------+---+----------------------+
| **Table 6. Study 025   |                    |   |                      |
| Summary of Efficacy    |                    |   |                      |
| Results**              |                    |   |                      |
+------------------------+--------------------+---+----------------------+
| **\                    | **Femara^®^\       | * |                      |
| **                     | (N = 453)**        | * |                      |
|                        |                    | T |                      |
|                        |                    | a |                      |
|                        |                    | m |                      |
|                        |                    | o |                      |
|                        |                    | x |                      |
|                        |                    | i |                      |
|                        |                    | f |                      |
|                        |                    | e |                      |
|                        |                    | n |                      |
|                        |                    | \ |                      |
|                        |                    | ( |                      |
|                        |                    | N |                      |
|                        |                    | = |                      |
|                        |                    | 4 |                      |
|                        |                    | 5 |                      |
|                        |                    | 4 |                      |
|                        |                    | ) |                      |
|                        |                    | * |                      |
|                        |                    | * |                      |
+------------------------+--------------------+---+----------------------+
| > **Median time to     | 9.4                |   | 6.0                  |
| > progression,         |                    |   |                      |
| > months\***           |                    |   |                      |
+------------------------+--------------------+---+----------------------+
|                        | *P* = .0001        |   |                      |
+------------------------+--------------------+---+----------------------+
| > **Median time to     | 9.1                |   | 5.7                  |
| > treatment failure,   |                    |   |                      |
| > months\***           |                    |   |                      |
+------------------------+--------------------+---+----------------------+
|                        | *P* = .0001        |   |                      |
+------------------------+--------------------+---+----------------------+
| > **Confirmed response | 137 (30)           |   | 92 (20)              |
| > rate (CR + PR), n    |                    |   |                      |
| > %\*\***              |                    |   |                      |
+------------------------+--------------------+---+----------------------+
|                        | *P* = .0006        |   |                      |
+------------------------+--------------------+---+----------------------+
| **Clinical benefit     | 221 (49)           |   | 173 (38)             |
| rate (CR + PR + SD ≥ 6 |                    |   |                      |
| months), n %\*\***     |                    |   |                      |
+------------------------+--------------------+---+----------------------+
|                        | *P* = .001         |   |                      |
+------------------------+--------------------+---+----------------------+
| CR = Complete          |                    |   |                      |
| response; PR = Partial |                    |   |                      |
| response; SD = Stable  |                    |   |                      |
| disease.               |                    |   |                      |
|                        |                    |   |                      |
| \*Cox regression.      |                    |   |                      |
|                        |                    |   |                      |
| \*\* Logistic          |                    |   |                      |
| regression.            |                    |   |                      |
+------------------------+--------------------+---+----------------------+

###### 

![](media/image3.wmf){width="4.0in" height="3.047222222222222in"}

**Figure 2.---**Kaplan-Meier estimate of time to progression. *P* =
.0001 (Cox regression analysis). Marks on curve = censored times.

**A. Supportive Analysis**

The analysis of TTP, adjusted for the key baseline covariates of
receptor status, prior adjuvant antiestrogen treatment, and dominant
site of disease, were almost identical to those of the unadjusted
analysis, as described below.

The supportive analyses confirmed that

-   Treatment with Femara significantly decreased the risk of
    progression (hazard ratio = 0.70; 95% CI = 0.60 to 0.81, *P* =
    .0001) and prolonged TTP (median, 9 months versus 6 months) compared
    with tamoxifen

```{=html}
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```
-   The presence of visceral metastases significantly increased the risk
    of progression (hazard ratio = 1.52; 95% CI = 1.25 to 1.85, *P* =
    .0001) compared with soft-tissue only disease

-   The presence of bone metastases significantly increased risk of
    progression (hazard ratio = 1.26, 95% CI = 1.02 to 1.56, *P* = .03)
    compared with soft-tissue only disease

-   Neither receptor status nor prior adjuvant treatment with
    antiestrogens significantly affected TTP

The stratified analyses (Table 7), conducted on the key baseline
covariates one at a time, confirmed that the treatment difference
adjusted over the strata for each covariate significantly favored
Femara.

+-------------------+----------+--------+----------+--------+-------+
| **Table 7.        |          |        |          |        |       |
| Stratified        |          |        |          |        |       |
| Analysis of TTP   |          |        |          |        |       |
| by Baseline       |          |        |          |        |       |
| Covariates        |          |        |          |        |       |
| (Supportive       |          |        |          |        |       |
| Analysis)**       |          |        |          |        |       |
+===================+==========+========+==========+========+=======+
|                   | **Fem    |        | **Tam    |        |       |
|                   | ara^®^** |        | oxifen** |        |       |
+-------------------+----------+--------+----------+--------+-------+
| **\               | **No.    | **     | **No.    | **     | **\   |
| \                 | events   | Median | events   | Median | Log-  |
| Baseline          | of       | TTP,   | of       | TTP,   | rank\ |
| covariate**       | pro      | mo     | pro      | mo     | *P*   |
|                   | gression | nths** | gression | nths** | va    |
|                   | (no.     |        | (no.     |        | lue** |
|                   | pat      |        | pat      |        |       |
|                   | ients)** |        | ients)** |        |       |
+-------------------+----------+--------+----------+--------+-------+
| **Prior adjuvant  |          |        |          |        | .0001 |
| treatment**       |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
| > None            | 250      | 9.7    | 284      | 6.0    |       |
|                   | (369)    |        | (371)    |        |       |
+-------------------+----------+--------+----------+--------+-------+
| > Adjuvant        | 58 (84)  | 8.8    | 66 (83)  | 5.9    |       |
| > treatment       |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
|                   |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
| **Receptor        |          |        |          |        | .0001 |
| status**          |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
| > ER and/or PgR   | 199      | 9.7    | 235      | 6.0    |       |
|                   | (294)    |        | (305)    |        |       |
+-------------------+----------+--------+----------+--------+-------+
| > Unknown and     | 109      | 9.2    | 115      | 6.0    |       |
| > other           | (159)    |        | (149)    |        |       |
+-------------------+----------+--------+----------+--------+-------+
|                   |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
| **Dominant site** |          |        |          |        | .0001 |
+-------------------+----------+--------+----------+--------+-------+
| > Soft tissue     | 68 (113) | 12.9   | 84 (116) | 6.4    |       |
| > only            |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
| > Bone ± soft     | 100      | 9.7    | 97 (130) | 6.2    |       |
| > tissue          | (146)    |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+
| > Viscera ± bone  | 140      | 8.3    | 169      | 4.7    |       |
| > ± soft tissue   | (194)    |        | (208)    |        |       |
+-------------------+----------+--------+----------+--------+-------+
| TTP = Time to     |          |        |          |        |       |
| tumor             |          |        |          |        |       |
| progression.      |          |        |          |        |       |
+-------------------+----------+--------+----------+--------+-------+

The hazard ratios and 95% confidence intervals for TTP by each baseline
covariate examined in the supportive analysis are shown in Figure 3.
