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Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational)

prospective randomized phase III trial in hormone sensitive postmenopausal early breast cancer

1US Oncology Research, Houston, TX, USA; 2Erasmus MC Daniel Den Hoed, Rotterdam, the Netherlands; 3University Hospital Freiburg, Freiburg, Germany; 4The University of Birmingham, Birmingham, United Kingdom; 5Institut du Sein Henri Hartmann (ISHH), Neuilly sur Seine, France; 6U. Z. Gasthuisberg, Leuven, Belgium; 7Athens University Medical School, Greece; 8Jichi Medical University, Shimotsuke, Japan; 9Leiden University Medical Center, Leiden, The Netherlands; 10Helios Medical Center Aue, Germany; 11Pfizer, New York; USA; 12Endocrine Cancer Group, Edinburgh University, Scotland

S.E. Jones1, C. Seynaeve2 , A. Hasenburg3, D. Rea4, JM. Vannetzel5, R. Paridaens6, C. Markopoulos7, Y. Hozumi8, H. Putter9, E. Hille9, D. Kieback10, L. Asmar1, J. Smeets11,

R. Urbanski11, J.M.S. Bartlett12, C.J.H. van de Velde9

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• Multinational, open-label, randomized study in postmenopausal, ER and/or PgR positive, early invasive breast cancer after completion of primary therapy

Exemestane 25 mgs daily

Tamoxifen 20 mgs daily

N = 5,800+

Total of 5 years treatment

DFS at 5 yearsPrimary end point:

Diagnosis and adequate prior therapy of early breast cancer

Original Study Design (2001)

RANDOMIZATION

Why the TEAM Study Design Was Amended

• Results of the Intergroup Exemestane Study (IES)* trial showed that patients who switched to exemestane after 2 to 3 years of tamoxifen benefited with:

• Significant improvement in DFS

• Significant reduction in risk of contralateral breast cancer

• Favorable safety profile

• In 2007, a survival advantage also

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*Coombes RC, et al. N Eng J Med. 2004;350:1081-92.

For scientific and ethical reasons, the Global Steering Committee decided to amend the TEAM protocol to evaluate sequential therapy with 2.5 to 3 years of tamoxifen followed by exemestane for a total of 5 yrs compared with upfront exemestane for 5 yrs

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TEAM Trial: Revised Design 2004

Exemestane

Tamoxifen

Total of 5 years’ treatment

Diagnosis and adequate

primary therapy of early breast

cancer

N = 9775 accrued Postmenopausal receptor-positive women

Exemestane

IES Positive Results

Co-primary end points

DFS at 2.75 yearsDFS at 5 years

RANDOMIZATION

TEAM Study Overview

• Conducted in 9 countries (US, Netherlands, Belgium, France, UK, Ireland, Greece, Germany, Japan)– Each country protocol contained prospective sub-

studies (19 total, 6 here at SABCS 2008) that are analyzed and reported individually

• Randomization performed within each country using stratification factors specific to that country

• Prospective plan to pool subject-level data for the primary, secondary, and exploratory analyses

• Oversight provided by a Global Steering Committee and an Independent Data Safety Monitoring Board

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TEAM : Key Eligibility Criteria

• Histological/cytological confirmed invasive adenocarcinoma of the breast (node positive and node negative)

• ER+ and/or Pg-R+ disease • Postmenopausal Status • Complete surgical resection with curative intent

– +/- radiotherapy and +/- chemotherapy according to local clinical practice

• Adjuvant hormonal treatment initiated within 10 weeks of surgery, and/or chemotherapy

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Efficacy Endpoints & Analyses

• Primary End Point– Disease Free Survival (DFS) (ITT) triggered by 723 events

Loco-regional or distant breast cancer recurrence Second primary or contra-lateral breast cancer Deaths from any cause

• Secondary End Points Overall survival (OS) Time to new primary breast cancer Long-term tolerability and safety Relapse-free survival (RFS) (ITT)

• Additional Analyses Occurrence of new non-breast primary cancer (not reported) Time to distant metastases DFS on study drug (as treated) Compliance with the switch to exemestane

