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 FIRST RESULTS OF THE HERA TRIALHERA TRIAL

ASCO, Scientific Session, May 16, 2005ASCO, Scientific Session, May 16, 2005

EU

71.5%

EASTERN EUROPE:

11%

JAPAN

12%

ASIA PACIFIC

CENTRAL &

SOUTH AMERICA

5.5%

ACCRUAL: 5090 WOMEN ACCRUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005)478 centers from 39 countries (2002-2005)

CANADA

NORDIC COUNTRIES

SOUTH AFRICA

AUSTRALIA – NEW ZEALAND

HERA TRIAL DESIGN

Women with HER2 POSITIVE invasive Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmedbreast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy radiotherapy

StratificationStratificationStratificationStratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy,

age, regionage, region

RandomizationRandomizationRandomizationRandomization

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 2 years3 weekly x 2 years

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 1 year3 weekly x 1 year

ObservationObservation

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: Primary endpoint: DFSDFS

Secondary endpoints: RFS, DDFS, OS, Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab2 years vs 1 year trastuzumab

EFFICACYEFFICACY

ENDPOINTS AND ANALYSIS PLAN

Target accrual: 4482Target accrual: 4482HR = 0.77 (power 80% 2 sided HR = 0.77 (power 80% 2 sided = 0.025) = 0.025)

for each pairwise test (1y vs nil or 2y vs nil)for each pairwise test (1y vs nil or 2y vs nil)

Target accrual: 4482Target accrual: 4482HR = 0.77 (power 80% 2 sided HR = 0.77 (power 80% 2 sided = 0.025) = 0.025)

for each pairwise test (1y vs nil or 2y vs nil)for each pairwise test (1y vs nil or 2y vs nil)

One interim efficacy analysis (n = 475 events)One interim efficacy analysis (n = 475 events)One primary core analysis (n = 951 events)One primary core analysis (n = 951 events)

SAFETYSAFETY

• TolerabilityTolerability• Incidence of cardiac Incidence of cardiac

dysfunction.dysfunction.

Three interim analysis of Three interim analysis of cardiac endpoints aftercardiac endpoints aftern = 300n = 300 n = 600n = 600 n = 900 n = 900 ptspts

Stopping rule: Stopping rule: 4% 4% absolute increase in primary absolute increase in primary

cardiac eventscardiac events

HERA FLOW CHARTHERA FLOW CHART

5090 Women enrolled5090 Women enrolled

5081 with available data5081 with available data1 year median follow-up1 year median follow-up

2y trastuzumabN=1694

Efficacy Efficacy AnalysisAnalysisN=3387N=3387

N= 1677N= 16771y trastuzumab1y trastuzumab

N=1736N=1736ObservationObservation

Safety Safety AnalysisAnalysisN=3413N=3413

N=3N=3N=20N=20N=26N=26

ObservationObservationN=1693N=1693

1y trastuzumab1y trastuzumabN=1694N=1694

PATIENT/TUMOR CHARACTERISTICS

Age (%)Age (%)

< 35 y< 35 y

35- 49 y35- 49 y50 - 59 y50 - 59 y 60 y60 ymissingmissing

Observation (n = 1693) 1 year trastuzumab (n = 1694)

Adjuvant chemotherapy (%)Adjuvant chemotherapy (%)

Anthracyclines + taxanesAnthracyclines + taxanes

No anthracyclines,No anthracyclines,no taxaneno taxane

AnthracyclinesAnthracyclines

missingmissing

7.3 7.6

31.844.343.7

16.20.2

32.7

0.216.2

6.26.1

26.025.50.1 0.2

68.3 67.9

Menopausal status at randomization (%)Menopausal status at randomization (%)

Observation (N=1693)Observation (N=1693) 1 year trastuzumab (N=1694)1 year trastuzumab (N=1694)

50.0

37.9

16.115.4

37.2

47.1 Postmenopausal

Uncertain

PremPrem

PATIENT/TUMOR CHARACTERISTICSPATIENT/TUMOR CHARACTERISTICS

Observation (N=1693)Observation (N=1693) 1 year trastuzumab (N=1694)1 year trastuzumab (N=1694)

28.532.1

11.1

28.328.9

32.910.2

27.9

Node neg.Node neg.1-3 + nodes1-3 + nodes 4 + nodes4 + nodes

0.20.20.10.1missingmissing

Nodal Status (%)Nodal Status (%)

