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1 Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive.

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Presentation on theme: "1 Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive."— Presentation transcript:

1 1 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 1 US Oncology Research, Houston, TX, USA; 2 Erasmus MC Daniel Den Hoed, Rotterdam, the Netherlands; 3 University Hospital Freiburg, Freiburg, Germany; 4 The University of Birmingham, Birmingham, United Kingdom; 5 Institut du Sein Henri Hartmann (ISHH), Neuilly sur Seine, France; 6 U. Z. Gasthuisberg, Leuven, Belgium; 7 Athens University Medical School, Greece; 8 Jichi Medical University, Shimotsuke, Japan; 9 Leiden University Medical Center, Leiden, The Netherlands; 10 Helios Medical Center Aue, Germany; 11 Pfizer, New York; USA; 12 Endocrine Cancer Group, Edinburgh University, Scotland S.E. Jones 1, C. Seynaeve 2, A. Hasenburg 3, D. Rea 4, JM. Vannetzel 5, R. Paridaens 6, C. Markopoulos 7, Y. Hozumi 8, H. Putter 9, E. Hille 9, D. Kieback 10, L. Asmar 1, J. Smeets 11, R. Urbanski 11, J.M.S. Bartlett 12, C.J.H. van de Velde 9

2 2 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 years Primary end point: Diagnosis and adequate prior therapy of early breast cancer Original Study Design (2001) RANDOMIZATIONRANDOMIZATION

3 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 3 *Coombes RC, et al. N Eng J Med. 2004;350: 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

4 4 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 years DFS at 5 years RANDOMIZATIONRANDOMIZATION

5 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 5

6 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 6

7 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 7

8 RESULTS Of First Planned Analysis at 2.75 Years All Patients Censored at 2.75 Years Patients Followed for 2.75 Years 8 Results

9 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

10 10 TEAM Trial Flow Chart 9775 Patients Randomized 4874 Randomized to Tamoxifen 4901 Randomized to Exemestane 4898 Exemestane in Efficacy Analysis 4853 Exemestane For Safety Analysis 4868 Tamoxifen in Efficacy Analysis 4817 Tamoxifen For Safety Analysis 6 Withdrawn Consent 51 Treatment Not Started 143 Ineligible 188 Lost to FU<2.75y 1434 Treatment Stopped <2.75y 3 Withdrawn Consent 45 Treatment Not Started 130 Ineligible 139 Lost to FU<2.75y 926 Treatment Stopped <2.75y

11 11 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 chemotherapy1743 (36)1774 (36) Radiotherapy3314 (69)3376 (70)

12 RESULTS MedDRA Coding 12 Adverse Events Gynecologic, Cardiovascular, Musculoskeletal categories

13 13 Selected Gynecologic Events ExemestaneTamoxifenP value Vaginal discharge1122.3%3336.8%< Vaginal haemorrhage781.6%1533.1% < Vaginal infection340.7%1082.2%< Uterine polyp40.1%250.5%< Endometrial hyperplasia30.0%962.0%< Endometrial cancer70.1%120.2%NS

14 14 Selected Cardiac/Vascular Events Exemestane (4853) Tamoxifen (4817) P value Cardiac disorders - Myocardial ischemia/infarction410.8%310.6%NS - Cardiac deaths180.4%110.2%NS Vascular disorders - Hot flush/flushing % %< Hypertension1633.3%1042.1%< Thromboembolic events440.9%1132.3%<0.001

15 Selected Musculoskeletal Events Exemestane (4853) Tamoxifen (4817) P value Arthralgia %4479.2%<0.001 Arthritis1473.0%831.7%<0.001 Reported osteoporosis2284.7%1042.1%<0.001 Reported fractures1332.7%1112.3%NS 15

16 16 Results Outcomes

17 17 DFS Events (ITT) Event, n (%) Tamoxifen n=4868 Exemestane n=4898 Total N=9766 Total DFS events388 (8.0)352 (7.2)740 (7.6) Local recurrence (includes ipsilateral breast cancer) 45 (0.9)42 (0.9)87 (0.9) Distant metastases244 (5.0)201 (4.1)445 (4.6) New primary BC (no distant metastasis) 17 (0.3)21 (0.4)38 (0.4) Intercurrent deaths82 (1.7)88 (1.8)170 (1.7)

18 18 Numbers at risk: Tamoxifen Exemestane /480973/470853/461562/ /4179 Cumulative Probability Probability Years since randomization /476579/463669/451686/ /4099 DFS Comparison at 2.75 Years (ITT) HR=0.89 (95% CI ) Adjusted Log rank P = Tamoxifen Exemestane Tamoxifen Exemestane

19 19 DFS: On-Study Drug and Pre-Switch — Excluding 96 Never Treated Patients Numbers at risk: Tamoxifen:481728/451072/420763/396271/366487/2817 Exemestane:485333/455264/434353/421047/ /3779 Cumulative Probability HR 0.83 (95% CI , P=0.02) Probability Years since randomization Tamoxifen Exemestane

20 20 Relapse-Free Survival (ITT) Cumulative Probability Numbers at risk: Tamoxifen:486821/476562/463661/451665/436497/4099 Exemestane:489825/480960/470840/461547/447392/4179 HR=0.85 (0.72–1.00; P=0.05) Probability Tamoxifen Exemestane Years since randomization

21 21 Cumulative Incidence of Distant Metastasis (ITT) Numbers at risk: Tamoxifen Exemestane /477169/465253/454771/ / /481554/473347/464656/ /4219 Time to Distant Metastases (ITT) HR=0.81 ( ; P <0.03) Probability Years since randomization Tamoxifen Exemestane

22 22 TEAM Trial Flow Chart 9775 Patients Randomized 4874 Randomized to Tamoxifen 4901 Randomized to Exemestane 4898 Exemestane in Efficacy Analysis 4853 Exemestane For Safety Analysis 4868 Tamoxifen in Efficacy Analysis 4817 Tamoxifen For Safety Analysis 6 Withdrawn Consent 51 Treatment Not Started 143 Ineligible 188 Lost to FU<2.75y 1434 treatment stopped <2.75y 3 Withdrawn Consent 45 Treatment Not Started 130 Ineligible 139 Lost to FU<2.75y 926 treatment stopped <2.75y 29.5% 18.9%

23 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) 23

24 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

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42 42 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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