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

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

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

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

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

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

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

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

PATIENT/TUMOR CHARACTERISTICS Age (%) < 35 y y y  60 y missing Observation (n = 1693)1 year trastuzumab (n = 1694) Adjuvant chemotherapy (%) Anthracyclines + taxanes No anthracyclines, no taxane Anthracyclines missing

Menopausal status at randomization (%) Observation (N=1693) 1 year trastuzumab (N=1694) Postmenopausal Uncertain Prem PATIENT/TUMOR CHARACTERISTICS

Observation (N=1693) 1 year trastuzumab (N=1694) Node neg nodes  4 + nodes missing Nodal Status (%) Hormone Receptor (%) HR negative HR positive Any (neoadjuvant) PATIENT/TUMOR CHARACTERISTICS

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%

OVERVIEW OF ADVERSE EVENTS Patients with at least one grade 3 or 4 AE (c) Treatment withdrawals 6 (b) 3 (a) Fatal AE 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%

SAFETY ANALYSIS POPULATION Cardiotoxicity 0.5% (95% CI: ) 0 % (95% CI: ) 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= % 0%

DISEASE-FREE SURVIVAL % alive and disease free at risk Months fromrandomization Events 2yr DFS% HR[95% CI]p value [0.43, 0.67]< year trastuzumab Observation No.

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%

DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation 012 All Any, neo-adjuvant chemotherapy Nodalstatus 0 pos, no neo-adjuvant chemotherapy n 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 yrs yrs  60 yrs Europe, Nordic, Canada, SA, Aus, NZ Region Asia Pacific, Japan Eastern Europe Central + South America Favors trastuzumab Favors observation 012 All Any, neo-adjuvant chemotherapy Nodalstatus 0 pos, no neo-adjuvant chemotherapy n 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 yrs yrs  60 yrs Europe, Nordic, Canada, SA, Aus, NZ Region Asia Pacific, Japan Eastern Europe Central + South America Favors trastuzumab Favors observation

SECONDARY EFFICACY ENDPOINTS Intent-to-treat Analysis RFSDDFSOS % CI p value (logrank) 2y outcome (%) < vs < vs < vs 96.0 Observation 1 year trastuzumab No of events

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

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

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

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

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

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