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AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...
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AROMASIN® (exemestane): Adjuvant Therapy for Early Stage ...

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  • This slide presentation is being used for educating physicians on the efficacy and safety of AROMASIN® (exemestane) in the adjuvant setting. AROMASIN has been approved for adjuvant treatment of postmenopausal women with estrogen-receptor positive (ER+) early breast cancer who have received 2 to 3 years of tamoxifen and are switched to AROMASIN for completion of a total of 5 consecutive years of adjuvant hormonal therapy.1
    The following slides are included for balance and must be presented when using this slide deck:
    Slide 10: AROMASIN® (exemestane) Tablets: Adjuvant Indication
    Slide 11: Important Safety Considerations
    Slide 25: Incidence (%) of Adverse Events: All Grades
    Slide 26: Incidence (%) of Adverse Events: All Grades
    Slide 27: Exemestane and Tamoxifen: Comparison of Adverse Events
    Slide 28: Other Event Rates
    These slides may not be altered in any way. Furthermore, efficacy results from 35- and 52-month follow-up must be presented together.
  • Breast cancer remains the most common form of cancer in women, accounting for nearly one third of all new cancers among women in the United States.1 Breast cancer tumors can be classified as one of 2 types: hormone dependent or hormone independent. Hormone-dependent tumors are ER+, progesterone receptor–positive (PR+), or both. Hormone-independent tumors are negative for both receptors. Approximately 3/4 of breast cancers are hormone dependent and can be treated with hormonal therapy.2
    Data from immunohistochemical assays used for determining the ER and PR status of women with breast cancer for 7016 breast carcinomas from 71 laboratories were analyzed between June 1996 and September 1998 to determine the frequency of receptor positivity. ER+/PR+ tumor frequency was 59.1%, ER+/PR– was 18.8%, ER–/PR– was 19.1%, and ER–/PR+ was 2.9% .3
    Approximately 75% of all diagnosed cases of breast cancer are among women aged 50 years or older.4 The relative percentage of breast cancer that is ER+ increases with age and peaks at approximately 75% in women over 70 years of age.5
  • Hormonal therapy is currently used as a treatment modality for all stages of hormone-receptor positive breast cancer.1
    The majority of breast cancers are stimulated by either estrogen or progesterone. As a consequence, the objective of hormonal therapy is to deprive the tumor of hormone-induced growth stimuli, either by blocking the ER or inhibiting estrogen synthesis.2,3
    There are a number of different treatment options, as follows:
    Selective estrogen receptor modulators (SERMs) (eg, tamoxifen) bind to the ER site, leading to attenuation of estrogen-responsive genes.2
    Aromatase inhibitors (eg, anastrozole and letrozole) and aromatase inactivators (eg, exemestane) (AIs) act to block the conversion of androgens into estrogens by inhibiting or inactivating the activity of this enzyme.4
    Ovarian ablation and/or suppression are current standard adjuvant endocrine therapies for premenopausal breast cancer.1
  • In a meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group, data were compiled from 37,000 women enrolled in 55 randomized trials that compared adjuvant tamoxifen with no tamoxifen in the treatment of early breast cancer. Of these 37,000 women, approximately 30,000 had ER+ tumors or untested tumors.1
    Among women with ER+ tumors, the reduction in the recurrence rates in the 5-year trials was 50% with tamoxifen. The proportional mortality reduction among women with ER+ tumors was 28%. Five-year therapy reduced recurrence of contralateral breast cancer by 47%.1
    The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 randomized trial looked at whether more than 5 years of tamoxifen administration would provide an advantage greater than that observed when administration of the drug was limited to 5 years.2
    A slight advantage was observed in patients who received only 5 years of tamoxifen relative to those who continued tamoxifen therapy past 5 years: disease-free survival (DFS), 82% versus 78% (P = .03); recurrence-free survival (RFS), 94% versus 92% (P = .13); and overall survival, 94% versus 91% (P = .07). A lack of benefit from additional tamoxifen therapy was independent of age or other characteristics.2
    Five years of tamoxifen was shown to be better than 2 years; >5 years of tamoxifen was worse than 5 years. The optimal duration for tamoxifen therapy is still unknown.1,2
  • Resistance to tamoxifen is complex and is an active research area in which many preclinical and clinical studies have been conducted. Some data support the notion that in a greater proportion of patients the residual or micrometastatic tumor cells may progressively become resistant to tamoxifen and could be stimulated by tamoxifen with continued use.1
    This slide is one of the hypotheses that depicts the theoretical increase in the percentage of ER+ micrometastases over time and supports the rationale for adding AIs after adjuvant tamoxifen. Ongoing tamoxifen therapy may benefit patients with tamoxifen-responsive tumor cells but would be detrimental to patients whose cells have become resistant to tamoxifen.1
  • Tumor inhibition is the main benefit of tamoxifen’s antagonist action. However, tamoxifen has an agonist effect as well. Both actions have pros and cons.1
    Hot flashes result from tamoxifen’s antiestrogen effect.2
    Clinical studies have shown that tamoxifen is a weak agonist for bone. In postmenopausal women, however, the gain in bone density after 2 years of tamoxifen therapy has been small. Tamoxifen therapy is also associated with decreases in low-density lipoprotein (LDL) cholesterol.2
    In addition, tamoxifen may develop unwanted agonist effects due to changes at the level of the ER itself, which may lead to resistance to tamoxifen at pre- and postreceptor points in the ER-response pathway.3
    Agonist tamoxifen therapy is also associated with a 2.5-fold increase in the incidence of endometrial carcinoma and an increase in thromboembolic events.1
  • Aromatase inhibitors and inactivators belong to a new generation of hormonal therapy agents. As part of the normal metabolism of cholesterol, the androgenic compounds androstenedione and testosterone are produced. Under normal circumstances, these androgenic compounds, the major source of estrogen in postmenopausal women, may be converted into the estrogenic compounds estrone and estradiol by the action of the aromatase enzyme.1
    Aromatase inhibitors and inactivators act to block the conversion of androgens into estrogens by blocking the activity of this enzyme.1
    In premenopausal women, the ovaries are the primary source of estrogen and ovarian ablation is the gold standard approach to reducing estrogen levels in these women. In postmenopausal women, estrogen is synthesized in the skin, muscle, adipose tissue, and breast cancers, requiring a systemic approach to estrogen suppression. Aromatase inhibition is effective in decreasing estrogen levels systemically in postmenopausal patients.1
  • Tamoxifen and AIs interfere with the supply of estrogen to breast cancer cells in distinct ways.1 The difference in mechanism of tamoxifen and AIs is reflected in the difference in the site of inhibition. Tamoxifen binds the ERs, thus blocking estrogen from binding. AIs inhibit estrogen synthesis by binding to aromatase, causing estrogen deprivation, thus achieving an endocrine response in ER+ breast cancer.2
    Unlike premenopausal women, the main source of estrogen in postmenopausal women is the conversion of androgens to estrogens by means of the aromatase enzyme in peripheral tissues, such as the breasts and fat.3
    Exemestane, an aromatase inactivator, irreversibly suppresses this synthesis of estrogen.2
  • Aromatase inhibitors and inactivators differ structurally and in their mechanisms of action. The steroidal inactivators exemestane and formestane are structurally similar to androstenedione, the natural substrate of aromatase.1,2
    Aminoglutethimide, letrozole, and anastrozole are nonsteroidal agents that reversibly inhibit the aromatase enzyme. Treatment with the aromatase inactivators or the inhibitors causes a marked reduction in the level of circulating and tissue estrogens.2
  • Exemestane, a steroidal inactivator, is marketed under the brand name AROMASIN® (exemestane).1
    In the United States, AROMASIN was initially approved in 1999 for the treatment of advanced breast cancer in postmenopausal women whose disease had progressed following tamoxifen treatment.1
    AROMASIN was approved in October 2005 for adjuvant treatment of postmenopausal women with ER+ early breast cancer who have received 2 to 3 years of tamoxifen and are switched to AROMASIN for completion of a total of 5 consecutive years of adjuvant hormonal therapy.1
    The recommended dose of AROMASIN is 25 mg qd after a meal.1
    For patients receiving AROMASIN with a potent CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of AROMASIN is 50 mg qd after a meal.1
    AROMASIN is manufactured by Pfizer Inc.
  • In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma Cmax and AUC 0-∞ of exemestane were decreased by 41% and 54%, respectively. Based on this study, the FDA requested dose modification information be included in the label.
  • This slide summarizes the study design for the phase 3, multinational, randomized, double-blind trial to test whether patients who remained disease free after 2 to 3 years of tamoxifen therapy were more effectively treated by switching to AROMASIN® (exemestane) than by continuing tamoxifen therapy for the remainder of their 5 years of treatment.1
    Exemestane: (ex-uh-MESS-tane)
    The postmenopausal women who had been diagnosed with primary breast cancer were randomized to receive AROMASIN (25 mg) or tamoxifen (20 or 30 mg) daily in order to complete a total of 5 years of adjuvant endocrine treatment.1 The 30 mg dose was used only in Denmark, where this dose was the standard of care.