Supportive analysis within strata for each baseline covariate confirmed
the superiority of Femara over tamoxifen.

![](media/image4.wmf)

**Figure 3.---**Hazard ratios and 95% confidence intervals for time to
progression within strata for each baseline covariate. Soft tissue =
soft tissue only, bone = bone ± soft tissue, viscera = viscera ± bone ±
soft tissue, tamoxifen = adjuvant tamoxifen, no tamoxifen = no adjuvant
tamoxifen.

### Stratified analysis conducted on 9 baseline covariates including 3 key baseline covariates, one at a time, indicated the superiority of Femara over tamoxifen on all covariates examined (Table 8). 

###### 

+----------------+----------+---------+-----------+---------+--------+
| **Table 8.     |          |         |           |         |        |
| Stratified     |          |         |           |         |        |
| Analysis of    |          |         |           |         |        |
| TTP by         |          |         |           |         |        |
| Baseline       |          |         |           |         |        |
| Covariates     |          |         |           |         |        |
| (Exploratory   |          |         |           |         |        |
| Analysis)**    |          |         |           |         |        |
+================+==========+=========+===========+=========+========+
|                | **Fem    |         | **Ta      |         |        |
|                | ara^®^** |         | moxifen** |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **\            | **No.    | *       | **No.     | *       | **\    |
| \              | events   | *Median | events of | *Median | Log    |
| Baseline       | of       | TTP,    | pr        | TTP,    | -rank\ |
| covariate**    | pro      | m       | ogression | m       | *P*    |
|                | gression | onths** | (no.      | onths** | v      |
|                | (no.     |         | pa        |         | alue** |
|                | pat      |         | tients)** |         |        |
|                | ients)** |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **Duration of  |          |         |           |         | .0001  |
| prior          |          |         |           |         |        |
| antiestrogen   |          |         |           |         |        |
| treatment\***  |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > 0 - 2 years  | 270      | 9.4     | 309 (403) | 6.0     |        |
|                | (395)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > ≥ 2 years    | 38 (58)  | 9.5     | 41 (51)   | 4.1     |        |
+----------------+----------+---------+-----------+---------+--------+
|                |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **Geographic   |          |         |           |         | .0001  |
| area**         |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > Europe       | 195      | 9.9     | 225 (292) | 6.2     |        |
|                | (288)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > North        | 32 (49)  | 9.7     | 35 (51)   | 6.0     |        |
| > America      |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > Rest of      | 81 (116) | 9.0     | 90 (111)  | 3.5     |        |
| > World        |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
|                |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **Age class**  |          |         |           |         | .0001  |
+----------------+----------+---------+-----------+---------+--------+
| > \< 70 years  | 215      | 8.8     | 246 (311) | 6.0     |        |
|                | (301)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > ≥ 70 years   | 93 (152) | 12.2    | 104 (143) | 5.8     |        |
+----------------+----------+---------+-----------+---------+--------+
|                |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **Disease-free |          |         |           |         | .0001  |
| interval\***   |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > \< 2 years   | 149      | 7.4     | 163 (209) | 5.8     |        |
|                | (202)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > ≥ 2 years    | 159      | 12.2    | 187 (245) | 6.2     |        |
|                | (251)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
|                |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **             |          |         |           |         | .0001  |
| Bisphosphonate |          |         |           |         |        |
| use\*\***      |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > No           | 278      | 9.5     | 312 (405) | 6.0     |        |
|                | (413)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > Yes          | 30 (40)  | 3.9     | 38 (49)   | 5.8     |        |
+----------------+----------+---------+-----------+---------+--------+
|                |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| **Body mass    |          |         |           |         | .0001  |
| index**        |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > \< 30        | 230      | 9.2     | 271 (348) | 6.0     |        |
| > kg/m^2^      | (337)    |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+
| > ≥ 30 kg/m^2^ | 68 (101) | 9.9     | 70 (92)   | 6.0     |        |
+----------------+----------+---------+-----------+---------+--------+
| \*Includes     |          |         |           |         |        |
| patients with  |          |         |           |         |        |
| Stage IV or    |          |         |           |         |        |
| earlier stage  |          |         |           |         |        |
| of disease at  |          |         |           |         |        |
| time of study  |          |         |           |         |        |
| entry.         |          |         |           |         |        |
|                |          |         |           |         |        |
| \*\*Includes   |          |         |           |         |        |
| patients       |          |         |           |         |        |
| irrespective   |          |         |           |         |        |
| of bone        |          |         |           |         |        |
| lesions at     |          |         |           |         |        |
| time of study  |          |         |           |         |        |
| entry.         |          |         |           |         |        |
+----------------+----------+---------+-----------+---------+--------+

### An exploratory analysis within strata of the baseline covariate of geographic area confirmed the superiority of Femara over tamoxifen. The hazard ratios and the 95% CI for TTP are shown in Figure 4.

### ![](media/image5.wmf)

### Figure 4.---Exploratory analysis of time to progression by geographic area.

### 

### In conclusion, the supportive and exploratory analyses demonstrated that Femara was significantly superior to tamoxifen in TTP for all baseline covariates examined.

