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

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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
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
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
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Original Study Design (2001)

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

RANDOMIZATION
Total of 5 years treatment
Tamoxifen 20 mgs daily
Diagnosis and adequate prior therapy of early
breast cancer
Exemestane 25 mgs daily
N 5,800
Primary end point
DFS at 5 years
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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

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
Coombes RC, et al. N Eng J Med.
20043501081-92.
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TEAM Trial Revised Design 2004
N 9775 accrued
IES Positive Results
Postmenopausal receptor-positive women
RANDOMIZATION
Diagnosis and adequate primary therapy of early
breast cancer
Tamoxifen
Exemestane
Exemestane
Total of 5 years treatment
Co-primary end points
DFS at 2.75 years DFS at 5 years
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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 Years All
Patients Censored at 2.75 Years 9600 Patients
Followed for 2.75 Years
RESULTS
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Patient Demographics
Characteristic Tamoxifen (n4868) Exemestane (n4898)
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 (gt2 cm and 5 cm) T3 (gt5 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)
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Adverse Events Gynecologic, Cardiovascular,
Musculoskeletal categories
MedDRA Coding
RESULTS
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Selected Gynecologic Events
Exemestane Exemestane Tamoxifen Tamoxifen P value
Vaginal discharge 112 2.3 333 6.8 lt 0.0001
Vaginal haemorrhage 78 1.6 153 3.1 lt 0.0001
Vaginal infection 34 0.7 108 2.2 lt 0.0001
Uterine polyp 4 0.1 25 0.5 lt 0.0001
Endometrial hyperplasia 3 0.0 96 2.0 lt 0.0001
Endometrial cancer 7 0.1 12 0.2 NS
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Selected Cardiac/Vascular Events
Exemestane (4853) Exemestane (4853) Tamoxifen (4817) Tamoxifen (4817) P value
Cardiac disorders Cardiac disorders Cardiac disorders Cardiac disorders Cardiac disorders Cardiac disorders
- Myocardial ischemia/infarction 41 0.8 31 0.6 NS
- Cardiac deaths 18 0.4 11 0.2 NS

Vascular disorders Vascular disorders Vascular disorders Vascular disorders Vascular disorders Vascular disorders
- Hot flush/flushing 1384 28.5 1606 33.3 lt0.001
- Hypertension 163 3.3 104 2.1 lt0.001
- Thromboembolic events 44 0.9 113 2.3 lt0.001
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Selected Musculoskeletal Events
Exemestane (4853) Exemestane (4853) Tamoxifen (4817) Tamoxifen (4817) P value
Arthralgia 875 17.9 447 9.2 lt0.001
Arthritis 147 3.0 83 1.7 lt0.001
Reported osteoporosis 228 4.7 104 2.1 lt0.001
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 n4868 Exemestane n4898 Total N9766
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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DFS On-Study Drug and Pre-Switch Excluding 96
Never Treated Patients
Cumulative Probability
0.10
Tamoxifen Exemestane
0.08
0.06
Probability
0.04
0.02
HR 0.83 (95 CI 0.71-0.97, P0.02)
0.00
0.0
0.5
1.0
1.5
2.0
2.5
Years since randomization
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
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Time to Distant Metastases (ITT)
Cumulative Incidence of Distant Metastasis (ITT)
0.10
Tamoxifen Exemestane
0.08
0.06
Probability
0.04
0.02
HR0.81 (0.67 - 0.98 P lt0.03)
0.00
0.0
0.5
1.0
1.5
2.0
2.5
Years since randomization
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
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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 P0.12)
• On-study drug disease-free survival (HR 0.83
  P0.02)
• Relapse-free survival (HR 0.85 P 0.05)
• Time to distant metastases (HR 0.81 Plt0.03)

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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

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