    The target enrollment was 4400 patients. The actual number of patients randomized to the study was 4740; 4739 patients were included in the safety analysis,2 and 4724 patients were included in the efficacy intent-to-treat (ITT) analysis. Sixteen patients from a single center were disqualified. These patients were excluded from all analyses because data from this center were considered unreliable.1,2
    It is important to note that 3 separate presentations came out of the Intergroup Exemestane Study (IES). Coombes et al reported data in the New England Journal of Medicine in 2004 and then presented an update at the San Antonio Breast Cancer Symposium in December of the same year. In 2006, another update was reported by Coombes et al at the American Society of Clinical Oncology (ASCO) Annual Meeting.2
    The data cited in the prescribing information are from the same analysis as the New England Journal of Medicine publication and the 52-month update data are from the same analysis as the 2006 ASCO presentation.1,2,3
    Patients in this study continue to be followed up.
  • Between February 1998 and February 2003, 4740 women from 37 countries and 20 cooperative groups were recruited.1,2 The study was coordinated by the International Collaborative Cancer Group (ICCG), Imperial College London, and conducted under the auspices of the Breast International Group (BIG).2
  • The primary end points in this IES were DFS, defined as the time from randomization to breast cancer recurrence at any site; diagnosis of contralateral breast cancer (CLBC); or death from any cause.1,2
    Prespecified secondary end points for this study included overall survival, distant recurrence-free survival (RFS), incidence of CLBC, and long-term tolerability. 1,2
    Although a component of DFS, CLBC and distant RFS were also documented separately as a secondary end point.1,2
    The primary end point was defined differently for several of the adjuvant AI trials. For the IES study, the number of events for the primary end point of DFS included local or metastatic recurrence, CLBC, or death from any cause.2 In the MA.17 study, the primary end point of DFS included recurrence in ipsilateral breast, chest wall, locoregional nodal, and metastatic sites.3 For the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study, the number of events for the primary end point of DFS included local recurrence, distant recurrence, CLBC, and deaths before recurrence.4 In the Australian Breast and Colorectal Cancer Study Group-8/Arimidex-Nolvaldex 95 (ABCSG-8/ARNO 95) trials, the primary end point of event-free survival (EFS) was defined as freedom from locoregional recurrences, distant metastases, and CLBC.5 Finally, for the smaller Italian Tamoxifen Arimidex (ITA) trial, the primary end point of progression-free survival (PFS) was defined as locoregional and distant recurrences but not including CLBC.6
    Substudies include patient assessment of quality of life, uterine thickness, bone metabolism, and bone mineral density (BMD). This presentation focuses on the main study.7
  • Key eligibility requirements for IES included being postmenopausal at the time of diagnosis, defined as being at least age 55 years with amenorrhea for >2 years or with amenorrhea for >1 year at the time of diagnosis. Patients with previous chemotherapy (CT) treatment were permitted. Patients are required to have ER+/ER unknown breast cancer.1,2
    Key exclusion criteria included known hormone-receptor negative status; clinical evidence of local relapse or distant metastasis since initial diagnosis; and patients with osteoporosis and/or osteoporotic fractures.1
    The definition for postmenopausal status for the IES trial corresponds to the National Comprehensive Cancer Network (NCCN) Guidelines criteria for menopause which include prior bilateral oophorectomy; age ≥ 60 years; age <60 years and amenorrheic for ≥ 12 months in the absence of CT, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range; and if taking tamoxifen, and age <60 years, then FSH and plasma estradiol level in postmenopausal ranges.3
  • In the IES study, both the AROMASIN® (exemestane) and tamoxifen groups were well balanced with respect to the key baseline characteristics.
    2352 patients were randomly assigned to the AROMASIN group; 2372 patients were assigned to the tamoxifen group.
    Mean age for both arms was 63 years.
    Approximately 98% of patients were Caucasian.
    About half of patients in both arms had node-positive tumors.
    About one third in both arms had received previous chemotherapy.1
  • ER status was evenly distributed between the AROMASIN® (exemestane) and tamoxifen groups. A large majority of the patients had ER+ tumors (85.4% and 84.8% in the AROMASIN and tamoxifen groups), and over half the patients in each group had ER+/PR+ tumors.1
    ER– primary tumor was an exclusion criteria for the study. Approximately 12% of patients were ER unknown and ~2.5% were eventually determined to be ER–. Hormone status for these patients was determined after randomization.2
    Histologic type was also evenly distributed between the 2 groups; a majority of patients had infiltrating ductal carcinoma (75.6% in the AROMASIN group and 77.2% in the tamoxifen group).1
  • The data filed with the FDA and the New England Journal of Medicine data sets are both based on the second interim analysis; however, for the label data submission there was additional time to collect more events and make the data set more complete. The median follow-up for the label data submission is 34.5 months versus 30.6 months in the New England Journal of Medicine.1
    Sixteen patients were disqualified from the ITT population for the label data set from a single center. These patients were excluded from all analyses because data from this center were considered unreliable.1
    Safety for the label data submission was reported as treatment emergent, whereas safety in the New England Journal of Medicine was reported as an incidence case analysis. Treatment-emergent events are typically provided in the prescribing information (PI) and reviewed by the FDA. It includes adverse events that arose for the first time or worsened while undergoing therapy. Incidence case analysis includes all adverse events that were recorded at any time during the study period. For instance, events that occurred after randomization but before the start of new therapy are excluded in treatment-emergent events, but included in incidence case analysis.1
    For the FDA filing, at 34.5 months of median follow-up, 520 first events were reported.2
    In March 2004, Coombes et al reported data in the New England Journal of Medicine that showed 449 first events at the time of initial data release, where >90% of patients had completed the planned 5-year therapy. The Data and Safety Monitoring Committee for the IES recommended early release of the data for publication after a planned second interim analysis showed better than anticipated efficacy results.3
  • Events contributing to DFS were defined as time from randomization to breast cancer recurrence, CLBC (second primary), and death from any cause (prior to breast cancer recurrence). Events contributing to death from any cause include deaths from breast cancer, deaths for other reasons, and deaths missing or unknown.1
    These data showed that DFS was significantly improved in the AROMASIN® (exemestane) arm. Most events were associated with distant recurrence.1
    At the 2004 San Antonio Breast Cancer Symposium (SABCS) update, 262 patients in the AROMASIN arm and 353 patients in the tamoxifen arm experienced an event.2
    A 52-month update was presented at the 2006 ASCO Annual Meeting. This analysis will be discussed later in this presentation.
  • DFS is defined as the time from randomization to breast cancer recurrence at any site, CLBC (second primary), and death from any cause.1
    The analysis for the primary end points is based on an ITT patient population. In the IES study, the DFS hazard ratio (HR) for all patients was found to be 0.69 (0.58-0.82; P = .00003).1
    The time to CLBC HR for the ITT patient population was 0.32 (0.15-0.72; P = .0034). The distant RFS HR was 0.74 (0.62-0.90; P = .002) and the HR for overall survival was 0.86 (0.67-1.10; P = NS).1
    At the 2004 SABCS, Coombes et al reported the 37-month efficacy results, which were consistent with the efficacy results submitted to the FDA in the AROMASIN® (exemestane) sNDA submission.2
  • DFS is defined as the time from randomization to breast cancer recurrence at any site, CLBC (second primary), and death from any cause. This slide gives the efficacy results for hormone-receptor positive patients.1
    The DFS HR for hormone-receptor positive patients was 0.65 (0.53-0.79; P=.00001).1
    The time to CLBC HR for hormone-receptor positive patients was 0.22 (0.08-0.57; P = .00069). The distant RFS HR was 0.73 (0.59-0.90; P = .00367) and the overall survival HR was 0.88 (0.67-1.17; P = NS).1
    At the 2004 SABCS, Coombes et al reported the 37-month efficacy results, which were consistent with the efficacy results submitted to the FDA in the AROMASIN® (exemestane) sNDA submission.2
  • Patients were randomly assigned to switch to AROMASIN® (exemestane) (n = 2352) or continue on tamoxifen (n = 2372) and were followed up for a median of 34.5 months. There were 213 events (9%) in the AROMASIN group and 307 events (13%) in the tamoxifen group, with an unadjusted HR of 0.69 (95% CI: 0.58-0.82; P = .00003). This translates into a 31% reduction in the risk of relapse for AROMASIN compared with tamoxifen.1
    The DFS HR for the hormone-receptor positive patient population was 0.65 (0.53-0.79; P = .00001).1
    These data are consistent with observations made in Coombes et al’s article from the March 2004 New England Journal of Medicine, as well as in the update presented in December 2004 at SABCS.2
    AROMASIN demonstrated consistent results in patients with node-positive or node-negative disease, and with or without prior CT.1
  • AROMASIN® (exemestane) demonstrated consistent results in patients with node-positive or node-negative disease, and with or without prior chemotherapy. HRs were unaffected by adjustment for prespecified baseline factors. Notably, no heterogeneity was found between number of positive nodes, use or type of previous CT, or use at any time of hormone-replacement therapy, suggesting all patients received clinical benefit.1,2
    These data are consistent with the observations made in Coombes’ article from the March 2004 New England Journal of Medicine.3
  • This slide shows overall survival for switching to AROMASIN® (exemestane) versus continuing tamoxifen therapy for the remainder of the 5 years of treatment.1,2
    In this data set submitted to the FDA at 34.5 months of median follow-up, there were 116 deaths in the AROMASIN group versus 137 in the tamoxifen group (P = .23).1 An effort was made to ensure that all events that occurred by the cutoff date were collected and included in the analysis. This reflects an update of the initial data released in March 2004, the New England Journal of Medicine publication in which Coombes et al reported that at 30 months of median follow-up, there were 93 deaths in the AROMASIN group and 106 in the tamoxifen group (P = .37).3
    Coombes et al presented follow-up data at SABCS 2004 demonstrating that at 37 months of median follow-up, there were 152 deaths in the AROMASIN group versus 187 in the tamoxifen group (P = .08).4
  • These data from the IES study show the common adverse events (defined as those occurring with an incidence of ≥ 5%) for all grades. AROMASIN® (exemestane) was generally well tolerated and adverse events were usually mild to moderate.1
    All patients in the exemestane and tamoxifen arms had received 2 to 3 years of prior tamoxifen therapy and had tolerated tamoxifen treatment.1
  • These data from the IES study show the common adverse events (defined as those occurring with an incidence of ≥ 5%) for all grades. AROMASIN® (exemestane) is generally well tolerated and adverse events were usually mild to moderate.1
    All patients in the exemestane and tamoxifen arms had received 2 to 3 years of prior tamoxifen therapy and had tolerated tamoxifen treatment.1
  • These data from the IES study show adverse events occurring at a rate of <5% of the study population, but are considered in clinical treatment decision making.1
    All patients in both arms had received 2 to 3 years of prior tamoxifen therapy and had tolerated tamoxifen treatment.1
  • The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane-treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane-treated patients and 0.3% of tamoxifen-treated patients. There were 6 deaths due to stroke on the exemestane arm compared with 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared with 2 on tamoxifen. IES was not designed to compare cardiovascular risks and randomization was not stratified to assess cardiovascular risk.1
    Cardiac adverse events were not recorded as treatment emergent. Instead, patients who had discontinued treatment were monitored for an extended period of time and included in the safety analysis.1 An additional safety update is planned.
