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

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AROMASINAROMASIN®® (exemestane): Adjuvant (exemestane): Adjuvant Therapy for Early Stage Breast Cancer Therapy 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.

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American Cancer Society. American Cancer Society. Cancer Facts and Figures 2005. Cancer Facts and Figures 2005. Atlanta, Ga: American Cancer Atlanta, 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 diagnosed Breast 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 40,870 It 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 receptor About 3/4 of breast cancers are estrogen receptor (ER)(ER)––and/or progesterone receptor (PR)and/or progesterone receptor (PR)––positive positive and are, therefore, suitable for hormonal therapyand are, therefore, suitable for hormonal therapy

• The majority of women diagnosed with breast cancer The majority of women diagnosed with breast cancer are postmenopausalare postmenopausal

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Hormonal Therapy OptionsHormonal Therapy Options

MechanismMechanism Therapeutic Modality ExamplesTherapeutic Modality Examples

ER blockadeER blockade Selective estrogen-receptor Selective estrogen-receptor modulators (SERMs)modulators (SERMs)

Selective estrogen-receptor Selective estrogen-receptor down-regulators (SERDs)down-regulators (SERDs)

Estrogen synthesis Estrogen synthesis suppression suppression (postmenopausal women)(postmenopausal women)

Aromatase inhibitor/inactivator (AI)Aromatase inhibitor/inactivator (AI)

Hormonal ablation Hormonal 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.

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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 over 2-year, and 5-year trials of tamoxifen therapy over placebo, respectivelyplacebo, respectively

• 28% reduction of death with 5 years of tamoxifen 28% reduction of death with 5 years of tamoxifen therapy over placebotherapy over placebo

• 47% relative risk reduction of contralateral breast 47% 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 over However, 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 approximately Meta-analysis of 55 trials and approximately 30,000 women with ER+ tumors30,000 women with ER+ tumors::

Meta-analysis of 55 trials and approximately Meta-analysis of 55 trials and approximately 30,000 women with ER+ tumors30,000 women with ER+ tumors::

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Resistance to Tamoxifen Over Time Resistance 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

+ M

icro

met

asta

ses

(%)

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Tamoxifen Has Both Antagonist and Tamoxifen 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 cancer Risk of endometrial cancer

and thromboembolic effectsand thromboembolic effects• Lowers cholesterol Lowers cholesterol • Preserves bone densityPreserves bone density

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EstroneEstrone EstradiolEstradiol

TestosteroneTestosterone

AIs and inactivators

AIs and inactivators

AndrostenedioneAndrostenedione

Aromatase Inhibition and Aromatase Inhibition and Inactivation: Mechanism of ActionInactivation: Mechanism of Action

CholesterolCholesterolCholesterolCholesterol

CortisolCortisol CortisolCortisol

ProgesteroneProgesteroneProgesteroneProgesterone

AldosteroneAldosteroneAldosteroneAldosterone

PregnenolonePregnenolonePregnenolonePregnenolone

Aro

mat

ase

Aro

mat

ase

Aro

mat

ase

Aro

mat

ase

Miller WR et al. Miller WR et al. Cancer Control. Cancer Control. 2002;9(suppl):9-15.2002;9(suppl):9-15.

Arom

ataseA

romatase

Arom

ataseA

romatase

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Differences in AI and Tamoxifen Differences 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

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Differences in the Structures of Differences in the Structures of Aromatase Inhibitors and Inactivators*Aromatase Inhibitors and Inactivators*

AndrostenedioneAndrostenedione

Steroidal Steroidal (inactivators)(inactivators)

Androgen substrateAndrogen substrate

Nonsteroidal Nonsteroidal (inhibitors)(inhibitors)

HHAminoglutethimiAminoglutethimi

dede

OO

NHNH22

CC22HH55

OONN

ExemestaneExemestane

OOCHCH22

OO

FormestanFormestanee

OO

OHOH

OO

OO

OO

LetrozoleLetrozole

CNCNNCNC

NNNN

NN

AnastrozolAnastrozolee

CHCH33

CHCH33

CHCH33

CHCH33

NNNN

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.

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AROMASINAROMASIN®® (exemestane) Tablets: (exemestane) Tablets: Adjuvant IndicationAdjuvant Indication

AROMASIN is indicated for adjuvant treatment of AROMASIN is indicated for adjuvant treatment of postmenopausal women with ER+ early breast postmenopausal women with ER+ early breast cancer who have received 2 to 3 years of cancer who have received 2 to 3 years of tamoxifen and are switched to AROMASIN for tamoxifen and are switched to AROMASIN for completion of a total of 5 consecutive years of completion of a total of 5 consecutive years of adjuvant hormonal therapy.adjuvant hormonal therapy.