### 

### *3.2.2 Overall Tumor Response*

Table 6 demonstrates the distribution of response by treatment. The
overall objective tumor response (CR + PR) rate was superior for Femara
(30%) compared with tamoxifen (20%) (odds ratio = 1.71, 95% CI = 1.26 to
2.31, *P* = .0006). Complete response was 8% on Femara and 3% on
tamoxifen. Time to response was not significantly different between
treatments (median = 3.2 months for both treatment groups). The rate of
clinical benefit (CR + PR or SD for ≥ 6 months) was significantly higher
for Femara (49%) compared with tamoxifen (38%) (odds ratio = 1.55; *P* =
.001).

The adjusted analysis (adjusted for the key covariates of receptor
status, prior adjuvant antiestrogen treatment, and dominant site of
disease) was similar to the unadjusted analysis (Odds ratio = 1.80, 95%
CI = 1.32 to 2.47, *P* = .0002).

Median duration of response and median duration of clinical benefit were
identical in both treatment groups (Figure 5). The duration of overall
tumor response calculated from the earliest date of documentation of
response (CR or PR) was 17 months for Femara and 16.5 months for
tamoxifen (hazard ratio = 0.82; 95% CI = 0.55 to 1.22; *P* = not
significant). Similarly, the duration of clinical benefit calculated
from the earliest date of documentation of CR, PR, or SD ≥ 6 months was
15.2 months for Femara and 14.8 months for tamoxifen (hazard ratio =
0.81; 95% CI = 0.62 to 1.07; *P* = not significant).

![](media/image6.wmf){width="5.235416666666667in"
height="4.054166666666666in"}![](media/image7.wmf){width="5.223611111111111in"
height="4.047916666666667in"}

**Figure 5.---**Kaplan-Meier estimates of duration of overall tumor
response (top) and duration of clinical benefit (bottom).

The duration of overall tumor response calculated from the date of
randomization was 23 months for both treatments (hazard ratio = 0.84;
95% CI = 0.56 to 1.26, *P* = NS). Similarly, the duration of clinical
benefit calculated from the data randomization was 19 months for both
treatments (Hazard ratio = 0.81; 95% CI = 0.62 to 1.07, *P* = not
significant).

**A. Supportive Analysis**

The analysis for ORR, adjusted for the key baseline covariates of prior
adjuvant antiestrogen treatment, receptor status, and dominant site of
disease was very similar to the unadjusted analysis as described below.
The supportive multivariate analysis indicated that slightly different
covariates impact overall response compared with those that were found
to impact TTP.

The supportive analysis confirmed that

-   Treatment with Femara significantly increased the odds of achieving
    a CR or PR (odds ratio = 1.80; 95% CI = 1.32 to 2.47, *P* = .0002)

-   The presence of visceral metastases significantly reduced the odds
    of achieving a CR or PR compared with soft-tissue only disease (odds
    ratio = 0.37, 95% CI = 0.26 to 0.53, *P* = .0001)

-   The presence of bone metastases significantly reduced the odds of
    achieving a CR or PR compared with soft-tissue only disease (odds
    ratio = 0.29, 95% CI = 0.19 to 0.44, *P* = .0001)

-   Prior adjuvant antiestrogen treatment significantly reduced the odds
    of achieving a CR or PR compared with antiestrogen-naive patients
    (odds ratio = 0.64; 95% CI = 0.41 to 0.98, *P* = .04)

-   A trend was observed for higher odds of achieving an objective tumor
    response in receptor-positive patients than in receptor-unknown
    patients (odds ratio = 1.37; 95% CI = 0.98 to 1.92, *P* = .07)

The stratified analysis (Table 9) conducted on key baseline covariates
one at a time, confirmed that the treatment difference adjusted over the
strata for each covariate significantly favored Femara.

+-------------------+------------------+------------------+------------+
| **Table 9.        |                  |                  |            |
| Stratified        |                  |                  |            |
| Analysis of       |                  |                  |            |
| Objective Overall |                  |                  |            |
| Tumor Response by |                  |                  |            |
| Baseline          |                  |                  |            |
| Covariates        |                  |                  |            |
| (Supportive       |                  |                  |            |
| Analysis)**       |                  |                  |            |
+-------------------+------------------+------------------+------------+
| **\               | **Femara^®^ CR + | **Tamoxifen CR + | **\        |
| Baseline          | PR,\             | PR,\             | *P*        |
| covariate**       | no. patients     | no. patients     | value\***  |
|                   | (%)**            | (%)**            |            |
+-------------------+------------------+------------------+------------+
| **Prior adjuvant  |                  |                  | .001       |
| treatment**       |                  |                  |            |
+-------------------+------------------+------------------+------------+
| > None            | 113 / 369 (31)   | 85 / 371 (23)    |            |
+-------------------+------------------+------------------+------------+
| > Adjuvant        | 24 / 84 (29)     | 7 / 83 (8)       |            |
| > treatment       |                  |                  |            |
+-------------------+------------------+------------------+------------+
|                   |                  |                  |            |
+-------------------+------------------+------------------+------------+
| **Receptor        |                  |                  | .001       |
| status**          |                  |                  |            |
+-------------------+------------------+------------------+------------+
| > ER+ and/or PgR+ | 92 / 294 (31)    | 63 / 305 (21)    |            |
+-------------------+------------------+------------------+------------+
| > Unknown and     | 45 / 159 (28)    | 29 / 149 (20)    |            |
| > other           |                  |                  |            |
+-------------------+------------------+------------------+------------+
|                   |                  |                  |            |
+-------------------+------------------+------------------+------------+
| **Dominant site** |                  |                  | .001       |
+-------------------+------------------+------------------+------------+
| > Soft tissue     | 54 / 113 (48)    | 40 / 116 (35)    |            |
| > only            |                  |                  |            |
+-------------------+------------------+------------------+------------+
| > Bone ± soft     | 32 / 146 (22)    | 18 /130 (14)     |            |
| > tissue          |                  |                  |            |
+-------------------+------------------+------------------+------------+
| > Visceral ± bone | 51 / 194 (26)    | 34 / 208 (16)    |            |
| > ± soft tissue   |                  |                  |            |
+-------------------+------------------+------------------+------------+
| \*Cochra          |                  |                  |            |
| n-Mantel-Haenszel |                  |                  |            |
| statistic.        |                  |                  |            |
|                   |                  |                  |            |
| CR = Complete     |                  |                  |            |
| response; PR =    |                  |                  |            |
| Partial response; |                  |                  |            |
| ER = Estrogen     |                  |                  |            |
| receptor; PgR =   |                  |                  |            |
| Progesterone      |                  |                  |            |
| receptor.         |                  |                  |            |
+-------------------+------------------+------------------+------------+

Supportive analysis within strata for each baseline covariate confirmed
the superiority of Femara over tamoxifen in all stratum except for
unknown receptor status and bone ± soft tissue disease. The odds ratios
and 95% confidence intervals for objective response are shown in Figure
6.