    The rate of “deaths due to any cause” is based on safety data and NOT the primary end point “deaths of any cause.”
    In study 027 of postmenopausal women with early breast cancer treated with exemestane (n = 73) or placebo (n = 73), plasma high-density lipoprotein (HDL) cholesterol was decreased in approximately 6% to 9% of patients treated with exemestane; total cholesterol, LDL cholesterol, triglycerides, apo-A1, apo-B, and lipoprotein-a were unchanged.1
  • This slide shows the percent change in BMD from baseline to 24 months for patients in 027 and the IES bone subprotocol.1 Study 027 specifically compared AROMASIN® (exemestane) to placebo, while the IES bone subprotocol compared AROMASIN after 2-3 years of tamoxifen with tamoxifen, which has a positive effect on bone, after 2-3 years of tamoxifen.2,3
    In 027, postmenopausal women with early breast cancer and no other risk factors were randomized to receive a 2-year treatment of AROMASIN (25 mg qd) or placebo. The primary objective was to evaluate BMD.2
    As shown by this slide, exemestane demonstrated increased reductions in BMD over time in both the lumbar spine and femoral neck compared with placebo in the 027 bone study.1
    Between April 2000 and February 2003, 206 patients (101 exemestane; 105 tamoxifen) from the main IES trial were entered into the IES bone subprotocol. At baseline, there were no significant differences in BMD, T-scores, or proportion of osteopenic patients between the 2 groups. The primary end point for this study was the annual change from baseline in lumbar spine and total hip BMD (as percentage of baseline BMD).4
    Overall, reductions in BMD over time were seen with exemestane compared with tamoxifen.1 The decrease in BMD in exemestane patients in the bone substudy compared with tamoxifen may be due, in part, to tamoxifen withdrawal rather than only to an exemestane effect.4
    Notably, the IES bone subprotocol studied the effects of exemestane versus tamoxifen, a “bone-builder,” while 027 reported the effects of exemestane versus placebo.4
  • An updated analysis of the IES trial data showed results from a median follow-up of 52.4 months. Improvement in DFS and OS continued to be seen in early breast cancer patients who switched to AROMASIN® (exemestane) after 2 to 3 years of tamoxifen.1
    Patients were on therapy for a median of 30 months and the median duration of follow-up after completion of therapy was 25 months.1 Analyses were performed for both ITT and ER+/ER unknown patients.
    One hundred and twenty two patients with previously ER unknown disease were later determined to be ER-negative and were subsequently removed from further analysis by the IES steering committee, with the approval of the Independent Data Monitoring Committee (IDMC).1
    The ER+/ER unknown subgroup, which specifically excludes ER-negative patients, was proposed by the ICCG Coordinating Data Center (CDC) and endorsed by the IES IDMC based on the well-established knowledge that ER-negative patients are unlikely to benefit from either treatment.
    At the 2006 ASCO meeting, the IES steering committee presented the data based on 56 months of follow-up. Both the 56-month data presented at ASCO and the 52-month follow-up presented here are based on the same analysis.1
  • Although the 2006 ASCO abstract reported 58-month median follow-up, upon further preparation for the presentation it was recalculated to be 55.7 months.
    The Pfizer analysis reports a 52.4-month median follow-up based on the same data-cut. This is a result of differences in the methods used by Pfizer and by the ICCG in censoring data. The ICCG calculated the median follow-up using a reverse Kaplan-Meier, ie, censoring at death and using date last known for each patient. This calculation gives more weight to the patients still alive. Pfizer’s calculation gave the same weight to all patients, alive or dead. ASCO also utilized an incident cases analysis which included all events while on the drug and after 2 years post follow-up, while Pfizer utilized a treatment emergent analysis that only included events while on the drug or 30 days after treatment cessation.
  • DFS is defined as the time from randomization to breast cancer recurrence at any site, CLBC (second primary), and death from any cause.1 This slide gives the efficacy results for the ITT population at 52.4 months of median follow-up.2
    The DFS HR for all patients was found to be 0.76 (0.67-0.88; P = .00015), with 354 events in the AROMASIN® (exemestane) group and 453 in the tamoxifen group.2
    The time to CLBC HR for the ITT patient population was 0.57 (0.33-0.99; P = .00041), with 20 events in the AROMASIN group vs 35 in the tamoxifen group. The distant RFS HR was 0.83 (0.70-0.98; P = .03), with 229 events in the AROMASIN group and 269 in the tamoxifen group.2
    The HR for overall survival was 0.85 (0.71-1.02; P = .07), with 222 and 262 events in the AROMASIN and tamoxifen groups, respectively.1
    When interpreting the HR information, it is important to note that on average patients had stopped taking either tamoxifen or AROMASIN therapy for 25 months.2
  • DFS is defined as the time from randomization to breast cancer recurrence at any site, CLBC (second primary), and death from any cause.1 This slide gives the efficacy results for the ER+/ER unknown population at 52.4 months of median follow-up.2
    The DFS HR for ER+/ER unknown patients was 0.75 (0.65-0.87; P=.00008), with 338 events in the AROMASIN® (exemestane) group compared with 437 in the tamoxifen group.2
    The time to CLBC HR for ER+/ER unknown patients was 0.54 (0.31-0.94; P = .027), with 19 events in the AROMASIN group vs 35 in the tamoxifen group. The distant RFS HR was 0.82 (0.69-0.97; P = .02), with 236 events in the AROMASIN group and 285 in the tamoxifen group.2
    The overall survival HR was 0.83 (0.69-0.99; P = .04), with 209 and 252 events in the AROMASIN and tamoxifen arms, respectively.2
    When interpreting the HR information, it is important to note that on average patients had stopped taking either tamoxifen or AROMASIN therapy for 25 months.2
  • This Kaplan-Meier curve shows the DFS of the IES study ITT population. Patients randomly assigned to switch to AROMASIN® (exemestane) (n = 2352) and those assigned to continue on tamoxifen (n = 2372) were followed up for a median of 52.4 months. There were 354 events (15%) in the AROMASIN group and 453 events (19%) in the tamoxifen group, with an unadjusted HR of 0.76 (95% CI: 0.67-0.88; P = .00015).1
    It is important to note that the median duration of therapy was 30 months after randomization while the median follow-up is 52 months.1
  • This slide shows the DFS of the IES study after a median of 52.4 months in the ER+/ER unknown population. This population consisted of 2295 patients in the AROMASIN® (exemestane) arm and 2306 in the tamoxifen arm. There were 338 events (15%) in the AROMASIN group and 437 events (19%) in the tamoxifen group, with an unadjusted HR of 0.75 (95% CI: 0.65-0.87; P = .00008).1
    Again, it is important to note that the median duration of therapy was 30 months after randomization while the median follow-up was 52 months.