Hormone Receptor (%)Hormone Receptor (%)

49.9

50.0

49.0HR negativeHR negative

HR positiveHR positive

Any (neoadjuvant)Any (neoadjuvant)

50.9

49.0

PATIENT/TUMOR CHARACTERISTICSPATIENT/TUMOR CHARACTERISTICS

ADJUVANT ENDOCRINE THERAPYADJUVANT ENDOCRINE THERAPY

ObservationObservation 1 year trastuzumab1 year trastuzumab

TAMTAM

66%66%8%8%

8%8%

17%17%

AIAI

TAMTAMAIAI

LHRH ± TAMLHRH ± TAM

TAMTAM

64%64%AIAI

TAMTAMAIAI

9%9%

11%11%

LHRH ± TAMLHRH ± TAM

16%16%

OVERVIEW OF ADVERSE EVENTSOVERVIEW OF ADVERSE EVENTS

7.97.91321324.34.37575Patients with at least one Patients with at least one grade 3 or 4 AEgrade 3 or 4 AE

8.58.5143 143 (c)(c)Treatment withdrawals Treatment withdrawals

6 6 (b)(b)3 3 (a)(a)Fatal AEFatal AE

7.07.01171174.74.78181Patients with at least one Patients with at least one SAESAE

%%NN%%NN

1 year trastuzumab1 year trastuzumab

(N=1677)(N=1677)

ObservationObservation

(N=1736)(N=1736)

a)a) Cardiac failure, suicide, unknownCardiac failure, suicide, unknownb)b) Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknownCerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknownc)c) Reason: safety in 6%, refusal in 2.5%Reason: safety in 6%, refusal in 2.5%

SAFETY ANALYSIS POPULATIONSAFETY ANALYSIS POPULATIONCardiotoxicityCardiotoxicity

0.5%0.5%

(95% CI: 0.25-1.02)(95% CI: 0.25-1.02)

0 %0 %

(95% CI: 0.00-0.21)(95% CI: 0.00-0.21)

Same LVEF criteriaSame LVEF criteriaandand symptomatic CHF symptomatic CHF NYHA class III/IV, NYHA class III/IV, confirmed by confirmed by cardiologist cardiologist

Cardiac deathCardiac death

7.1 %7.1 %2.2 %2.2 %Decrease by Decrease by 10 EF points 10 EF points and LVEF < 50% and LVEF < 50%

1 year trastuzumab1 year trastuzumab

N=1677N=1677

ObservationObservation

N=1736N=1736

0.1% 0%

DISEASE-FREE SURVIVAL

% alive and

disease free

280

85.8

40

at riskMonths from randomization

0 5 10 15 20 25

1693 1428 994 580 87

1694 1472 1067 629 303 102

Events2 yr

DFS % HR [95% CI] p value

127 0.54 [0.43, 0.67] <0.0001

220 77.4

1 year trastuzumab

Observation

1009080706050

302010

0

No.

3%3% n=6n=6 n=3n=3 2%2%

n=6n=6 5%5%

DISEASE-FREE SURVIVALType of First Event

Observation Observation n= 220 eventsn= 220 events

1 year trastuzumab1 year trastuzumabn= 127 eventsn= 127 events

n=154n=154 n= 85n= 85 67%67%

23%23% n=50n=50

3%3% n=7n=7

1%1% n=3n=3

n=6n=6 5%5%

Distant eventDistant event

Loco regional eventLoco regional event

Contralateral breast CaContralateral breast Ca

Death as first eventDeath as first event

Second non breast malignancySecond non breast malignancy

70%70%

n=27n=27 21% 21%

DFS BENEFIT IN SUBGROUPSDFS BENEFIT IN SUBGROUPSHR: 1 year trastuzumab vs observationHR: 1 year trastuzumab vs observation

0 1 2

All

Any, neo-adjuvant chemotherapyNodalstatus

0 pos, no neo-adjuvant chemotherapy

3387

3581100

872

2032307

n

0.54

0.530.52

0.77

0.640.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxaneAdjuvant chemotherapy regimen