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RESULTS

Of First Planned Analysis at 2.75 YearsAll Patients Censored at 2.75 Years

9600+ Patients Followed for 2.75 Years

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Results

The TEAM Trial: Accrual by Country

Total number of patients = 9775

UK/Ireland: 1275

France: 1230

Greece: 207

NL/Belgium: 3167

Germany: 1480

USA: 2232

Japan: 184

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TEAM Trial Flow Chart

9775 Patients Randomized

4874 Randomized to Tamoxifen

4901 Randomized to Exemestane

4898 Exemestane in Efficacy Analysis

4853 ExemestaneFor Safety Analysis

4868 Tamoxifen in Efficacy Analysis

4817 TamoxifenFor Safety Analysis

6 Withdrawn Consent

51 Treatment Not Started

143 Ineligible188 Lost to FU<2.75y

1434 Treatment Stopped <2.75y

3 Withdrawn Consent

45 Treatment Not Started

130 Ineligible139 Lost to FU<2.75y

926 Treatment Stopped <2.75y

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Patient Demographics

Characteristic Tamoxifen (n=4868)

Exemestane (n=4898)

Mean age (range) 64 (35-91) 65 (36-96)

Histological grade, n (%) G1 (well) G2 (moderate) G3-G4 (poor)

834 (19)2362 (53)1232 (27)

843 (19)2433 (54)1206 (27)

T Stage, n (%) T1 (≤2 cm) T2 (>2 cm and ≤5 cm) T3 (>5 cm)

2848 (59)1763 (36)

174 (4)

2843 (58)1828 (37)

161 (3)

N Stage, n (%) N negative N positive Unknown

2555 (52)2279 (47)34 (1)

2558 (52)2306 (47)34 (1)

ER and/or PgR positive, n (%) 4859 (100) 4887(100)Most extensive surgery, n (%) Mastectomy Wide local excision

2183 (45)2680 (55)

2148 (44)2744 (56)

Adjuvant chemotherapy 1743 (36) 1774 (36)

Radiotherapy 3314 (69) 3376 (70)

RESULTSMedDRA Coding

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Adverse EventsGynecologic, Cardiovascular, Musculoskeletal categories

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Selected Gynecologic Events

Exemestane Tamoxifen P value

Vaginal discharge 112 2.3% 333 6.8% < 0.0001

Vaginal haemorrhage 78 1.6% 153 3.1% < 0.0001

Vaginal infection 34 0.7% 108 2.2% < 0.0001

Uterine polyp 4 0.1% 25 0.5% < 0.0001

Endometrial hyperplasia 3 0.0% 96 2.0% < 0.0001

Endometrial cancer 7 0.1% 12 0.2% NS

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Selected Cardiac/Vascular Events

Exemestane (4853)

Tamoxifen (4817) P value

Cardiac disorders

- Myocardial ischemia/infarction 41 0.8% 31 0.6% NS

- Cardiac deaths 18 0.4% 11 0.2% NS

Vascular disorders

- Hot flush/flushing 1384 28.5% 1606 33.3% <0.001

- Hypertension 163 3.3% 104 2.1% <0.001

- Thromboembolic events 44 0.9% 113 2.3% <0.001

Selected Musculoskeletal Events

Exemestane(4853)

Tamoxifen (4817) P value

Arthralgia 875 17.9% 447 9.2% <0.001

Arthritis 147 3.0% 83 1.7% <0.001

Reported osteoporosis 228 4.7% 104 2.1% <0.001

Reported fractures 133 2.7% 111 2.3% NS

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Results Outcomes

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DFS Events (ITT)

Event, n (%)Tamoxifen

n=4868Exemestane

n=4898Total

N=9766

Total DFS events 388 (8.0) 352 (7.2) 740 (7.6)

Local recurrence (includes ipsilateral breast cancer) 45 (0.9) 42 (0.9) 87 (0.9)

Distant metastases 244 (5.0) 201 (4.1) 445 (4.6)

New primary BC (no distant metastasis) 17 (0.3) 21 (0.4) 38 (0.4)

Intercurrent deaths 82 (1.7) 88 (1.8) 170 (1.7)