  • This slide shows OS for switching to AROMASIN® (exemestane) vs continuing tamoxifen therapy after 52.4 months of follow-up.1
    The ITT population showed the same statistical trend as seen at the 34.5-month follow-up in favor of AROMASIN, with 222 deaths in the AROMASIN group vs 262 in the tamoxifen group (P = .07).1
  • This slide shows OS in the ER+/ER unknown population, comparing the groups switching to AROMASIN® (exemestane) vs continuing tamoxifen therapy after 52.4 months of follow-up.1
    In the ER+/ER unknown population, there were 209 deaths in the AROMASIN group vs 252 in the tamoxifen group, with a P value demonstrating statistical significance (P = .043).1
  • These safety data from the IES study 52.4-month follow-up show the most common adverse events reported by ≥ 5% of subjects in either group or between-treatment comparisons achieving statistical significance at a 1% level. These adverse events were reported as treatment emergent. AROMASIN® (exemestane) was generally well tolerated and adverse events were usually mild to moderate.1
    All patients in both arms had tolerated tamoxifen treatment well enough to continue therapy for at least 2 years.2
  • This slide is a continuation of the previous slide and shows further safety data from the 52.4-month follow-up to the IES study. As with the prior slide, these adverse events were reported as treatment emergent (with the exception of fracture rate), with only the most common adverse events reported by ≥ 5% of subjects in either group or between-treatment comparisons achieving statistical significance at a 1% level shown.1
    Of note, the fracture rate reported here is an incident cases analysis showing a rate of 7.0% and 4.9% in the AROMASIN® (exemestane) and tamoxifen arms, respectively (P = .002). When performing a treatment emergent analysis, the rates are 4.5% and 3.3% in the AROMASIN® and tamoxifen groups, respectively (P = 0.038). It is important to once again note that the incident cases analysis included all events while on the drug and after 2 years post–follow-up, while the treatment emergent analysis only included events while on the drug or 30 days after treatment cessation.1
  • The cardiovascular events recorded during the 52.4-month median follow-up of the IES study are shown here. The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 4.5% in AROMASIN® (exemestane) treated patients and 4.2% in tamoxifen-treated patients. Stroke occurred in 0.3% of patients in the exemestane arm and 0.5% of those in the tamoxifen arm. Cardiac failure was observed in 1.0% of exemestane-treated patients and 0.8% of tamoxifen-treated patients. IES was not designed to compare cardiovascular risks, and randomization was not stratified to assess cardiovascular risk.1
    Cardiac adverse events were recorded as treatment emergent.1
  • After median follow-up of 52.4 months, patients with early breast cancer who switched to AROMASIN® (exemestane) after 2 to 3 years of tamoxifen therapy showed significant improvement in DFS at 25 months after the completion of therapy.1
    Risk of dying was reduced by 15% for the ITT population (P=.07362) and by 17% in patients with ER+/ER unknown early breast cancer (P=.0425) in those who switched to AROMASIN.1
    AROMASIN was generally safe and well tolerated after 52.4 months of follow-up.1
  • In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma Cmax and AUC 0-∞ of exemestane were decreased by 41% and 54%, respectively. Based on this study, the FDA requested dose modification information be included in the label.
  • Transcript

    • 1. 1 AROMASINAROMASIN®® (exemestane): Adjuvant(exemestane): Adjuvant Therapy for Early Stage Breast CancerTherapy for Early Stage Breast Cancer After 2 to 3 Years of TamoxifenAfter 2 to 3 Years of Tamoxifen Please see full prescribing information.Please see full prescribing information.
    • 2. 2 American Cancer Society.American Cancer Society. Cancer Facts and Figures 2005.Cancer Facts and Figures 2005. Atlanta, Ga: American CancerAtlanta, Ga: American Cancer Society, Inc.; 2005Society, Inc.; 2005;; Johnston et al.Johnston et al. Nat Rev Cancer.Nat Rev Cancer. 2003;32003;3::821-831.821-831. Breast CancerBreast Cancer • Breast cancer is the most commonly diagnosedBreast cancer is the most commonly diagnosed cancer among women in the United Statescancer among women in the United States • It is estimated that 212,930 new cases and 40,870It is estimated that 212,930 new cases and 40,870 deaths will result from breast cancer in 2005deaths will result from breast cancer in 2005 • About 3/4 of breast cancers are estrogen receptorAbout 3/4 of breast cancers are estrogen receptor (ER)(ER)––and/or progesterone receptor (PR)and/or progesterone receptor (PR)––positivepositive and are, therefore, suitable for hormonal therapyand are, therefore, suitable for hormonal therapy • The majority of women diagnosed with breast cancerThe majority of women diagnosed with breast cancer are postmenopausalare postmenopausal
    • 3. 3 Hormonal Therapy OptionsHormonal Therapy Options MechanismMechanism Therapeutic Modality ExamplesTherapeutic Modality Examples ER blockadeER blockade Selective estrogen-receptorSelective estrogen-receptor modulators (SERMs)modulators (SERMs) Selective estrogen-receptorSelective estrogen-receptor down-regulators (SERDs)down-regulators (SERDs) Estrogen synthesisEstrogen synthesis suppressionsuppression (postmenopausal women)(postmenopausal women) Aromatase inhibitor/inactivator (AI)Aromatase inhibitor/inactivator (AI) Hormonal ablationHormonal ablation (premenopausal women)(premenopausal women) LHRH analogues, radiation,LHRH analogues, radiation, surgerysurgery OtherOther Androgens, progesterone,Androgens, progesterone, progestational agentsprogestational agents LHRHLHRH == luteinizing hormone-releasing hormone.luteinizing hormone-releasing hormone. Hayes DF et al. In: Robertson et al, eds.Hayes DF et al. In: Robertson et al, eds. Endocrine Therapy of Breast CancerEndocrine Therapy of Breast Cancer. 2002:3-10.. 2002:3-10. Robertson JF.Robertson JF. Clin TherClin Ther. 2002;24(suppl A):A17-A30.. 2002;24(suppl A):A17-A30.
    • 4. 4 Tamoxifen Has Been the Standard of CareTamoxifen Has Been the Standard of Care • 21%, 28%, and 50% relative risk reduction in 1-year,21%, 28%, and 50% relative risk reduction in 1-year, 2-year, and 5-year trials of tamoxifen therapy over2-year, and 5-year trials of tamoxifen therapy over placebo, respectivelyplacebo, respectively • 28% reduction of death with 5 years of tamoxifen28% reduction of death with 5 years of tamoxifen therapy over placebotherapy over placebo • 47% relative risk reduction of contralateral breast47% relative risk reduction of contralateral breast cancer with 5 years of therapy over placebocancer with 5 years of therapy over placebo • Current standard of tamoxifen treatment is 5 years.Current standard of tamoxifen treatment is 5 years. However, the absolute benefit per year decreases overHowever, the absolute benefit per year decreases over the duration of therapythe duration of therapy Early Breast Cancer Trialists’ Collaborative Group.Early Breast Cancer Trialists’ Collaborative Group. LancetLancet. 1998;351:1451-1467.. 1998;351:1451-1467. Fisher B et al.Fisher B et al. J Natl Cancer Inst.J Natl Cancer Inst. 2001;93:684-690.2001;93:684-690. Meta-analysis of 55 trials and approximatelyMeta-analysis of 55 trials and approximately 30,000 women with ER+ tumors30,000 women with ER+ tumors::
    • 5. 5 Resistance to Tamoxifen Over TimeResistance to Tamoxifen Over Time Hypothetical ModelHypothetical Model Based on Clinical ObservationBased on Clinical Observation Mamounas E.Mamounas E. Oncology (Huntingt)Oncology (Huntingt). 2001;15:35-39.. 2001;15:35-39. ER+, Sensitive to Tamoxifen ER+, Stimulated by Tamoxifen Year 0 20 40 60 80 100 1 2 3 4 5 ER+Micrometastases(%)
    • 6. 6 Tamoxifen Has Both Antagonist andTamoxifen Has Both Antagonist and Agonist EffectsAgonist Effects Riggs L et al.Riggs L et al. N Engl J Med.N Engl J Med. 2003;348:618-629. Johnston SRD et al.2003;348:618-629. Johnston SRD et al. Nat Rev CancerNat Rev Cancer.. 2003;3:821-831.2003;3:821-831. TamoxifenTamoxifen AntagonisAntagonistt AgonistAgonist • Tumor inhibitionTumor inhibition • Hot flashesHot flashes • Potential tumor stimulationPotential tumor stimulation • ↑↑ Risk of endometrial cancerRisk of endometrial cancer and thromboembolic effectsand thromboembolic effects • Lowers cholesterolLowers cholesterol • Preserves bone densityPreserves bone density
    • 7. 7 EstroneEstrone EstradiolEstradiol TestosteroneTestosterone AIs and inactivators AIs and inactivators AndrostenedioneAndrostenedione Aromatase Inhibition andAromatase Inhibition and Inactivation: Mechanism of ActionInactivation: Mechanism of Action CholesterolCholesterolCholesterolCholesterol ↑ CortisolCortisol↑ CortisolCortisol ProgesteroneProgesteroneProgesteroneProgesterone AldosteroneAldosteroneAldosteroneAldosterone PregnenolonePregnenolonePregnenolonePregnenolone AromataseAromataseAromataseAromatase Miller WR et al.Miller WR et al. Cancer Control.Cancer Control. 2002;9(suppl):9-15.2002;9(suppl):9-15. AromataseAromataseAromataseAromatase
    • 8. 8 Differences in AI and TamoxifenDifferences in AI and Tamoxifen Mechanism of ActionMechanism of Action EREsEREs == estrogen response elements.estrogen response elements. Johnston SRD et al.Johnston SRD et al. Nat Rev Cancer.Nat Rev Cancer. 2003;3:821-831. Adapted with permission:2003;3:821-831. Adapted with permission: http://www.nature.com.http://www.nature.com. AndrogensAndrogens AI (eg, exemestane)AI (eg, exemestane)AromataseAromataseAromataseAromatase EstrogensEstrogens TamoxifenTamoxifenTamoxifenTamoxifen ↑ ProliferationProliferation↑ ProliferationProliferation ER target genesER target genesER target genesER target genesEREsEREsEREsEREs ERER ERER
    • 9. 9 Differences in the Structures ofDifferences in the Structures of Aromatase Inhibitors and Inactivators*Aromatase Inhibitors and Inactivators* AndrostenedioneAndrostenedione Steroidal (inactivators)Steroidal (inactivators) Androgen substrateAndrogen substrate Nonsteroidal (inhibitors)Nonsteroidal (inhibitors) HH AminoglutethimideAminoglutethimide OO NHNH22 CC22 HH55 OONN ExemestaneExemestane OO CHCH22 OO FormestaneFormestane OO OHOH OO OO OO LetrozoleLetrozole CNCNNCNC NN NN NN AnastrozoleAnastrozole CHCH33 CHCH33 CHCH33 CHCH33 NN NN NN CNCNNCNC *The clinical significance of these differences is unknown.*The clinical significance of these differences is unknown. Goss PE et al.Goss PE et al. J Clin Oncol.J Clin Oncol. 2001;19:881-894; Goss P. Available at:2001;19:881-894; Goss P. Available at: http://www.medscape.com/viewprogram/1022_pnt. Accessed September 26, 2005.http://www.medscape.com/viewprogram/1022_pnt. Accessed September 26, 2005.