![](media/image8.wmf)

**Figure 6.---**Odds ratios and 95% confidence intervals for objective
response within strata for each baseline covariate. Upper bound for CI
for adjuvant tamoxifen = 10.8. Soft tissue = soft tissue only, bone =
bone ± soft tissue, viscera = viscera ± bone ± soft tissue, tamoxifen =
adjuvant tamoxifen, no tamoxifen = no adjuvant tamoxifen.

#### 

#### **B. Exploratory Analysis**

Stratified analysis conducted on 9 baseline covariates (including the 3
key baseline covariates, one at a time) indicated the superiority of
Femara over tamoxifen for ORR on all covariates examined (Table 10).

+-----------------+-----------------+---------------------+-----------+
| **Table 10.     |                 |                     |           |
| Stratified      |                 |                     |           |
| Analysis of     |                 |                     |           |
| Objective       |                 |                     |           |
| Overall Tumor   |                 |                     |           |
| Response by     |                 |                     |           |
| Baseline        |                 |                     |           |
| Covariates      |                 |                     |           |
| (Exploratory    |                 |                     |           |
| Analysis)**     |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| **\             | **Femara^®^     | **Tamoxifen CR +    | **\       |
| Baseline        | CR + PR,\       | PR,\                | *P*       |
| covariate**     | no. patients    | no. patients (%)**  | valu      |
|                 | (%)**           |                     | e\*\*\*** |
+-----------------+-----------------+---------------------+-----------+
| **Duration of   |                 |                     | > .001    |
| prior           |                 |                     |           |
| antiestrogen    |                 |                     |           |
| therapy\***     |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| > 0 to \< 2     | 119 / 395 (30)  | 89 / 403 (22)       |           |
| > years         |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| > ≥ 2 years     | 18 / 58 (31)    | 3 / 51 (6)          |           |
+-----------------+-----------------+---------------------+-----------+
|                 |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| **Geographical  |                 |                     | > .001    |
| area**          |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| > Europe        | 94 / 288 (33)   | 65 /292 (22)        |           |
+-----------------+-----------------+---------------------+-----------+
| > North America | 13 / 49 (27)    | 9 / 51 (18)         |           |
+-----------------+-----------------+---------------------+-----------+
| > Rest of World | 30 / 116 (26)   | 18 / 111 (16)       |           |
+-----------------+-----------------+---------------------+-----------+
|                 |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| **Age class**   |                 |                     | > .001    |
+-----------------+-----------------+---------------------+-----------+
| > \< 70 years   | 79 / 301 (26)   | 67 / 311 (22)       |           |
+-----------------+-----------------+---------------------+-----------+
| > ≥ 70 years    | 58 / 152 (38)   | 25 / 143 (18)       |           |
+-----------------+-----------------+---------------------+-----------+
|                 |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| **Disease-free  |                 |                     | > .0001   |
| interval\***    |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| > \< 2 years    | 60 / 202 (30)   | 44 / 209 (21)       |           |
+-----------------+-----------------+---------------------+-----------+
| > ≥ 2 years     | 77 / 251(31)    | 48 / 245 (20)       |           |
+-----------------+-----------------+---------------------+-----------+
|                 |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| *               |                 |                     | > .0001   |
| *Bisphosphonate |                 |                     |           |
| use\*\***       |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| > No            | 130 / 413 (32)  | 85 / 405 (21)       |           |
+-----------------+-----------------+---------------------+-----------+
| > Yes           | 7 / 40 (18)     | 7 / 49 (14)         |           |
+-----------------+-----------------+---------------------+-----------+
|                 |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| **Body mass     |                 |                     | > .0001   |
| index**         |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+
| > \< 30 kg/m^2^ | 100 / 337 (30)  | 63 / 348 (18)       |           |
+-----------------+-----------------+---------------------+-----------+
| > ≥ 30 kg/m^2^  | 32 / 101(32)    | 25 / 92 (27)        |           |
+-----------------+-----------------+---------------------+-----------+
| \*Includes      |                 |                     |           |
| patients with   |                 |                     |           |
| Stage IV or     |                 |                     |           |
| earlier stage   |                 |                     |           |
| of disease at   |                 |                     |           |
| time of study   |                 |                     |           |
| entry.          |                 |                     |           |
|                 |                 |                     |           |
| \*\*Includes    |                 |                     |           |
| patients        |                 |                     |           |
| irrespective of |                 |                     |           |
| bone lesions at |                 |                     |           |
| time of study   |                 |                     |           |
| entry.          |                 |                     |           |
|                 |                 |                     |           |
| \*\*\*Cochran   |                 |                     |           |
| Mantel Haenszel |                 |                     |           |
| statistic.      |                 |                     |           |
+-----------------+-----------------+---------------------+-----------+

### *3.2.3 Number of Deaths*

##  There were 304 deaths when the primary analysis was conducted (See section 3.1.5 Survival Analyses and Section 5.0 Safety in Phase III studies).

## 

## *3.2.4 Other Analyses*

### A. Time to Worsening Performance Status

The median time to worsening of KPS was not reached in the Femara group
compared with just under 30 months in the tamoxifen group. The KPS
worsened in 77 patients (17%) for Femara, 107 patients (24%) for
tamoxifen. There was a significant difference between treatments in the
time to worsening of KPS by at least 20 points (hazard ratio 0.62; 95%
CI = 0.46 to 0.83; *P* = .002).