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Numbers at risk:Tamoxifen

Exemestane 4898 36/4809 73/4708 53/4615 62/4473 128/4179

Cumulative Probability

Pro

bab

ility

Years since randomization

4868 33/4765 79/4636 69/4516 86/4364 121/4099

DFS Comparison at 2.75 Years (ITT)

HR=0.89 (95% CI 0.77-1.03)Adjusted Log rank P = 0.12

0.00

0.02

0.04

0.06

0.08

0.10

0.0 0.5 1.0 1.5 2.0 2.5

TamoxifenExemestaneTamoxifenExemestane

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DFS: On-Study Drug and Pre-Switch— Excluding 96 Never Treated Patients

Numbers at risk:Tamoxifen: 4817 28/4510 72/4207 63/3962 71/3664 87/2817

Exemestane: 4853 33/4552 64/4343 53/4210 47/4067 114/3779

Cumulative Probability

HR 0.83 (95% CI 0.71-0.97, P=0.02)

Pro

bab

ility

0.00

0.02

0.04

0.06

0.08

0.10

Years since randomization0.0 0.5 1.0 1.5 2.0 2.5

TamoxifenExemestane

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Relapse-Free Survival (ITT)Cumulative Probability

Numbers at risk:Tamoxifen: 4868 21/4765 62/4636 61/4516 65/4364 97/4099

Exemestane: 4898 25/4809 60/4708 40/4615 47/4473 92/4179

HR=0.85 (0.72–1.00; P=0.05)

Pro

bab

ility

0.00

0.02

0.04

0.06

0.08

0.10TamoxifenExemestane

Years since randomization0.0 0.5 1.0 1.5 2.0 2.5

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Cumulative Incidence of Distant Metastasis (ITT)

Numbers at risk:Tamoxifen

Exemestane 4868 26/4771 69/4652 53/4547 71/4406 110/4146

4898 29/4815 54/4733 47/4646 56/4510 112/4219

Time to Distant Metastases (ITT)

HR=0.81 (0.67 - 0.98; P <0.03)

Pro

bab

ility

0.00

0.02

0.04

0.06

0.08

0.10

Years since randomization0.0 0.5 1.0 1.5 2.0 2.5

TamoxifenExemestane

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TEAM Trial Flow Chart

9775 Patients Randomized

4874 Randomized to Tamoxifen

4901 Randomized to Exemestane

4898 Exemestane in Efficacy Analysis

4853 ExemestaneFor Safety Analysis

4868 Tamoxifen in Efficacy Analysis

4817 TamoxifenFor Safety Analysis

6 Withdrawn Consent

51 Treatment Not Started

143 Ineligible188 Lost to FU<2.75y

1434 treatment stopped <2.75y

3 Withdrawn Consent

45 Treatment Not Started

130 Ineligible139 Lost to FU<2.75y

926 treatment stopped <2.75y29.5% 18.9%

Conclusions (1)

• First report of planned analysis of TEAM involving 9775 patients randomized to initial therapy with either Tamoxifen or Exemestane at a median follow up of 2.75 years

• Overall, event rate in both groups is quite low at 2.75 years (570 breast cancer events)

• Exemestane was associated with improvement in:– Disease-free survival (HR: 0.89; P=0.12) – On-study drug disease-free survival (HR 0.83; P=0.02)

– Relapse-free survival: (HR: 0.85; P = 0.05)– Time to distant metastases (HR: 0.81; P<0.03)

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Conclusions (2)

• Two issues were uncovered during the analysis: high rates of early discontinuation to tamoxifen, and timing of the switch to exemestane; both may have affected outcome (DFS)

• No unexpected safety issues with exemestane relative to tamoxifen

• These treatment results considering all study end points are comparable to first reports of other endocrine trials with aromatase inhibitors v. tamoxifen

• 5-year results of tamoxifen/exemestane switch compared to exemestane alone are expected in 2009

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Acknowledgments

• We would like to thank:– All patients who agreed to participate– All investigators conducting the trial– All data managers and other trial support

staff collecting and processing patient data– The Global Steering Committee – The IDMC– Pfizer