    • 10. 10 AROMASINAROMASIN®® (exemestane) Tablets:(exemestane) Tablets: Adjuvant IndicationAdjuvant Indication AROMASIN is indicated for adjuvant treatment ofAROMASIN is indicated for adjuvant treatment of postmenopausal women with ER+ early breastpostmenopausal women with ER+ early breast cancer who have received 2 to 3 years ofcancer who have received 2 to 3 years of tamoxifen and are switched to AROMASIN fortamoxifen and are switched to AROMASIN for completion of a total of 5 consecutive years ofcompletion of a total of 5 consecutive years of adjuvant hormonal therapy.adjuvant hormonal therapy. Please see full prescribing information.Please see full prescribing information.
    • 11. 11 Important Safety ConsiderationsImportant Safety Considerations • AROMASINAROMASIN®® (exemestane) should not be used in women who are(exemestane) should not be used in women who are – PremenopausalPremenopausal – Nursing or pregnantNursing or pregnant – Known to be hypersensitive to the drugKnown to be hypersensitive to the drug – Taking estrogen-containing agentsTaking estrogen-containing agents • For patients receiving exemestane with a potent CYP 3A4 inducer,For patients receiving exemestane with a potent CYP 3A4 inducer, such as rifampicin or phenytoin, the recommended dose ofsuch as rifampicin or phenytoin, the recommended dose of exemestane is 50 mg qd after a mealexemestane is 50 mg qd after a meal • In patients with early breast cancer, elevations in bilirubin, alkalineIn patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receivingphosphatase, and creatinine were more common in those receiving AROMASINAROMASIN • Reductions in bone mineral density over time are seen with use ofReductions in bone mineral density over time are seen with use of AROMASINAROMASIN Please see full prescribing information.Please see full prescribing information.
    • 12. 12 IES Trial DesignIES Trial Design Multinational, Double-Blinded, Randomized, Landmark TrialMultinational, Double-Blinded, Randomized, Landmark Trial RR AA NN DD OO MM II ZZ AA TT II OO NN RR AA NN DD OO MM II ZZ AA TT II OO NN Diagnosis andDiagnosis and Initial TreatmentInitial Treatment of Earlyof Early Breast CancerBreast Cancer TamoxifenTamoxifen 2 to 3 years2 to 3 years 20 mg po qd*20 mg po qd* (n(n == 2372)2372) AROMASINAROMASIN®® 2 to 3 years2 to 3 years 25 mg po qd25 mg po qd (n(n == 2352)2352) Total of 5 Consecutive YearsTotal of 5 Consecutive Years of Hormonal Therapyof Hormonal Therapy Total of 5 Consecutive YearsTotal of 5 Consecutive Years of Hormonal Therapyof Hormonal Therapy TamoxifenTamoxifen TherapyTherapy 2 to 3 years2 to 3 years NN == 47244724 Patient stratification:Patient stratification: Node statusNode status Prior chemotherapy (CT)Prior chemotherapy (CT) Hormone receptor statusHormone receptor status NN == 47244724 Patient stratification:Patient stratification: Node statusNode status Prior chemotherapy (CT)Prior chemotherapy (CT) Hormone receptor statusHormone receptor status *Approximately 3% of patient population received tamoxifen 30 mg po qd.*Approximately 3% of patient population received tamoxifen 30 mg po qd. Median follow-up 34.5 months.Median follow-up 34.5 months. Please see full prescribing information.Please see full prescribing information. Patient EndsPatient Ends Therapy andTherapy and ContinuesContinues Follow-upFollow-up
    • 13. 13 IES: Collaboration BetweenIES: Collaboration Between 20 International Trials Groups20 International Trials Groups A total of 367 hospitals in 37 countriesA total of 367 hospitals in 37 countries Total number of patients = 4740Total number of patients = 4740 United StatesUnited States 364364 South AmericanSouth American ArgentinaArgentina 148148 PeruPeru 77 AfricaAfrica South AfricaSouth Africa 1919 EgyptEgypt 77 AustraliaAustralia AustraliaAustralia 4848 New ZealandNew Zealand 2222 AsiaAsia Hong Kong 6Hong Kong 6 EuropeEurope United KingdomUnited Kingdom 594594 IrelandIreland 5858 FranceFrance 398398 BelgiumBelgium 171171 SwitzerlandSwitzerland 5555 GermanyGermany 185185 DenmarkDenmark 136136 GreeceGreece 4141 ItalyItaly 616616 LuxembourgLuxembourg 44 NetherlandsNetherlands 306306 BulgariaBulgaria 8383 CroatiaCroatia 117117 Czech RepublicCzech Republic 6464 EstoniaEstonia 55 HungaryHungary 7777 RussiaRussia 4848 SlovakiaSlovakia 6161 SloveniaSlovenia 4040 YugoslaviaYugoslavia 4141 RomaniaRomania 6363 PolandPoland 311311 SpainSpain 254254 PortugalPortugal 2828 MaltaMalta 1212 NorwayNorway 126126 SwedenSweden 163163 IsraelIsrael 6262 BosniaBosnia 22 Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY.
    • 14. 14 IES Study End PointsIES Study End Points • Primary end pointPrimary end point – Disease-free survival (DFS) defined as:Disease-free survival (DFS) defined as:  Breast cancer recurrence at any siteBreast cancer recurrence at any site  Contralateral breast cancer (CLBC) (secondContralateral breast cancer (CLBC) (second primary)primary)  Death from any cause (prior toDeath from any cause (prior to breast cancer recurrence)breast cancer recurrence) • Secondary end pointsSecondary end points – Overall survivalOverall survival – Distant RFSDistant RFS – Contralateral breast cancerContralateral breast cancer – Long-term tolerabilityLong-term tolerability Coombes RC et al.Coombes RC et al. N Engl J MedN Engl J Med. 2004;350:1081-1092.. 2004;350:1081-1092.
    • 15. 15 IES Key Entry CriteriaIES Key Entry Criteria • Inclusion criteriaInclusion criteria – 2 to 3 years of adjuvant tamoxifen therapy2 to 3 years of adjuvant tamoxifen therapy – Confirmed postmenopausal status atConfirmed postmenopausal status at time of diagnosistime of diagnosis – Previous CT permittedPrevious CT permitted – ER+/ER unknown statusER+/ER unknown status • Exclusion criteriaExclusion criteria – Known ERKnown ER–– statusstatus – Clinical evidence of local relapse or distantClinical evidence of local relapse or distant metastasesmetastases – Osteoporosis and/or osteoporotic fracturesOsteoporosis and/or osteoporotic fractures Data on file. Pfizer Inc, New York, NY. Coombes RC et al.Data on file. Pfizer Inc, New York, NY. Coombes RC et al. N Engl J MedN Engl J Med. 2004;350:1081-1092.. 2004;350:1081-1092.
    • 16. 16 Patient CharacteristicsPatient Characteristics CharacteristicCharacteristic Switch toSwitch to AROMASINAROMASIN®® (n = 2352)(n = 2352) Continue onContinue on TamoxifenTamoxifen (n = 2372)(n = 2372) DemographicsDemographics Median age, yearsMedian age, years 6363 6363 Race (%)Race (%) CaucasianCaucasian Other (including Hispanic, Asian, Black)Other (including Hispanic, Asian, Black) 98.498.4 1.61.6 98.498.4 1.61.6 Adjuvant Chemotherapy (%)Adjuvant Chemotherapy (%) YesYes NoNo 32.932.9 67.167.1 32.432.4 67.667.6 Nodal status (%)Nodal status (%) NegativeNegative PositivePositive 1 to 3 nodes positive1 to 3 nodes positive 4 to 9 nodes positive4 to 9 nodes positive >9 nodes positive>9 nodes positive Other*Other* 51.751.7 44.744.7 30.730.7 10.210.2 3.73.7 3.73.7 51.851.8 44.044.0 29.829.8 10.310.3 3.63.6 4.54.5 *Includes not reported, unknown, or missing nodal status.*Includes not reported, unknown, or missing nodal status. Please see full prescribing information.Please see full prescribing information.
