Exemestane Versus Tamoxifen
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Exemestane Versus Tamoxifen

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Exemestane Versus Tamoxifen Exemestane Versus Tamoxifen Presentation Transcript

  • 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
    • 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) R A N D O M I Z A T I O N
  • 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
    *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
  • 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 R A N D O M I Z A T I O N
  • 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
  • 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
  • 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
  • RESULTS Of First Planned Analysis at 2.75 Years All Patients Censored at 2.75 Years 9600+ Patients Followed for 2.75 Years 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
  • 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
  • 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)
  • RESULTS MedDRA Coding Adverse Events Gynecologic, Cardiovascular, Musculoskeletal categories
  • 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
  • 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
  • Results Outcomes
  • DFS Events (ITT) Event, n (%) Tamoxifen n=4868 Exemestane n=4898 Total 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)
  • Numbers at risk: Tamoxifen Exemestane 4898 36/4809 73/4708 53/4615 62/4473 128/4179 Cumulative Probability Probability 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 Tamoxifen Exemestane Tamoxifen Exemestane
  • 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) Probability 0.00 0.02 0.04 0.06 0.08 0.10 Years since randomization 0.0 0.5 1.0 1.5 2.0 2.5 Tamoxifen Exemestane
  • Relapse-Free Survival (ITT) Cumulative Probability HR=0.85 (0.72–1.00; P =0.05) Probability 0.00 0.02 0.04 0.06 0.08 0.10 Tamoxifen Exemestane Years since randomization 0.0 0.5 1.0 1.5 2.0 2.5 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
  • 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) Probability 0.00 0.02 0.04 0.06 0.08 0.10 Years since randomization 0.0 0.5 1.0 1.5 2.0 2.5 Tamoxifen Exemestane
  • TEAM Trial Flow Chart 29.5% 18.9% 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
  • 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)
  • 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