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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 of such 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, alkaline In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving phosphatase, and creatinine were more common in those receiving AROMASINAROMASIN

• Reductions in bone mineral density over time are seen with use of Reductions in bone mineral density over time are seen with use of AROMASINAROMASIN

Please see full prescribing information.Please see full prescribing information.Please see full prescribing information.Please see full prescribing information.

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IES Trial DesignIES Trial DesignMultinational, Double-Blinded, Randomized, Landmark TrialMultinational, Double-Blinded, Randomized, Landmark Trial

RRAANNDDOOMMIIZZAATTIIOONN

RRAANNDDOOMMIIZZAATTIIOONN

Diagnosis and Diagnosis and Initial Treatment Initial Treatment

of Early of Early Breast CancerBreast Cancer TamoxifenTamoxifen

2 to 3 years2 to 3 years20 mg po qd*20 mg po qd*

(n (n == 2372)2372)

AROMASINAROMASIN®® 2 to 3 years 2 to 3 years 25 mg po qd25 mg po qd

(n(n == 2352)2352)

Total of 5 Consecutive Years Total of 5 Consecutive Years of Hormonal Therapyof Hormonal Therapy

Total of 5 Consecutive Years Total of 5 Consecutive Years of Hormonal Therapyof Hormonal Therapy

Tamoxifen Tamoxifen Therapy Therapy 2 to 3 years2 to 3 years

NN == 47244724Patient stratification:Patient stratification:Node statusNode statusPrior chemotherapy (CT)Prior chemotherapy (CT)Hormone receptor statusHormone receptor status

NN == 47244724Patient stratification:Patient stratification:Node statusNode statusPrior 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 Ends Patient Ends Therapy and Therapy and

Continues Continues Follow-upFollow-up

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IES: Collaboration Between IES: 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 AmericanArgentinaArgentina 148148PeruPeru 77

AfricaAfricaSouth AfricaSouth Africa 1919EgyptEgypt 77

AustraliaAustraliaAustraliaAustralia 4848New ZealandNew Zealand 2222

AsiaAsiaHong Kong 6Hong Kong 6

EuropeEuropeUnited KingdomUnited Kingdom 594594IrelandIreland 5858FranceFrance 398398BelgiumBelgium 171171SwitzerlandSwitzerland 5555GermanyGermany 185185DenmarkDenmark 136136GreeceGreece 4141ItalyItaly 616616LuxembourgLuxembourg 44NetherlandsNetherlands 306306

BulgariaBulgaria 8383CroatiaCroatia 117117Czech RepublicCzech Republic 6464EstoniaEstonia 55HungaryHungary 7777RussiaRussia 4848SlovakiaSlovakia 6161SloveniaSlovenia 4040YugoslaviaYugoslavia 4141RomaniaRomania 6363PolandPoland 311311SpainSpain 254254PortugalPortugal 2828MaltaMalta 1212NorwayNorway 126126SwedenSweden 163163IsraelIsrael 6262BosniaBosnia 22

Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY.

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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) (second Contralateral breast cancer (CLBC) (second

primary)primary) Death from any cause (prior to Death 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.

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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 at Confirmed 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–– status status– Clinical evidence of local relapse or distant Clinical 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.

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Patient CharacteristicsPatient Characteristics

CharacteristicCharacteristic

Switch to Switch to AROMASINAROMASIN®®

(n = 2352)(n = 2352)

Continue on Continue on TamoxifenTamoxifen(n = 2372)(n = 2372)

DemographicsDemographicsMedian age, years Median age, years 6363 6363

Race (%)Race (%) CaucasianCaucasian

Other (including Hispanic, Asian, Black)Other (including Hispanic, Asian, Black)98.498.4 1.6 1.6

98.498.4 1.6 1.6

Adjuvant Chemotherapy (%)Adjuvant Chemotherapy (%)

YesYes

NoNo32.932.9

67.167.132.432.4

67.667.6

Nodal status (%)Nodal status (%)NegativeNegativePositivePositive

1 to 3 nodes positive1 to 3 nodes positive 4 to 9 nodes positive4 to 9 nodes positive

>9 nodes positive>9 nodes positiveOther*Other*

51.751.744.744.730.730.710.210.23.73.73.73.7

51.851.844.044.029.829.810.310.33.63.64.54.5

*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.