    • 17. 17 PatientPatient Characteristics (cont’d)Characteristics (cont’d) *These include patients with tumors for which the ER status was unknown at randomization.*These include patients with tumors for which the ER status was unknown at randomization. Please see full prescribing information.Please see full prescribing information. CharacteristicCharacteristic Switch toSwitch to AROMASINAROMASIN®® (n(n == 2352)2352) Continue onContinue on TamoxifenTamoxifen (n(n == 2372)2372) ER status* (%)ER status* (%) ER+/PR+ER+/PR+ ER+/PR– or PR-unknownER+/PR– or PR-unknown OtherOther ER unknown/PR+ or PR unknownER unknown/PR+ or PR unknown ER–/PR+ER–/PR+ ER–/PR– or PR unknownER–/PR– or PR unknown MissingMissing 56.6%56.6% 28.8%28.8% 14.6%14.6% 12.2%12.2% 0.3%0.3% 2.0%2.0% 0.1%0.1% 55.6%55.6% 29.2%29.2% 15.2%15.2% 12.3%12.3% 0.3%0.3% 2.4%2.4% 0.2%0.2% Histologic type (%)Histologic type (%) Infiltrating ductalInfiltrating ductal Infiltrating lobularInfiltrating lobular OtherOther 75.6%75.6% 14.5%14.5% 9.8%9.8% 77.2%77.2% 13.5%13.5% 9.0%9.0%
    • 18. 18 Results From the 34.5 Month Follow-up:Results From the 34.5 Month Follow-up: Label Data and NEJM PublicationLabel Data and NEJM Publication • N Engl J MedN Engl J Med publication, March 2004 (Npublication, March 2004 (N ==4742*; median4742*; median f/u 30.6 mo; eventsf/u 30.6 mo; events ==449)449) – Cutoff date June 30, 2003Cutoff date June 30, 2003 – Events received by cutoff dateEvents received by cutoff date – Safety reported as incidence case analysis afterSafety reported as incidence case analysis after randomizationrandomization • FDA approved label (NFDA approved label (N==4740; median f/u 34.5 mo;4740; median f/u 34.5 mo; eventsevents==520)520) – Cutoff date June 30, 2003Cutoff date June 30, 2003 – Events occurred by cutoff dateEvents occurred by cutoff date – Safety reported as treatment emergentSafety reported as treatment emergent *2 patients were found to be counted twice.*2 patients were found to be counted twice. f/uf/u == follow-up.follow-up. Data on file. Pfizer Inc, New York, NY;Data on file. Pfizer Inc, New York, NY; Coombes RC et al.Coombes RC et al. N Engl J MedN Engl J Med. 2004;350:1081-1092.. 2004;350:1081-1092. Please see full prescribing information.Please see full prescribing information.
    • 19. 19 Number of Events to DFS at 34.5 MonthsNumber of Events to DFS at 34.5 Months Switch toSwitch to AROMASINAROMASIN®® (n(n == 2352)2352) Continue onContinue on TamoxifenTamoxifen (n(n == 2372)2372) TotalTotal Local-regional recurrenceLocal-regional recurrence 34 (1.5%)34 (1.5%) 45 (1.9%)45 (1.9%) 7979 Distant recurrenceDistant recurrence 126 (5.4%)126 (5.4%) 183 (7.7%)183 (7.7%) 309309 Second primarySecond primary—CLBC—CLBC 7 (0.3%)7 (0.3%) 25 (1.0%)25 (1.0%) 3232 Deaths of any causeDeaths of any cause** 45 (1.9%)45 (1.9%) 54 (2.3%)54 (2.3%) 9999 Ipsilateral breast cancerIpsilateral breast cancer 1 (0.04%)1 (0.04%) 00 11 Total number of eventsTotal number of events 213 (9.1%)213 (9.1%) 307 (13.0%)307 (13.0%) 520520 ** Includes deaths for other reasons and deaths missing or unknown.Includes deaths for other reasons and deaths missing or unknown. Please see full prescribing information.Please see full prescribing information.
    • 20. 20 Efficacy Results: ITT PopulationEfficacy Results: ITT Population ITT PopulationITT Population HRHR 95% CI95% CI PP ValueValue DFSDFS 0.690.69 0.58-0.820.58-0.82 .00003.00003 CLBCCLBC 0.320.32 0.15-0.720.15-0.72 .0034.0034 Distant RFSDistant RFS 0.740.74 0.62-0.900.62-0.90 .002.002 Overall survivalOverall survival 0.860.86 0.67-1.100.67-1.10 NSNS ITTITT == intent-to-treat; HRintent-to-treat; HR == hazard ratio; CIhazard ratio; CI == confidence interval; NSconfidence interval; NS == not significant.not significant.
    • 21. 21 Efficacy Results: Hormone-ReceptorEfficacy Results: Hormone-Receptor Positive PatientsPositive Patients Hormone-ReceptorHormone-Receptor Positive PatientsPositive Patients HRHR 95% CI95% CI PP ValueValue DFSDFS 0.650.65 0.53-0.790.53-0.79 .00001.00001 CLBCCLBC 0.220.22 0.08-0.570.08-0.57 .00069.00069 Distant RFSDistant RFS 0.730.73 0.59-0.900.59-0.90 .00367.00367 Overall survivalOverall survival 0.880.88 0.67-1.170.67-1.17 NSNS Please see full prescribing information.Please see full prescribing information.
    • 22. 22 Disease-Free SurvivalDisease-Free Survival Months From RandomizationMonths From Randomization Patients,DFS(%)Patients,DFS(%) 100100 8080 6060 4040 2020 00 00 2020 4040 60601010 3030 5050 7070 AROMASINAROMASIN®® ITT PopulationITT Population TamoxifenTamoxifen Median follow-upMedian follow-up == 34.5 months34.5 months EventsEvents PatientsPatients AROMASIN (nAROMASIN (n == 2352)2352) 213213 9%9% Tamoxifen (nTamoxifen (n == 2372)2372) 307307 13%13% Please see full prescribing information.Please see full prescribing information. HRHR == 0.69 (0.58-0.82)0.69 (0.58-0.82) PP == .00003.00003
    • 23. 23 *P*P == .00003; CT.00003; CT == chemotherapy; PgRchemotherapy; PgR == progesterone receptor.progesterone receptor. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information. DFS Subgroup Analysis: Forest PlotDFS Subgroup Analysis: Forest Plot HR Log ScaleHR Log Scale 0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 Hazard RatioHazard Ratio HR (95% CI)HR (95% CI) 0.69 (0.58-0.82)*0.69 (0.58-0.82)* 0.70 (0.56-0.88)0.70 (0.56-0.88) 0.67 (0.51-0.88)0.67 (0.51-0.88) 0.67 (0.46-0.96)0.67 (0.46-0.96) 0.63 (0.46-0.85)0.63 (0.46-0.85) 0.74 (0.54-1.02)0.74 (0.54-1.02) 0.65 (0.53-0.79)0.65 (0.53-0.79) SubgroupSubgroup All patientsAll patients No previous CTNo previous CT Previous CTPrevious CT 4-9 nodes positive4-9 nodes positive 1-3 nodes positive1-3 nodes positive Nodes negativeNodes negative ER and/or PgR+ER and/or PgR+ >9 nodes positive>9 nodes positive 0.62 (0.36-1.07)0.62 (0.36-1.07) 1.41.4 ER+/PgRER+/PgR–– ER+/PgR+ER+/PgR+ 0.66 (0.51-0.84)0.66 (0.51-0.84) 0.68 (0.45-1.020.68 (0.45-1.02))
    • 24. 24 Overall SurvivalOverall Survival Months From RandomizationMonths From Randomization PatientsSurviving(%)PatientsSurviving(%) 100100 8080 6060 4040 2020 00 00 2020 4040 60601010 3030 5050 7070 TamoxifenTamoxifen AROMASINAROMASIN®® Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information. ITT PopulationITT Population Median follow-upMedian follow-up == 34.5 months34.5 months DeathsDeaths PatientsPatients AROMASIN (nAROMASIN (n == 2352)2352) 116116 5%5% Tamoxifen (nTamoxifen (n == 2372)2372) 137137 6%6% HRHR == 0.86 (0.67-1.10)0.86 (0.67-1.10) PP == NSNS
    • 25. 25 Body System andBody System and Adverse EventAdverse Event Switch to AROMASINSwitch to AROMASIN®® (n(n == 2252)2252) Continue on TamoxifenContinue on Tamoxifen (n(n == 2280)2280) General DisordersGeneral Disorders FatigueFatigue 16.1%16.1% 14.7%14.7% MusculoskeletalMusculoskeletal ArthralgiaArthralgia Pain in limbPain in limb Back painBack pain OsteoarthritisOsteoarthritis 14.6%14.6%†† 9.0%9.0%†† 8.6%8.6% 5.9%5.9% 8.6%8.6% 6.4%6.4% 7.2%7.2% 4.5%4.5% GastrointestinalGastrointestinal NauseaNausea 8.5%8.5% 8.7%8.7% VascularVascular Hot flushesHot flushes HypertensionHypertension 21.2%21.2% 9.8%9.8% 19.9%19.9% 8.4%8.4% Incidence (%) of Adverse Events*: All GradesIncidence (%) of Adverse Events*: All Grades *Adverse events occurring ≥5%.*Adverse events occurring ≥5%. †† Statistically significant.Statistically significant. Please see full prescribing information.Please see full prescribing information.
    • 26. 26 Body System andBody System and Adverse EventAdverse Event SwitchSwitch to AROMASINto AROMASIN®® (n(n == 2252)2252) Continue on TamoxifenContinue on Tamoxifen (n(n == 2280)2280) NervousNervous HeadacheHeadache DizzinessDizziness 13.1%13.1% 9.7%9.7% 10.8%10.8% 8.4%8.4% PsychiatricPsychiatric InsomniaInsomnia DepressionDepression 12.4%12.4%†† 6.2%6.2% 8.9%8.9% 5.6%5.6% SkinSkin Sweating increasedSweating increased 11.8%11.8% 10.4%10.4% EyesEyes Visual disturbanceVisual disturbance 5.0%5.0% 3.8%3.8% Incidence (%) of Adverse Events*: All GradesIncidence (%) of Adverse Events*: All Grades *Adverse events occurring ≥5%.*Adverse events occurring ≥5%. †† Statistically significant.Statistically significant. Please see full prescribing information.Please see full prescribing information.
