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HERA: KEY DESIGN ELEMENTS, RESULTS AND FUTURE PLANS

HERA: KEY DESIGN ELEMENTS, RESULTS AND FUTURE PLANS. NSABP 17 SEPTEMBER 2005 Brian Leyland-Jones Minda De Gunzberg Professor of Oncology, McGill University, Montreal, Canada. ASCO, Scientific Session, May 16, 2005. FIRST RESULTS OF THE HERA TRIAL.

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HERA: KEY DESIGN ELEMENTS, RESULTS AND FUTURE PLANS

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  1. HERA: KEY DESIGN ELEMENTS, RESULTS AND FUTURE PLANS NSABP 17 SEPTEMBER 2005 Brian Leyland-Jones Minda De Gunzberg Professor of Oncology, McGill University, Montreal, Canada

  2. ASCO, Scientific Session, May 16, 2005 FIRST RESULTS OF THE HERA TRIAL A randomized three-arm multi-centre comparison of: • 1 year trastuzumab • 2 years trastuzumab • or no trastuzumab in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy

  3. ACCRUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005) NORDIC COUNTRIES EASTERN EUROPE:  11% CANADA 71.5% EU JAPAN  12% ASIA PACIFIC CENTRAL & SOUTH AMERICA 5.5% AUSTRALIA – NEW ZEALAND SOUTH AFRICA

  4. HERA TRIAL DESIGN Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 1 year Observation

  5. KEY DIFFERENCES • Any accepted adjuvant chemotherapy regimen • Trastuzumab not initiated until after the completion of all chemo and radiation therapy • Trastuzumab administered on a q3 weekly schedule • The only trial asking a duration question (by including a 2 year arm) • Large proportion (one-third) of node negative patients

  6. KEY INCLUSION CRITERIA • Centrally confirmed HER-2 overexpression or amplification • Node-positive or (sentinel) node-negative with  T1c • Completed  4 cycles of approved (neo)adjuvant chemotherapy regimen • Baseline LVEF  55% (Echo or MUGA) • Known hormone receptor status

  7. ENDPOINTS AND ANALYSIS PLAN Target accrual: 4482 HR = 0.77 (power 80% 2 sided  = 0.025) for each pairwise test (1y vs nil or 2y vs nil) SAFETY EFFICACY • Tolerability • Incidence of cardiac dysfunction. Primary endpoint: DFS Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab Three interim analysis of cardiac endpoints aftern = 300 n = 600 n = 900 pts Stopping rule:  4% absolute increase in primary cardiac events One interim efficacy analysis (n = 475 events) One primary core analysis (n = 951 events)

  8. HERA FLOW CHART 5090 Women enrolled 5081 with available data 1 year median follow-up Efficacy Analysis N=3387 2y trastuzumab N=1694 1y trastuzumab N=1694 Observation N=1693 N=20 N=3 N=26 Safety Analysis N=3413 N=1736 Observation N= 1677 1y trastuzumab

  9. < 35 y 35- 49 y 50 - 59 y  60 y missing No anthracyclines, no taxane Anthracyclines missing PATIENT/TUMOR CHARACTERISTICS Age (%) Observation (n = 1693) 1 year trastuzumab (n = 1694) 7.3 7.6 43.7 44.3 32.7 31.8 16.2 16.2 0.2 0.2 Adjuvant chemotherapy (%) 6.1 6.2 68.3 67.9 25.5 26.0 0.1 0.2 Anthracyclines + taxanes

  10. PATIENT/TUMOR CHARACTERISTICS Menopausal status at randomization (%) Observation (N=1693) 1 year trastuzumab (N=1694) Prem 15.4 16.1 37.2 37.9 Uncertain 47.1 50.0 Postmenopausal

  11. PATIENT/TUMOR CHARACTERISTICS Observation (N=1693) 1 year trastuzumab (N=1694) Nodal Status (%) Any (neoadjuvant) 10.2 11.1 Node neg. 32.9 32.1 1-3 + nodes 28.9 28.5  4 + nodes 27.9 28.3 missing 0.1 0.2 Hormone Receptor (%) HR negative 49.9 49.0 49.0 HR positive 50.0 50.9

  12. LHRH ± TAM LHRH ± TAM 16% 17% TAMAI TAMAI 11% 8% TAM TAM 8% 9% AI 66% AI 64% ADJUVANT ENDOCRINE THERAPY 1 year trastuzumab Observation