### *3.2.5 Summary*

In this, the largest randomized clinical trial in this patient
population, Femara demonstrated superior efficacy compared with
tamoxifen. Most importantly, Femara significantly reduced the risk of
progression (*P* = .0001) and prolonged median time to progression\
(9.4 months versus 6 months). Further, objective tumor response rate,
clinical benefit rate, and time to treatment failure were all
significantly improved in the Femara group compared with the tamoxifen
group. Objective tumor response rate was 30% in the Femara group versus
20% in the tamoxifen group (*P* = .0006). Supportive and exploratory
analyses adjusted for important baseline prognostic factors also
demonstrated the statistically significant superiority of Femara. These
data support the use of Femara as the endocrine therapy of choice for
postmenopausal women with advanced breast cancer, setting a new standard
of care in this patient population.

**4.0** **SUPPORTIVE PHASE IIB/III STUDY 024**

**4.1 Study Design**

Study 024 was an international, multicenter, double-blind, double-dummy,
randomized, parallel-group, phase IIb/III trial of once-daily doses of
Femara (2.5 mg) or tamoxifen (20 mg) in postmenopausal women with ER
and/or PgR positive primary breast cancer (clinical stage T2, T3,
T4~a-c~, N0-2, M0). The study was designed to detect a statistically
significant and clinically meaningful difference in clinical response
rate between Femara and tamoxifen. Study treatment was given for 4
months prior to surgery unless withdrawn due to PD, an adverse event, or
at patient/investigator request. Following surgery, treatment with
Femara in the adjuvant setting was at the investigator's discretion.
During this period, the study blind was not to be broken. Study 024 was
supportive of the pivotal Study 025 in that it preselected a group of
breast cancer patients who would most likely respond to endocrine
therapy (postmenopausal women with ER and/or PgR positive tumors) and
who were more importantly never exposed to either endocrine or other
forms of therapy. Therefore, these truly therapy-naïve patients
represent an appropriate group of patients in whom to evaluate
differences between two endocrine therapies.

***4.1.1 Entry Criteria***

Postmenopausal women with primary invasive and histologically confirmed
breast cancer (clinical stage T2, T3, T4~a-c~, N0-2, M0) were eligible
for this study. The protocol allowed only patients who were candidates
for mastectomy or were inoperable to be enrolled. Patients with clinical
stage T2 disease were eligible if the lesion was not considered by the
investigator to be eligible for breast-conserving surgery. Eligible
patients had measurable tumor by clinical examination, mammography, and
ultrasound. Patients with evidence of inflammatory breast cancer or
distant metastasis were excluded.

***4.1.2 Randomization Procedures***

A computer-generated randomization list was created by Novartis so that
treatments were balanced within each country. A double-dummy technique
was used to ensure that study medication was blinded. The patients,
investigators and their staffs, and all Novartis personnel involved in
the conduct and monitoring of the trial were blinded to trial drug
codes. Treatment codes were unblinded after database lock for Novartis
staff only, but patients and investigators and their staffs remained
blinded to trial drug codes. Medication was unblinded for 2 patients (1
on Femara, 1 on tamoxifen) during the trial to decide on further
treatment.

***4.1.3 Treatment Administration***

In the Femara treatment group, patients received 1 tablet of Femara (2.5
mg) and 1 placebo tablet for daily oral administration. In the tamoxifen
treatment group, patients received 1 tamoxifen tablet (20 mg) and 1
placebo tablet for daily oral administration.

***4.1.4 Study Endpoints***

**A. Efficacy Assessments**

The primary efficacy endpoint was tumor response as assessed by clinical
examination using WHO criteria. Tumor response was defined as the
percentage of patients in each treatment group with a CR or a PR as
determined clinically in the breast by palpation at 4 months. Palpable
ipsilateral axillary lymph nodal involvement downgraded a clinical CR in
tumor. Secondary endpoints included tumor response as assessed by
mammography and by ultrasound at 4 months using WHO criteria and the
percentage of patients who underwent breast-conserving surgery
(quadrantectomy/lumpectomy) instead of mastectomy.

# B. Safety Assessments

Safety assessments consisted of monitoring and reporting all adverse
events classified by all NCI CTC criteria and all serious adverse events
(with their severity and relationship to study drug.

***4.1.5 Statistical Analysis***

All patients randomly assigned treatment who took at least 1 dose of
study medication and with histologic or cytologic confirmation of breast
cancer were included in the ITT population, except for patients from two
GCP-noncompliant centers. For safety, all patients randomly assigned
treatment who took at least 1 dose of study medication were included in
the safety population, except for patients from two GCP-noncompliant
centers. The data were analyzed by Parexel International (Sheffield, UK)
under the supervision of Novartis. All efficacy analyses were performed
on the intent-to-treat (ITT) population, and response at 4 months was
tabulated. If a patient discontinued study treatment earlier than 4
months (+/- 2 weeks), and had a last assessment of CR, PR, or SD, her
final response on all methods was considered not evaluable (NE). If a
patient discontinued study treatment earlier than 4 months (+/- 2 weeks)
and had a last assessment of PD, the earlier diagnosis of PD was
counted.

**A. Primary Endpoint**

The primary endpoint---the proportion of patients in each treatment
group with a CR or PR on clinical assessment---was analyzed by the
stratified Mantel-Haenszel chi-square test by tumor size and nodal
involvement.

# B. Secondary Endpoints

The secondary endpoints---including the proportion of patients in each
treatment group with a CR or PR assessed by mammography and ultrasound
and the rate of breast conserving surgery---were analyzed similarly, by
the stratified Mantel-Haenszel chi-square test.

***4.1.6 Sample Size and Power Considerations***

It was assumed that the tamoxifen group would have a clinical objective
response rate (CR + PR) of 65%, and that a clinically meaningful
improvement would be a response rate of 80%. Clinical response was to be
based on WHO criteria. A sample size of 302 patients was estimated as
sufficient to detect as significant (2-sided test at the 5% level of
significance with 80% power) a difference of 15% between treatment
groups in clinical objective response. It was expected that 50% of the
patients treated with tamoxifen would undergo breast-conserving surgery.
It was postulated that 70% of the patients treated with Femara would
undergo breast-conserving surgery. The sample size calculated for the
primary endpoint was estimated as adequate for detecting as significant
this difference (103 patients in each treatment group would be needed
for a 2-sided test at the 5% level of significance with 80% power).