Anthracycline, no taxaneAnthracycline + taxane

NegativeReceptor status/endocrine therapy

Pos + no endocrine therapyPos + endocrine therapy

<35 yrsAge group

35-49 yrs50-59 yrs

60 yrs

Europe, Nordic, Canada, SA, Aus, NZRegion

Asia Pacific, JapanEastern Europe

Central + South America

972953

0.510.53

1674 0.514671234

0.490.68

251 0.4714901091

0.520.53

549 0.70

2430 0.58405364

0.420.31

188 0.90

Favorstrastuzumab

Favorsobservation

0 1 2

All

Any, neo-adjuvant chemotherapyNodalstatus

0 pos, no neo-adjuvant chemotherapy

3387

3581100

872

2032307

n

0.54

0.530.52

0.77

0.640.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxaneAdjuvant chemotherapy regimen

Anthracycline, no taxaneAnthracycline + taxane

NegativeReceptor status/endocrine therapy

Pos + no endocrine therapyPos + endocrine therapy

<35 yrsAge group

35-49 yrs50-59 yrs

60 yrs

Europe, Nordic, Canada, SA, Aus, NZRegion

Asia Pacific, JapanEastern Europe

Central + South America

972953

0.510.53

1674 0.514671234

0.490.68

251 0.4714901091

0.520.53

549 0.70

2430 0.58405364

0.420.31

188 0.90

Favorstrastuzumab

Favorsobservation

SECONDARY EFFICACY ENDPOINTSSECONDARY EFFICACY ENDPOINTSIntent-to-treat AnalysisIntent-to-treat Analysis

RFSRFS DDFSDDFS OSOS

0.500.50 0.510.51

0.760.76

95% CI95% CIpp value (logrank) value (logrank)2y outcome (%)2y outcome (%)

0.40-0.630.40-0.63< 0.0001< 0.0001

78.6 vs 87.278.6 vs 87.2

0.40-0.660.40-0.66< 0.0001< 0.0001

81.8 vs 89.781.8 vs 89.7

0.47-1.230.47-1.23<0.26<0.26

95.0 vs 96.095.0 vs 96.0ObservationObservation1 year trastuzumab1 year trastuzumab

No of No of eventsevents

209209 113113 179179 9898 3737 2929

CONCLUSIONS: 1CONCLUSIONS: 1

At one year median follow-up:At one year median follow-up:

• Trastuzumab given every 3 weeks for one year following Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancerfor women with HER-2 positive early breast cancer

• Trastuzumab significantly reduces the risk of distant Trastuzumab significantly reduces the risk of distant metastasesmetastases

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

Trastuzumab therapy is associated with a Trastuzumab therapy is associated with a low incidence of severe symptomatic low incidence of severe symptomatic

congestive heart failure; longer follow-up is congestive heart failure; longer follow-up is needed to better quantify this riskneeded to better quantify this risk

CONCLUSIONS: 2CONCLUSIONS: 2

These data support the use of These data support the use of trastuzumab as adjuvant treatment trastuzumab as adjuvant treatment

for women with HER-2 positive early for women with HER-2 positive early breast cancerbreast cancer

CONCLUSIONS: OVERALLCONCLUSIONS: OVERALL

All patients continue to be followed All patients continue to be followed for long-term safety: patients in for long-term safety: patients in

the observation arm will be offered the observation arm will be offered trastuzumab trastuzumab

FOLLOW-UP: 1FOLLOW-UP: 1

6

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

ER-negative; Study 8541

Low CAFMid CAF

Hi CAF

RR=0.64 (Hi v Lo)p=0.002

Disease

-free Survival

10

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

Low CAFMid CAF

Hi CAF

RR=0.86 (Hi v Lo)p=0.35

Disease

-free Survival

ER-pos itive; Study 8541

8

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

q3wk

q2wk

RR=0.77p=0.05

Disease

-free Survival

ER-negative; Study 9741

12

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20Years

q3wk

q2wk RR=0.90p=0.44

Disease

-free Survival

ER-pos itive; Study 9741

HERA TRIAL DESIGN

Women with HER2 POSITIVE invasive Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmedbreast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy radiotherapy

StratificationStratificationStratificationStratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy,

age, regionage, region

RandomizationRandomizationRandomizationRandomization

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 2 years3 weekly x 2 years

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 1 year3 weekly x 1 year

ObservationObservation

Results regarding optimal trastuzumab Results regarding optimal trastuzumab duration (1 versus 2 years) should be duration (1 versus 2 years) should be

available by 2008available by 2008

FOLLOW-UP: 2FOLLOW-UP: 2