  13. OVERVIEW OF ADVERSE EVENTS Observation (N=1736) 1 year trastuzumab (N=1677) N % N % Patients with at least one grade 3 or 4 AE 75 4.3 132 7.9 Patients with at least one SAE 81 4.7 117 7.0 3 (a) 6 (b) Fatal AE Treatment withdrawals 143 (c) 8.5 • Cardiac failure, suicide, unknown • Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknown • Reason: safety in 6%, refusal in 2.5%

  14. SAFETY ANALYSIS POPULATION Cardiotoxicity Observation N=1736 1 year trastuzumab N=1677 Decrease by  10 EF points and LVEF < 50% 2.2 % 7.1 % 0 % (95% CI: 0.00-0.21) 0.5% (95% CI: 0.25-1.02) Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist Cardiac death 0% 0.1%

  15. DISEASE-FREE SURVIVAL 1 year trastuzumab % alive and disease free 100 90 80 Observation 70 60 50 2 yr 40 DFS % Events HR [95% CI] p value 30 127 85.8 0.54 [0.43, 0.67] <0.0001 20 220 77.4 10 0 0 5 10 15 20 25 Months from randomization No. at risk 1694 1472 1067 629 303 102 1693 1428 994 580 280 87

  16. DISEASE-FREE SURVIVALType of First Event Observation n= 220 events 1 year trastuzumab n= 127 events 70% Distant event n=154 n= 85 67% 23% n=50 n=27 21% Loco regional event n=6 5% 3% n=7 Contralateral breast Ca n=3 2% 3% n=6 Second non breast malignancy 1% n=3 n=6 5% Death as first event

  17. DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation Hazard Hazard ratio ratio n n All All 3387 3387 0.54 0.54 Nodal Nodal status status Any, neo Any, neo - - adjuvant chemotherapy adjuvant chemotherapy 358 358 0.53 0.53 0 pos, no neo 0 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 1100 1100 0.52 0.52 1 1 - - 3 pos, no neo 3 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 972 972 0.51 0.51 ³ ³ 4 pos, no neo 4 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 953 953 0.53 0.53 Adjuvant chemotherapy regimen Adjuvant chemotherapy regimen No anthracycline or taxane No anthracycline or taxane 203 203 0.64 0.64 Anthracycline, no taxane Anthracycline, no taxane 2307 2307 0.43 0.43 Anthracycline + taxane Anthracycline + taxane 872 872 0.77 0.77 Receptor status/endocrine therapy Receptor status/endocrine therapy Negative Negative 1674 1674 0.51 0.51 Pos + no endocrine therapy Pos + no endocrine therapy 467 467 0.49 0.49 1234 1234 0.68 0.68 Pos + endocrine therapy Pos + endocrine therapy Age group Age group <35 yrs <35 yrs 251 251 0.47 0.47 35 35 - - 49 yrs 49 yrs 1490 1490 0.52 0.52 50 50 - - 59 yrs 59 yrs 1091 1091 0.53 0.53 ³ ³ 60 yrs 60 yrs 549 549 0.70 0.70 Region Region Europe, Nordic, Canada, SA, Aus, NZ Europe, Nordic, Canada, SA, Aus, NZ 2430 2430 0.58 0.58 Asia Pacific, Japan Asia Pacific, Japan 405 405 0.42 0.42 Eastern Europe Eastern Europe 364 364 0.31 0.31 Central + South America Central + South America 188 188 0.90 0.90 Favors Favors Favors Favors 0 0 1 1 2 2 trastuzumab trastuzumab observation observation

  18. 0.76 0.51 0.50 Observation 1 year trastuzumab SECONDARY EFFICACY ENDPOINTS Intent-to-treat Analysis RFS DDFS OS No of events 209 113 179 98 37 29 95% CI p value (logrank) 2y outcome (%) 0.40-0.63 < 0.0001 78.6 vs 87.2 0.40-0.66 < 0.0001 81.8 vs 89.7 0.47-1.23 <0.26 95.0 vs 96.0

  19. CONCLUSIONS: 1 • At one year median follow-up: • Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancer • Trastuzumab significantly reduces the risk of distant metastases • Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone receptor status, ...) and of type of adjuvant chemotherapy received

  20. CONCLUSIONS: 2 Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer follow-up is needed to better quantify this risk

  21. CONCLUSIONS: OVERALL These data support the use of trastuzumab as adjuvant treatment for women with HER-2 positive early breast cancer

  22. FOLLOW-UP: 1 • All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab

  23. HERA TRIAL DESIGN Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 1 year Observation

  24. FOLLOW-UP: 2 • Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008

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