**4.2 Patient Demographics**

***4.2.1 Patient Enrollment***

From March 1998 until August 1999, a total of 337 patients were enrolled
at 55 centers in 16 countries. Countries with \> 10% enrollment included
Germany (24%), Brazil (15%), and the United Kingdom (11%). The
intent-to-treat (ITT) population excludes 13 patients: 4 who were
randomly assigned study treatment (Femara) but were subsequently found
not to have histologic or cytologic evidence of breast cancer at study
entry; and 9 patients from two GCP non-compliant centers (4 Femara, 5
tamoxifen). Efficacy analyses were based on ITT population. The safety
population excludes 9 from the GCP non-compliant centers (4 Femara, 5
tamoxifen) and one patient who never took study medication on Femara.

***4.2.2 Patient Characteristics***

The Femara and tamoxifen treatment groups were well balanced with
respect to baseline demographics and disease characteristics (Table 11).

+---------------------+-----------------+-----------------+---+-----------+
| #### **Ta           |                 |                 |   |           |
| ble 11. Patient Dem |                 |                 |   |           |
| ographic and Diseas |                 |                 |   |           |
| e Characteristics b |                 |                 |   |           |
| y Treatment Group** |                 |                 |   |           |
+---------------------+-----------------+-----------------+---+-----------+
| ####                | #### **Pati     |                 |   |           |
|                     | ents, no. (%)** |                 |   |           |
+---------------------+-----------------+-----------------+---+-----------+
|                     | **Femara^®^     | **Tamoxifen (20 |   | **Total\  |
|                     | (2.5 mg)\       | mg)\            |   | (N =      |
|                     | (N =154)**      | (N =170)**      |   | 324)**    |
+---------------------+-----------------+-----------------+---+-----------+
| **Median age, years | 68 (44 - 91)    | 67 (48 - 89)    | 6 |           |
| (range**)           |                 |                 | 7 |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 |   |           |
|                     |                 |                 | - |           |
|                     |                 |                 | 9 |           |
|                     |                 |                 | 1 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| **Receptor status** |                 |                 |   |           |
+---------------------+-----------------+-----------------+---+-----------+
| > ER+ and PgR+      | 90 (58)         | 91 (54)         |   | 181 (56)  |
+---------------------+-----------------+-----------------+---+-----------+
| > ER+ or PgR+       | 64 (42)         | 76 (45)         |   | 140 (43)  |
+---------------------+-----------------+-----------------+---+-----------+
| > Both unknown      | 0 (0)           | > 1 (\< 1)      |   | > 1 (\<   |
|                     |                 |                 |   | > 1)      |
+---------------------+-----------------+-----------------+---+-----------+
| > ER--, PgR--       | 0 (0)           | 2 (1)           |   | > 2 (\<   |
|                     |                 |                 |   | > 1)      |
+---------------------+-----------------+-----------------+---+-----------+
| #####               |                 |                 |   |           |
|  **Clinical stage** |                 |                 |   |           |
+---------------------+-----------------+-----------------+---+-----------+
| > T2                | 77 (50)         | 91 (54)         | 1 |           |
|                     |                 |                 | 6 |           |
|                     |                 |                 | 8 |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 5 |           |
|                     |                 |                 | 2 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| > T3                | 42 (27)         | 31 (18)         | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | 7 |           |
|                     |                 |                 | 3 |           |
|                     |                 |                 | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 2 |           |
|                     |                 |                 | 3 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| > T4                | 35 (23)         | 48 (28)         | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | 8 |           |
|                     |                 |                 | 3 |           |
|                     |                 |                 | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 2 |           |
|                     |                 |                 | 6 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| > N0                | 76 (49)         | 84 (49)         | 1 |           |
|                     |                 |                 | 6 |           |
|                     |                 |                 | 0 |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | 9 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| > N1                | 67 (44)         | 67 (39)         | 1 |           |
|                     |                 |                 | 3 |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | 1 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| > N2                | 11 (7)          | 19 (11)         | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | 3 |           |
|                     |                 |                 | 0 |           |
|                     |                 |                 | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 9 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| **Proposed          |                 |                 |   |           |
| surgery**           |                 |                 |   |           |
+---------------------+-----------------+-----------------+---+-----------+
| > Mastectomy        | 134 (87)        | 146 (86)        | 2 |           |
|                     |                 |                 | 8 |           |
|                     |                 |                 | 0 |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 8 |           |
|                     |                 |                 | 6 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| > Not operable      | 20 (13)         | 24 (14)         | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | > |           |
|                     |                 |                 |   |           |
|                     |                 |                 | ( |           |
|                     |                 |                 | 1 |           |
|                     |                 |                 | 4 |           |
|                     |                 |                 | ) |           |
+---------------------+-----------------+-----------------+---+-----------+
| ER = Estrogen       |                 |                 |   |           |
| receptor; PgR =     |                 |                 |   |           |
| Progesterone        |                 |                 |   |           |
| receptor.           |                 |                 |   |           |
+---------------------+-----------------+-----------------+---+-----------+

**4.3 Efficacy**

***4.3.1 Summary of Results***

The response rate, regardless of the efficacy endpoint evaluated, and
the rate of breast-conserving surgery were statistically significantly
higher for the Femara group compared with the tamoxifen group (Table
12).

  --------------------------------------------------------------------------------------
  **Table 12. Summary of                                                      
  Responses**                                                                 
  ------------------------ ------------- ----------------- ------------------ ----------
                           **Patients,                                        
                           no. (%)**                                          

  **\                                    **Femara^®^ (2.5  **Tamoxifen (20    ***\
  Efficacy endpoint**                    mg)\              mg)\               P* value**
                                         (N = 154)**       (N = 170)**        

  Clinical response                      85 (55)           61 (36)            \< .001
  (palpation)                                                                 

  Ultrasound response                    54 (35)           43 (25)            .042

  Mammographic response                  53 (34)           28 (17)            \< .001

  Breast-conserving                      69 (45)           59 (35)            .022
  surgery                                                                     
  --------------------------------------------------------------------------------------

######## 

For the entire ITT population, 15% (50/324) of the patients did not
undergo surgical resection following treatment with study drug: 12%
(19/154) in the Femara group and 18% (31/170) in the tamoxifen group.