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Patient Patient 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


(n(n == 2352)2352)

Continue on Continue on TamoxifenTamoxifen(n(n == 2372)2372)

ER status* (%)ER status* (%) ER+/PR+ER+/PR+ ER+/PR– or PR-unknown ER+/PR– or PR-unknown Other Other

ER unknown/PR+ or PR ER unknown/PR+ or PR unknownunknown ER–/PR+ER–/PR+

ER–/PR– or PR unknownER–/PR– or PR unknownMissingMissing

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 ductalInfiltrating lobularInfiltrating lobularOtherOther

75.6%75.6%14.5%14.5% 9.8% 9.8%

77.2%77.2%13.5%13.5% 9.0% 9.0%

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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 (N publication, March 2004 (N == 4742*; median 4742*; median f/u 30.6 mo; eventsf/u 30.6 mo; events == 449)449)– Cutoff date June 30, 2003 Cutoff date June 30, 2003 – Events received by cutoff dateEvents received by cutoff date– Safety reported as incidence case analysis after Safety reported as incidence case analysis after

randomization randomization

• 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.

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Number of Events to DFS at 34.5 MonthsNumber of Events to DFS at 34.5 Months


(n(n == 2352)2352)

Continue on Continue 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%) 520 520

**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.

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Efficacy Results: ITT PopulationEfficacy Results: ITT Population

ITT PopulationITT Population HRHR 95% CI95% CI PP Value Value

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.

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Efficacy Results: Hormone-Receptor Efficacy Results: Hormone-Receptor Positive PatientsPositive Patients

Hormone-Receptor Hormone-Receptor Positive PatientsPositive Patients HRHR 95% CI95% CI PP Value Value

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


Overall survivalOverall survival 0.880.88 0.67-1.170.67-1.17 NSNS


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Disease-Free SurvivalDisease-Free Survival

Months From RandomizationMonths From Randomization

Pat

ien

ts, D

FS

(%

)P

atie

nts

, DF

S (

%)

100100

8080

6060

4040

2020

0000 2020 4040 60601010 3030 5050 7070

AROMASINAROMASIN®®

ITT PopulationITT Population ITT PopulationITT Population

Tamoxifen Tamoxifen

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%


HRHR == 0.69 (0.58-0.82) 0.69 (0.58-0.82) PP == .00003.00003

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*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 Scale0.40.4 0.60.6 0.80.8 1.01.0 1.21.2

Hazard RatioHazard RatioHR (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))

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Overall SurvivalOverall Survival


Pat

ien

ts S

urv

ivin

g (

%)

Pat

ien

ts S

urv

ivin

g (

%)

100100

8080

6060

4040

2020

0000 2020 4040 60601010 3030 5050 7070

TamoxifenTamoxifenAROMASINAROMASIN®®

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.


Median follow-upMedian follow-up == 34.5 months34.5 months

DeathsDeaths PatientsPatients


Tamoxifen (nTamoxifen (n == 2372)2372) 137137 6%6%HRHR == 0.86 (0.67-1.10)0.86 (0.67-1.10)PP == NSNS

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Body System andBody System andAdverse EventAdverse Event

Switch to AROMASINSwitch to AROMASIN® ®

(n(n == 2252)2252)Continue on Tamoxifen Continue on Tamoxifen

(n(n == 2280)2280)

General DisordersGeneral Disorders FatigueFatigue 16.1%16.1% 14.7%14.7%

MusculoskeletalMusculoskeletal ArthralgiaArthralgia Pain in limb Pain 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%

Vascular Vascular 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.

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Body System and Body System and Adverse EventAdverse Event

SwitchSwitch to AROMASIN to AROMASIN®® (n(n == 2252)2252)

Continue on Tamoxifen Continue on Tamoxifen (n(n == 2280)2280)

NervousNervous

HeadacheHeadache Dizziness Dizziness

13.1% 13.1% 9.7% 9.7%

10.8%10.8% 8.4% 8.4%

PsychiatricPsychiatric

InsomniaInsomnia

DepressionDepression12.4%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.

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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%)

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Other Event RatesOther Event Rates

Adverse EventAdverse Event


(n(n == 2352)2352)

Continue on Continue on TamoxifenTamoxifen(n(n == 2372)2372)

Discontinuation rateDiscontinuation rate 6.3%6.3% 5.1%5.1%

Incidence of cardiac ischemic Incidence of cardiac ischemic events* events*

1.6%1.6% 0.6%0.6%

Incidence of observed cardiac Incidence 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.*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.

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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.**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* ExemestaneExemestanen=29n=29

TamoxifenTamoxifenn=38n=38

ExemestaneExemestanen=59n=59

PlaceboPlacebon=65n=65

Lumbar Lumbar Spine (%)Spine (%)

−−3.143.14 −−0.180.18 −−3.513.51 −−2.352.35

Femoral Femoral Neck (%)Neck (%)

−−4.154.15 −−0.330.33 −−4.574.57 −−2.592.59

IES Bone SubprotocolIES Bone SubprotocolIES Bone SubprotocolIES Bone Subprotocol 027027027027

No patient with normal BMD at baseline No patient with normal BMD at baseline developed osteoporosis while on therapydeveloped osteoporosis while on therapy

30

IES Trial 35-Month Follow-up ConclusionsIES Trial 35-Month Follow-up Conclusions

Switching to AROMASINSwitching to AROMASIN®® after 2 to 3 years of after 2 to 3 years of tamoxifen results in significantly improved DFS tamoxifen results in significantly improved DFS and was generally safe and well toleratedand was generally safe and well tolerated


31

IES 52.4-Month UpdateIES 52.4-Month Update

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 unknown Analyses presented here are for the ITT and ER+/ER unknown patientspatients

• 122 patients with previously ER unknown disease were 122 patients with previously ER unknown disease were subsequently found to be ER-negative; they were not eligible subsequently 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 Collaborative IDMC=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.