    • 27. 27 Exemestane and Tamoxifen:Exemestane and Tamoxifen: Comparison of Adverse Events*Comparison of Adverse Events* *Events occurring at a rate of <5%.*Events occurring at a rate of <5%. Please see full prescribing information.Please see full prescribing information. • Exemestane was associated with a higher incidence of:Exemestane was associated with a higher incidence of: – Osteoporosis (4.6% vs 2.8%)Osteoporosis (4.6% vs 2.8%) – Osteochondrosis and trigger finger (0.3% vs 0%)Osteochondrosis and trigger finger (0.3% vs 0%) – Paresthesia (2.6% vs 0.9%)Paresthesia (2.6% vs 0.9%) – Carpal tunnel syndrome (2.4% vs 0.2%)Carpal tunnel syndrome (2.4% vs 0.2%) – Neuropathy (0.6% vs 0.1%)Neuropathy (0.6% vs 0.1%) – Diarrhea (4.2% vs 2.2%)Diarrhea (4.2% vs 2.2%) • Tamoxifen was associated with a higher incidence of:Tamoxifen was associated with a higher incidence of: – Muscle cramps (3.1% vs 1.5%)Muscle cramps (3.1% vs 1.5%) – Thromboembolism (2.0% vs 0.9%)Thromboembolism (2.0% vs 0.9%) – Endometrial hyperplasia (1.7% vs 0.6%)Endometrial hyperplasia (1.7% vs 0.6%) – Uterine polyps (2.4% vs 0.4%)Uterine polyps (2.4% vs 0.4%)
    • 28. 28 Other Event RatesOther Event Rates Adverse EventAdverse Event Switch toSwitch to AROMASINAROMASIN®® (n(n ==2352)2352) Continue onContinue on TamoxifenTamoxifen (n(n==2372)2372) Discontinuation rateDiscontinuation rate 6.3%6.3% 5.1%5.1% Incidence of cardiac ischemicIncidence of cardiac ischemic events*events* 1.6%1.6% 0.6%0.6% Incidence of observed cardiacIncidence of observed cardiac failurefailure Deaths due to any causeDeaths due to any cause Deaths due to strokeDeaths due to stroke Deaths due to cardiac failureDeaths due to cardiac failure 0.4%0.4% 1.3%1.3% .3%.3% .2%.2% 0.3%0.3% 1.4%1.4% .1%.1% .1%.1% *Events include: myocardial infarction, angina, and myocardial ischemia.*Events include: myocardial infarction, angina, and myocardial ischemia. Please see full prescribing information.Please see full prescribing information.
    • 29. 29 AROMASINAROMASIN®® (exemestane) Bone Profile Was(exemestane) Bone Profile Was Investigated in 2 Well-Controlled StudiesInvestigated in 2 Well-Controlled Studies **For patients who had 24-month data.For patients who had 24-month data. Please see full prescribing information.Please see full prescribing information. BMD*BMD* ExemestaneExemestane n=29n=29 TamoxifenTamoxifen n=38n=38 ExemestaneExemestane n=59n=59 PlaceboPlacebo n=65n=65 LumbarLumbar Spine (%)Spine (%) −−3.143.14 −−0.180.18 −−3.513.51 −−2.352.35 FemoralFemoral Neck (%)Neck (%) −−4.154.15 −−0.330.33 −−4.574.57 −−2.592.59 IES Bone SubprotocolIES Bone Subprotocol 027027 No patient with normal BMD at baselineNo patient with normal BMD at baseline developed osteoporosis while on therapydeveloped osteoporosis while on therapy
    • 30. 30 IES Trial 35-Month Follow-up ConclusionsIES Trial 35-Month Follow-up Conclusions Switching to AROMASINSwitching to AROMASIN®® after 2 to 3 years ofafter 2 to 3 years of tamoxifen results in significantly improved DFStamoxifen results in significantly improved DFS and was generally safe and well toleratedand was generally safe and well tolerated Please see full prescribing information.Please see full prescribing information.
    • 31. 31 IES 52.4-Month UpdateIES 52.4-Month Update
    • 32. 32 IES: 52.4-Month Update OverviewIES: 52.4-Month Update Overview • Median follow-up at 52.4 monthsMedian follow-up at 52.4 months – DFS events: 354 on AROMASINDFS events: 354 on AROMASIN®® ; 453 on tamoxifen; 453 on tamoxifen – OS events: 222 on AROMASINOS events: 222 on AROMASIN®® ; 262 on tamoxifen; 262 on tamoxifen • Median duration of follow-up after completion of therapy:Median duration of follow-up after completion of therapy: 25 months25 months • Analyses presented here are for the ITT and ER+/ER unknownAnalyses presented here are for the ITT and ER+/ER unknown patientspatients • 122 patients with previously ER unknown disease were122 patients with previously ER unknown disease were subsequently found to be ER-negative; they were not eligiblesubsequently found to be ER-negative; they were not eligible per protocol and were excluded from ER+/ER unknown analysisper protocol and were excluded from ER+/ER unknown analysis • ER+/ER unknown (as suggested by the IDMC of the study) – This subgroup, which specifically excludes ER-negative patients, was proposed by the ICCG CDC and endorsed by the IES IDMC based on the well-established knowledge that ER-negative patients are unlikely to benefit from either treatment IDMC=Independent Data Monitoring Committee; ICCG-CDC=International CollaborativeIDMC=Independent Data Monitoring Committee; ICCG-CDC=International Collaborative Cancer Group Coordinating Data Center.Cancer Group Coordinating Data Center. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 33. 33 ASCO 2006 and This PresentationASCO 2006 and This Presentation SC=steering committee. *Excluding patients subsequently confirmed with ER negativity. Data on file. Pfizer Inc, New York, NY. Coombes et al. Presented at: the American Society of Clinical Oncology Annual Meeting; June 2-6, 2006; Atlanta, Ga. DateDate June 2006June 2006 October 2006October 2006 Presented/publishedPresented/published ASCOASCO Pfizer Clinical Study ReportPfizer Clinical Study Report Triggered byTriggered by IDMC & SC agreed –IDMC & SC agreed – analyze at 95% ≥ 3 yrs f/uanalyze at 95% ≥ 3 yrs f/u & ER+/unknown& ER+/unknown** Same data cutoff used forSame data cutoff used for ASCO presentationASCO presentation ( Feb 27, 2006)( Feb 27, 2006) Median f/u in survivingMedian f/u in surviving patientspatients 55.7 months55.7 months 52.4 months52.4 months (No censoring, same weight(No censoring, same weight to patients dead or alive)to patients dead or alive) DFS eventsDFS events 808808 807807 (1 ipsilateral breast now(1 ipsilateral breast now angiosarcoma)angiosarcoma) OS eventsOS events 483483 484484 (Date of death for 1(Date of death for 1 more pt now available)more pt now available)
    • 34. 34 Efficacy Results at 52.4 Months:Efficacy Results at 52.4 Months: ITT PopulationITT Population ITT PopulationITT Population HR*HR* 95% CI95% CI PP ValueValue DFSDFS 0.760.76 0.67-0.880.67-0.88 .00015.00015 CLBCCLBC 0.570.57 0.33-0.990.33-0.99 .00041.00041 Distant RFSDistant RFS 0.830.83 0.70-0.980.70-0.98 .03.03 Overall survivalOverall survival 0.850.85 0.71-1.020.71-1.02 .07.07 *When interpreting the HR information, it is important to note that on average patients*When interpreting the HR information, it is important to note that on average patients had stopped taking either tamoxifen or AROMASINhad stopped taking either tamoxifen or AROMASIN®® therapy for 25 months.therapy for 25 months. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 35. 35 Efficacy Results at 52.4 Months:Efficacy Results at 52.4 Months: ER+/ER Unknown PopulationER+/ER Unknown Population ER+/ER UnknownER+/ER Unknown PopulationPopulation HR*HR* 95% CI95% CI PP ValueValue DFSDFS 0.750.75 0.65-0.870.65-0.87 .00008.00008 CLBCCLBC 0.540.54 0.31-0.940.31-0.94 .027.027 Distant RFSDistant RFS 0.820.82 0.69-0.970.69-0.97 .02.02 Overall survivalOverall survival 0.830.83 0.69-.990.69-.99 .04.04 *When interpreting the HR information, it is important to note that on average patients*When interpreting the HR information, it is important to note that on average patients had stopped taking either tamoxifen or AROMASINhad stopped taking either tamoxifen or AROMASIN®® therapy for 25 months.therapy for 25 months. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 36. 36 Disease-Free Survival: 52.4 MonthsDisease-Free Survival: 52.4 MonthsPatients,DFS(%)Patients,DFS(%) 1.01.0 0.80.8 0.60.6 0.40.4 0.20.2 00 00 2020 4040 60601010 3030 5050 8080 AROMASINAROMASIN®® ITT PopulationITT Population TamoxifenTamoxifen HRHR == 0.76 (0.67-0.88)0.76 (0.67-0.88) PP == .00015.00015 7070 Median follow-up: 52 monthsMedian follow-up: 52 months Median duration of therapy: 30 monthsMedian duration of therapy: 30 months EventsEvents PatientsPatients AROMASIN (nAROMASIN (n == 2352)2352) 354354 15%15% Tamoxifen (nTamoxifen (n == 2372)2372) 453453 19%19% Months From RandomizationMonths From Randomization Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 37. 