Twenty patients did not have surgery because of disease progression, and
all of these patients went on to receive other therapies, including
chemotherapy and radiotherapy. Six patients were inoperable, and 13
patients refused surgery. Five patients had medical conditions that
contraindicated surgery. In the case of 1 patient, there was no
available hospital bed. The remaining 5 patients were withdrawn from the
study because of ER or PgR negative disease (n = 2), an increase in
tumor markers (n = 1), an adverse event (hepatitis; n = 1), and bone
metastases (n = 1).

The clinical tumor response rate (CR + PR) was significantly higher with
Femara than with tamoxifen (55% versus 36%; *P* \< .001). The response
rate was significantly higher for Femara by all methods (clinical,
ultrasound, mammography). Significantly more patients underwent
breast-conserving therapy after Femara treatment than after tamoxifen
treatment (45% versus 35%;\
*P* = .022).

**5.0 SAFETY IN PHASE III STUDIES**

**5.1 Study 025 Safety Results**

The median duration of core treatment in the Femara group was 11 months
compared with a median of 6 months in the tamoxifen group. The median
duration of treatments may not necessarily reflect the median duration
of progression, as patients may have continued to receive therapy after
their date of progression. The nature and frequency of all adverse
events irrespective of relationship to study drug were similar in the
Femara and tamoxifen treatment groups. The overall incidence of the most
frequently reported adverse events is summarized by preferred term in
Table 13.

+-----------------------+-----------------------+----------------------+
| **Table 13. Number of |                       |                      |
| Patients With Most    |                       |                      |
| Frequent Adverse      |                       |                      |
| Events Regardless of  |                       |                      |
| Study Drug            |                       |                      |
| Relationship (≥ 10%   |                       |                      |
| in Either Group) by   |                       |                      |
| Preferred Term**      |                       |                      |
+=======================+=======================+======================+
|                       | **Patients, no. (%)** |                      |
+-----------------------+-----------------------+----------------------+
| **Adverse event**     | **Femara^®^ (N        | **Tamoxifen (N       |
|                       | =455)**               | =455)**              |
+-----------------------+-----------------------+----------------------+
| Bone pain             | 89 (20)               | > 83 (18)            |
+-----------------------+-----------------------+----------------------+
| Hot flashes (NOS)     | 81 (18)               | > 70 (15)            |
+-----------------------+-----------------------+----------------------+
| Pain back             | 77 (17)               | > 79 (17)            |
+-----------------------+-----------------------+----------------------+
| Nausea                | 66 (15)               | > 72 (16)            |
+-----------------------+-----------------------+----------------------+
| Arthralgia            | 63 (14)               | > 58 (13)            |
+-----------------------+-----------------------+----------------------+
| Dyspnea (NOS)         | 62 (14)               | > 66 (15)            |
+-----------------------+-----------------------+----------------------+
| Cough                 | 49 (11)               | > 47 (10)            |
+-----------------------+-----------------------+----------------------+
| Fatigue               | 48 (11)               | > 51 (11)            |
+-----------------------+-----------------------+----------------------+
| NOS = Not otherwise   |                       |                      |
| specified.            |                       |                      |
+-----------------------+-----------------------+----------------------+

Thromboembolic events irrespective of drug relationship were reported in
6 (1%) patients in the Femara group and in 11 (2%) patients in the
tamoxifen group. Pulmonary embolus was reported in 2 patients, 1 in each
treatment group. Cardiovascular events (myocardial infarction, angina)
occurred in 15 patients (3%) on Femara and in 13 patients (3%) on
tamoxifen. Cerebral arterial events occurred in 12 patients (3%) on
Femara and 9 patients (2%) on tamoxifen. A total of 53 patients were
reported to have bone fractures, including 25 on Femara (6%) and 27 on
tamoxifen (6%), and 1 patient on combination therapy. The majority of
these events were related to bone metastasis. In addition, 14 patients
were reported to have bone fractures during the crossover phase. The
numbers of patients with newly occurring or worsening liver enzymes to
CTC grade 3 or 4 was low and similar in both treatment arms.

Discontinuations due to adverse events were reported in 2% of
Femara-treated patients and in 3% of tamoxifen-treated patients.
Discontinuations due to death were reported equally in both groups at
2%. There were no treatment-related deaths.

**5.2 Study 024 Safety Results**

The nature and frequency of commonly reported adverse events (≥ 5% in
either group) irrespective of relationship to study drug, including hot
flashes (Femara 20%, tamoxifen 25%), headache (Femara 8%, tamoxifen 5%),
nausea (Femara 6%, tamoxifen 8%), fatigue (Femara 5%, tamoxifen 5%), and
viral infection (Femara 3%, tamoxifen 7%) were similar for the Femara
and tamoxifen groups.

No deaths were reported during the study or within 30 days of any
patient receiving the last dose of study drug. In total, 4 patients
discontinued medication because of an adverse event (1 patient in the
Femara group for pulmonary embolism; 3 patients on tamoxifen for
hepatitis C, erythema multiforme, and cholestasis).

**6.0 BENEFIT/RISK ASSESSMENT**

In patients diagnosed with metastatic breast cancer, therapy is
palliative, with the aim of delaying the progress of the underlying
disease using treatments that exert a minimum negative effect on the
quality of life of the patient. Hormonal therapy, which is known to be
well tolerated, is considered to represent a very attractive therapeutic
intervention in this indication.

The results of Study 025, a large, randomized, double-blind trial,
indicate that the efficacy of Femara is significantly greater than that
of tamoxifen in the treatment of advanced breast cancer in
postmenopausal women. Femara was significantly superior in the primary
endpoint, TTP, and in the secondary endpoints, TTF, ORR, and clinical
benefit rate. Overall time to progression was more than 40% longer for
Femara than for tamoxifen, which offers a significant clinical advantage
to these patients over existing therapies. The robustness of this result
is consistently demonstrated within the different patient subgroups,
always maintaining statistical significance favoring treatment with
Femara. The superior efficacy of Femara over tamoxifen has also been
demonstrated in the supportive trial (Study 024) of preoperative therapy
in postmenopausal ER and/or PgR positive breast cancer patients
comparing Femara with tamoxifen over 4 months of treatment prior to
surgical resection of a primary tumor. In this group of patients with
*de novo* hormone receptor-positive breast cancer, who were naive to
both chemotherapy and hormonal therapy, Femara was superior to tamoxifen
in demonstrating a therapeutic effect in tumor regression, allowing
patients to undergo breast-conserving surgery.

