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. 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 FIRST RESULTS OF THE HERA TRIAL ASCO, Scientific Session, May 16, 2005

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

4. HERA TRIAL DESIGN Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy StratificationStratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region RandomizationRandomization 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. Primary endpoint: DFS Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab EFFICACY 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) Target accrual: 4482 HR = 0.77 (power 80% 2 sided  = 0.025) for each pairwise test (1y vs nil or 2y vs nil) One interim efficacy analysis (n = 475 events) One primary core analysis (n = 951 events) SAFETY TolerabilityTolerability Incidence of cardiac dysfunction.Incidence of cardiac dysfunction. Three interim analysis of cardiac endpoints after n = 300n = 600n = 900 pts Stopping rule:  4% absolute increase in primary cardiac events

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

9. PATIENT/TUMOR CHARACTERISTICS Age (%) < 35 y 35- 49 y 50 - 59 y  60 y missing Observation (n = 1693)1 year trastuzumab (n = 1694) Adjuvant chemotherapy (%) Anthracyclines + taxanes No anthracyclines, no taxane Anthracyclines missing 7.37.6 31.8 44.343.7 16.2 0.2 32.7 0.2 16.2 6.26.1 26.0 25.5 0.10.2 68.3 67.9

10. Menopausal status at randomization (%) Observation (N=1693) 1 year trastuzumab (N=1694) 50.0 37.9 16.115.4 37.2 47.1 Postmenopausal Uncertain Prem PATIENT/TUMOR CHARACTERISTICS

11. Observation (N=1693) 1 year trastuzumab (N=1694) 28.5 32.1 11.1 28.3 28.9 32.9 10.2 27.9 Node neg. 1-3 + nodes  4 + nodes 0.20.1 missing Nodal Status (%) Hormone Receptor (%) 49.9 50.0 49.0 HR negative HR positive Any (neoadjuvant) 50.9 49.0 PATIENT/TUMOR CHARACTERISTICS

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

13. OVERVIEW OF ADVERSE EVENTS 7.91324.375 Patients with at least one grade 3 or 4 AE 8.5 143 (c) Treatment withdrawals 6 (b) 3 (a) Fatal AE 7.01174.781 Patients with at least one SAE %N%N 1 year trastuzumab (N=1677) (N=1677)Observation(N=1736) a) Cardiac failure, suicide, unknown b) Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknown c) Reason: safety in 6%, refusal in 2.5%

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

15. DISEASE-FREE SURVIVAL % alive and disease free 280 85.8 40 at risk Months fromrandomization 0510152025 1693142899458087 169414721067629303102 Events 2yr DFS% HR[95% CI]p value 1270.54[0.43, 0.67]<0.0001 22077.4 1 year trastuzumab Observation 100 90 80 70 60 50 30 20 10 0 No.

16. 3%n=6 n=32% n=65% DISEASE-FREE SURVIVAL Type of First Event Observation n= 220 events 1 year trastuzumab n= 127 events n=154 n= 85 67% 23% n=50 3%n=7 1%n=3 n=65% Distant event Loco regional event Contralateral breast Ca Death as first event Second non breast malignancy 70% n=27 21%

17. DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation 012 All Any, neo-adjuvant chemotherapy Nodalstatus 0 pos, no neo-adjuvant chemotherapy 3387 358 1100 872 203 2307 n 0.54 0.53 0.52 0.77 0.64 0.43 Hazard ratio 1-3 pos, no neo-adjuvant chemotherapy  4 pos, no neo-adjuvant chemotherapy No anthracycline or taxane Adjuvant chemotherapy regimen Anthracycline, no taxane Anthracycline + taxane Negative Receptor status/endocrine therapy Pos + no endocrine therapy Pos + endocrine therapy <35 yrs Age group 35-49 yrs 50-59 yrs  60 yrs Europe, Nordic, Canada, SA, Aus, NZ Region Asia Pacific, Japan Eastern Europe Central + South America 972 953 0.51 0.53 16740.51 467 1234 0.49 0.68 2510.47 1490 1091 0.52 0.53 5490.70 24300.58 405 364 0.42 0.31 1880.90 Favors trastuzumab Favors observation 012 All Any, neo-adjuvant chemotherapy Nodalstatus 0 pos, no neo-adjuvant chemotherapy 3387 358 1100 872 203 2307 n 0.54 0.53 0.52 0.77 0.64 0.43 Hazard ratio 1-3 pos, no neo-adjuvant chemotherapy  4 pos, no neo-adjuvant chemotherapy No anthracycline or taxane Adjuvant chemotherapy regimen Anthracycline, no taxane Anthracycline + taxane Negative Receptor status/endocrine therapy Pos + no endocrine therapy Pos + endocrine therapy <35 yrs Age group 35-49 yrs 50-59 yrs  60 yrs Europe, Nordic, Canada, SA, Aus, NZ Region Asia Pacific, Japan Eastern Europe Central + South America 972 953 0.51 0.53 16740.51 467 1234 0.49 0.68 2510.47 1490 1091 0.52 0.53 5490.70 24300.58 405 364 0.42 0.31 1880.90 Favors trastuzumab Favors observation

18. SECONDARY EFFICACY ENDPOINTS Intent-to-treat Analysis RFSDDFSOS 0.50 0.51 0.76 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 Observation 1 year trastuzumab No of events 209113179983729

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 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 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 Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone receptor status,...) and of type of adjuvant chemotherapy received

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

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

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

25. HERA TRIAL DESIGN Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy StratificationStratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region RandomizationRandomization 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

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