37 Disease-Free Survival: 52.4 MonthsDisease-Free Survival: 52.4 Months 00 2020 4040 60601010 3030 5050 80807070 HRHR == 0.75 (0.65-0.87)0.75 (0.65-0.87) PP == .00008.00008 1.01.0 0.80.8 0.60.6 0.40.4 0.20.2 00 ER+/ER Unknown PopulationER+/ER Unknown Population Months From RandomizationMonths From Randomization AROMASINAROMASIN®® TamoxifenTamoxifen Patients,DFS(%)Patients,DFS(%) Median follow-up: 52 monthsMedian follow-up: 52 months Median duration of therapy: 30 monthsMedian duration of therapy: 30 months EventsEvents PatientsPatients AROMASIN (nAROMASIN (n == 2295)2295) 338338 15%15% Tamoxifen (nTamoxifen (n == 2306)2306) 437437 19%19% Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 38. 38 Overall Survival: 52.4 MonthsOverall Survival: 52.4 Months 00 2020 4040 60601010 3030 5050 80807070 HRHR == 0.85 (0.71-1.02)0.85 (0.71-1.02) PP == .07.07 1.01.0 0.80.8 0.60.6 0.40.4 0.20.2 00 Months From RandomizationMonths From Randomization AROMASINAROMASIN®® TamoxifenTamoxifen Median follow-up: 52 monthsMedian follow-up: 52 months Median duration of therapy: 30 monthsMedian duration of therapy: 30 months EventsEvents PatientsPatients AROMASIN (nAROMASIN (n == 2352)2352) 222222 9%9% Tamoxifen (nTamoxifen (n == 2372)2372) 262262 11%11% ITT PopulationITT Population PatientsSurviving(%)PatientsSurviving(%) Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 39. 39 Overall Survival: 52.4 MonthsOverall Survival: 52.4 Months Months From RandomizationMonths From Randomization 1.01.0 0.80.8 0.60.6 0.40.4 0.20.2 0.00.0 00 2020 4040 60601010 3030 5050 8080 TamoxifenTamoxifen AROMASINAROMASIN®® HRHR == 0.83 (0.69-0.99)0.83 (0.69-0.99) PP == .043.043 ER+/ER Unknown PopulationER+/ER Unknown Population 7070 PatientsSurviving(%)PatientsSurviving(%) Median follow-up: 52 monthsMedian follow-up: 52 months Median duration of therapy: 30 monthsMedian duration of therapy: 30 months EventsEvents PatientsPatients AROMASIN (nAROMASIN (n == 2295)2295) 209209 9%9% Tamoxifen (nTamoxifen (n == 2306)2306) 252252 11%11% Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 40. 40 Adverse Events: 52.4 MonthsAdverse Events: 52.4 Months MedDRA Preferred TermMedDRA Preferred Term AROMASINAROMASIN®® (n=2249)(n=2249) TamoxifenTamoxifen (n=2279)(n=2279) Subjects with any illness or AESubjects with any illness or AE 84.7%84.7% 82.8%82.8% Hot flushesHot flushes 21.8%21.8% 20.1%20.1% FatigueFatigue 16.3%16.3% 15.1%15.1% Arthralgia*Arthralgia* 17.6%17.6% 10.8%10.8% HeadacheHeadache 13.6%13.6% 11.2%11.2% Sweating increasedSweating increased 12.0%12.0% 10.6%10.6% Insomnia*Insomnia* 12.9%12.9% 9.0%9.0% DizzinessDizziness 10.0%10.0% 8.8%8.8% HypertensionHypertension 9.9%9.9% 8.4%8.4% NauseaNausea 8.9%8.9% 9.1%9.1% Back painBack pain 9.3%9.3% 7.7%7.7% DepressionDepression 6.2%6.2% 5.6%5.6% Weight increasedWeight increased 5.7%5.7% 6.1%6.1% Pain in limbPain in limb 6.4%6.4% 4.7%4.7% **PP values achieving significance.values achieving significance. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 41. 41 Adverse Events: 52.4 Months (cont’d)Adverse Events: 52.4 Months (cont’d) MedDRA Preferred TermMedDRA Preferred Term AROMASINAROMASIN®® (n=2249)(n=2249) TamoxifenTamoxifen (n=2279)(n=2279) Subjects with any illness or AESubjects with any illness or AE 84.7%84.7% 82.8%82.8% Vaginal hemorrhageVaginal hemorrhage 4.0%4.0% 5.3%5.3% Osteoporosis*Osteoporosis* 5.2%5.2% 2.9%2.9% Diarrhea*Diarrhea* 4.2%4.2% 2.2%2.2% Muscle cramp*Muscle cramp* 1.4%1.4% 3.2%3.2% Paraesthesia*Paraesthesia* 2.8%2.8% 1.0%1.0% Carpal tunnel syndrome*Carpal tunnel syndrome* 2.8%2.8% 0.2%0.2% Thromboembolism*Thromboembolism* 0.7%0.7% 1.8%1.8% Uterine polyp*Uterine polyp* 0.4%0.4% 1.8%1.8% Uterine polypectomy*Uterine polypectomy* 0.2%0.2% 0.8%0.8% Endometrial hyperplasia*Endometrial hyperplasia* <0.1%<0.1% 0.9%0.9% Gastric ulcer*Gastric ulcer* 0.7%0.7% <0.1%<0.1% Fracture rate*Fracture rate* 7.0%7.0% 4.9%4.9% **PP values achieving significance.values achieving significance. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. Please see full prescribing information.Please see full prescribing information.
    • 42. 42 Cardiovascular Events: 52.4 MonthsCardiovascular Events: 52.4 Months AROMASINAROMASIN®® (n=2249)(n=2249) Tamoxifen (n=2279)Tamoxifen (n=2279) Ischemic cardiovascular diseaseIschemic cardiovascular disease 4.5%4.5% 4.2%4.2% AnginaAngina 4.1%4.1% 4.0%4.0% Myocardial infarctionMyocardial infarction 0.4%0.4% 0.1%0.1% Other ischemic CVDOther ischemic CVD 0.3%0.3% 0.1%0.1% Ischemic cerebrovascular dis.Ischemic cerebrovascular dis. 0.8%0.8% 1.0%1.0% StrokeStroke 0.3%0.3% 0.5%0.5% Transient ischemic attackTransient ischemic attack 0.5%0.5% 0.3%0.3% Other isch. cerebrovasc. dis.Other isch. cerebrovasc. dis. 0.1%0.1% 0.2%0.2% Other cardiovascular eventOther cardiovascular event 15.2%15.2% 13.6%13.6% Heart failureHeart failure 1.0%1.0% 0.8%0.8% HypertensionHypertension 10.0%10.0% 8.5%8.5% Peripheral vascular diseasePeripheral vascular disease 0.6%0.6% 0.4%0.4% Other cardiovascular eventOther cardiovascular event 4.9%4.9% 5.3%5.3% Venous thromboembolic event*Venous thromboembolic event* 0.9%0.9% 2.2%2.2% Deep vein thrombosis*Deep vein thrombosis* 0.8%0.8% 2.2%2.2% Pulmonary embolismPulmonary embolism <<0.1%0.1% <<0.1%0.1% **PP values achieving significance.values achieving significance. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY. PleasePlease see full prescribing information.see full prescribing information.
    • 43. 43 Conclusions: 52.4-Month UpdateConclusions: 52.4-Month Update • At 25 months after the completion of therapy,At 25 months after the completion of therapy, switching to AROMASINswitching to AROMASIN®® (exemestane)(exemestane) showed significant improvement in DFS in earlyshowed significant improvement in DFS in early breast cancer patients treated with 2 to 3 yearsbreast cancer patients treated with 2 to 3 years of tamoxifenof tamoxifen • Switching to AROMASIN reduced the risk ofSwitching to AROMASIN reduced the risk of dying by 15% for the ITT population (dying by 15% for the ITT population (PP=.07)=.07) and by 17% in ER+/ER unknown early breastand by 17% in ER+/ER unknown early breast cancer (cancer (PP=.04)=.04) • AROMASIN was generally safe and wellAROMASIN was generally safe and well tolerated after 52.4 months.tolerated after 52.4 months. Please see full prescribing information.Please see full prescribing information.
    • 44. 44 AROMASINAROMASIN®® (exemestane)(exemestane) Adjuvant IndicationAdjuvant Indication AROMASIN is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received 2 to 3 years of tamoxifen and are switched to AROMASIN for completion of a total of 5 consecutive years of adjuvant hormonal therapy. Please see full prescribing information.Please see full prescribing information.
    • 45. 45 Important Safety ConsiderationsImportant Safety Considerations • AROMASINAROMASIN®® (exemestane) should not be used in women who are(exemestane) should not be used in women who are – PremenopausalPremenopausal – Nursing or pregnantNursing or pregnant – Known to be hypersensitive to the drugKnown to be hypersensitive to the drug – Taking estrogen-containing agentsTaking estrogen-containing agents • For patients receiving exemestane with a potent CYP 3A4 inducer,For patients receiving exemestane with a potent CYP 3A4 inducer, such as rifampicin or phenytoin, the recommended dose ofsuch as rifampicin or phenytoin, the recommended dose of exemestane is 50 mg qd after a mealexemestane is 50 mg qd after a meal • In patients with early breast cancer, elevations in bilirubin, alkalineIn patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receivingphosphatase, and creatinine were more common in those receiving AROMASINAROMASIN • Reductions in BMD over time are seen with use of AROMASINReductions in BMD over time are seen with use of AROMASIN Please see full prescribing information.Please see full prescribing information.

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