The safety results obtained with Femara in this indication were entirely
consistent with the profile documented thus far, clearly showing that
the benefits associated with the use of the drug outweigh any potential
risks in this patient population. The most common adverse events in both
Femara and tamoxifen were bone pain, hot flashes, back pain, and nausea.
Most adverse events were mild to moderate in severity. As expected, only
a small percentage of patients discontinued from the studies due to
adverse events. The frequency of deaths was also low, and most were
considered cancer related. In addition, adverse event data from
approximately 3,200 patients in 4 ongoing or recently completed studies
showed a similar safety profile.

Overall, the data sufficiently and consistently support a recommendation
for Femara as the first choice in the selection of an endocrine
treatment for advanced breast cancer in postmenopausal women.

**7.0 OVERALL CONCLUSIONS**

In Study 025, the largest trial of endocrine treatment for the
first-line treatment of postmenopausal women with advanced breast
cancer, Femara was superior to tamoxifen as demonstrated by the
following:

-   Significantly longer time to progression

-   Significantly higher objective tumor response rate

-   Significantly higher clinical benefit rate

-   Significantly longer time to treatment failure

-   Consistently superior results in all subgroup analyses

Study 024 demonstrated the superiority of Femara compared with tamoxifen
in overall response rate, by clinical parameters and radiologic methods.
This results are derived from a selected group of postmenopausal
patients with primary hormone-sensitive breast cancer in whom any
potential bias due to previous treatment with tamoxifen or other
therapies was eliminated. The results of study 024 are, therefore,
supportive of the pivotal study 025. Femara was equally well tolerated
as tamoxifen in both studies with a lower number of thromboembolic
events.

Therefore, results of these adequate and well-controlled studies
convincingly demonstrate that Femara is a first-line treatment in
postmenopausal women with advanced breast cancer, setting a new standard
of care in this patient population.

**8.0 REFERENCES**

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3\. Gershanovich M, Chaudri HA, Campos D, et al. Letrozole, a new oral
aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg
daily and aminoglutethimide in postmenopausal women with advanced breast
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4\. Hamilton A, Piccart M. The third-generation non-steroidal aromatase
inhibitors: a review of their clinical benefits in the second-line
hormonal treatment of advanced breast cancer. *Ann Oncol*.
1999;10:377-384.

5\. Dowsett M, Pfister C, Johnston SR, et al. Impact of tamoxifen on the
pharmacokinetics and endocrine effects of the aromatase inhibitor
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rationale and current progress. *J Steroid Biochem Mol Biol*.
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7\. Clark GM, Osborne CK, McGuire WL. Correlations between estrogen
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8\. Haskell CM. Systemic treatment for metastatic breast cancer. Haskell
CM, Berek JS, ed. *Cancer Treatment*. 4th ed. Philadelphia: W.B.
Saunders; 1995:354-367.

9\. Bhatnagar AS, Hausler A, Schieweck K, Lang M, Bowman R. Highly
selective inhibition of estrogen biosynthesis by CGS 20267, a new
non-steroidal aromatase inhibitor. *J Steroid Biochem Mol Biol*.
1990;37:1021-1027.

10\. Knudsen JF, Mahesh VB. Initiation of precocious sexual maturation
in the immature rat treated with dehydroepiandrosterone.
*Endocrinology*. 1975;97:458-468.

11\. Kraulis I, Traikov H, Sharpe M, Ruf KB, Naftolin F. Steroid
induction of gonadotropin surges in the immature rat. I. Priming effects
of androgens. *Endocrinology*. 1978;103:1822-1828.

12\. Hausler A, Monnet G, Borer C, Bhatnagar AS. Evidence that
corticosterone is not an obligatory intermediate in aldosterone
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13\. Geisler J, Anker G, Dowsett M, Lønning PE. Letrozole suppresses
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2000;19:102a.

14\. Dixon JM, Love CDB, Tucker S, et al. Letrozole as primary medical
therapy for locally advanced breast cancer \[abstract\]. *The Breast.*
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15\. Sioufi A, Gauducheau N, Pineau V, et al. Absolute bioavailability
of letrozole in healthy postmenopausal women. *Biopharm Drug Dispos*.
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16\. Sioufi A, Sandrenan N, Godbillon J, et al. Comparative
bioavailability of letrozole under fed and fasting conditions in 12
healthy subjects after a 2.5 mg single oral administration. *Biopharm
Drug Dispos*. 1997;18:489-497.

17\. Colussi DM, Parisot CY, Lefevre GY. Plasma protein binding of
letrozole, a new nonsteroidal aromatase enzyme inhibitor. *J Clin
Pharmacol*. 1998;38:727-735.

18\. Wirz B, Valles B, Parkinson A, et al. CYP3A6 are involved in the
biotransformation of letrozole \[abstract\]. *Proceedings of the 7th
North American ISSX Meeting.* 1996;10:359.

19\. Ingle JN, Suman VJ, Johnson PA, et al. Evaluation of tamoxifen plus
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1999;5:1642-1649.

Composition of Data Monitoring Committee

  ------------------------------ ----------------------------------------
  **Member**                     **Affiliation**

  Dr. Thomas Fleming (DMC Chair) University of Washington, Seattle, WA,
                                 USA

  Professor Klaus Hoeffken       University of Jena, Jena, Germany

  Professor Per Lønning          University of Bergen, Bergen, Norway

  Dr. Kathleen Pritchard         Toronto-Sunnybrook Regional Cancer
                                 Centre, Toronto, Canada

  Dr. Beat Thuerlimann           IBCSG (International Breast Cancer Study
                                 Group), St. Gallen, Switzerland

  Dr. D. Lawrence Wickerham      NSABP, Pittsburgh, PA, USA

                                 
  ------------------------------ ----------------------------------------