IDMC=Independent Data Monitoring Committee; ICCG-CDC=International Collaborative IDMC=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

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 Report Pfizer Clinical Study Report

Triggered byTriggered by IDMC & SC agreed – IDMC & SC agreed – analyze at 95% ≥ 3 yrs f/u analyze at 95% ≥ 3 yrs f/u

& ER+/unknown& ER+/unknown**

Same data cutoff used for Same data cutoff used for ASCO presentation ASCO presentation

( Feb 27, 2006)( Feb 27, 2006)

Median f/u in surviving Median 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 807 807

(1 ipsilateral breast now (1 ipsilateral breast now angiosarcoma)angiosarcoma)

OS eventsOS events 483483 484484

(Date of death for 1(Date of death for 1more pt now available)more pt now available)

34

Efficacy Results at 52.4 Months: Efficacy Results at 52.4 Months: ITT Population ITT Population

ITT PopulationITT Population HR*HR* 95% CI95% CI PP Value Value

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


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

Efficacy Results at 52.4 Months: Efficacy Results at 52.4 Months: ER+/ER Unknown PopulationER+/ER Unknown Population

ER+/ER Unknown ER+/ER Unknown PopulationPopulation HR*HR* 95% CI95% CI PP Value Value

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


Overall survivalOverall survival 0.830.83 0.69-.990.69-.99 .04.04



36

Disease-Free Survival: 52.4 MonthsDisease-Free Survival: 52.4 MonthsP

atie

nts

, DF

S (

%)

Pat

ien

ts, D

FS

(%

)

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0000 2020 4040 60601010 3030 5050 8080



Tamoxifen Tamoxifen

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 monthsMedian duration of therapy: 30 monthsMedian duration of therapy: 30 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.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

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 ER+/ER Unknown PopulationER+/ER Unknown Population



Tamoxifen Tamoxifen

Pat

ien

ts, D

FS

(%

)P

atie

nts

, DF

S (

%)






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



Tamoxifen Tamoxifen






Pat

ien

ts S

urv

ivin

g (

%)

Pat

ien

ts S

urv

ivin

g (

%)


39

Overall Survival: 52.4 MonthsOverall Survival: 52.4 Months


1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.000 2020 4040 60601010 3030 5050 8080

TamoxifenTamoxifen


HRHR == 0.83 (0.69-0.99)0.83 (0.69-0.99)PP == .043.043

ER+/ER Unknown PopulationER+/ER Unknown Population ER+/ER Unknown PopulationER+/ER Unknown Population

7070

Pat

ien

ts S

urv

ivin

g (

%)

Pat

ien

ts S

urv

ivin

g (

%)






40

Adverse Events: 52.4 MonthsAdverse Events: 52.4 Months

MedDRA Preferred TermMedDRA Preferred TermAROMASINAROMASIN®®

(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 21.21.88%% 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% 10.10.66%%

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.


41

Adverse Events: 52.4 Months (cont’d)Adverse Events: 52.4 Months (cont’d)

MedDRA Preferred TermMedDRA Preferred TermAROMASINAROMASIN®®

(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% 2.2.22%%

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.


42

Cardiovascular Events: 52.4 MonthsCardiovascular Events: 52.4 MonthsAROMASINAROMASIN®® (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 00.3%.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% 113.6%3.6%

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. Please Please see full prescribing information.see full prescribing information.**PP values achieving significance. values achieving significance. Data on file. Pfizer Inc, New York, NY. Data on file. Pfizer Inc, New York, NY. Please Please see full prescribing information.see full prescribing information.

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 early showed significant improvement in DFS in early breast cancer patients treated with 2 to 3 years breast cancer patients treated with 2 to 3 years of tamoxifenof tamoxifen

• Switching to AROMASIN reduced the risk of Switching 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 breast and by 17% in ER+/ER unknown early breast cancer (cancer (PP=.04)=.04)

• AROMASIN was generally safe and well AROMASIN was generally safe and well tolerated after 52.4 months. tolerated after 52.4 months.


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.


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 of such 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, alkaline In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving phosphatase, 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


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

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