A randomized three-arm multi-centre comparison of: 1 year Herceptin®1 year Herceptin® 2 years Herceptin®2 years Herceptin® or no Herceptin®or no Herceptin®

A randomized three-arm multi-centre comparison of:A randomized three-arm multi-centre comparison of:• 1 year Herceptin®1 year Herceptin®• 2 years Herceptin®2 years Herceptin®• or no Herceptin®or no Herceptin®

in women with HER-2 positive primary breast cancer in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapywho have completed adjuvant chemotherapy

Martine J. Piccart-Gebhart, MD, PhD on behalf of: Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating The Breast International Group (BIG), NON-BIG participating

groups, Independent sites, F. Hoffmann – La Roche Ltd.groups, Independent sites, F. Hoffmann – La Roche Ltd.

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 EASTERN EUROPE: EUROPE:

11%11%

JAPAN JAPAN

12%12%

ASIA ASIA PACIFICPACIFIC

CENTRAL &

SOUTH AMERICA

5.5%5.5%

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

CANADACANADA

NORDIC NORDIC COUNTRIESCOUNTRIES

SOUTH SOUTH AFRICAAFRICA

AUSTRALIA – AUSTRALIA – NEW ZEALANDNEW ZEALAND

HERA TRIAL DESIGN 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 INCLUSION CRITERIAKEY INCLUSION CRITERIA

• Centrally confirmed HER-2 overexpression Centrally confirmed HER-2 overexpression or amplificationor amplification

• Node-positive or (sentinel) node-negative Node-positive or (sentinel) node-negative with with T1c T1c

• Completed Completed 4 cycles of approved 4 cycles of approved (neo)adjuvant chemotherapy regimen(neo)adjuvant chemotherapy regimen

• Baseline LVEF Baseline LVEF 55% (Echo or MUGA) 55% (Echo or MUGA)• Known hormone receptor statusKnown 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 PLANENDPOINTS 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 trastuzumab2y trastuzumabN=1694N=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 CHARACTERISTICSPATIENT/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


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


ADJUVANT ENDOCRINE THERAPYADJUVANT ENDOCRINE THERAPY

ObservationObservation 1 year trastuzumab1 year trastuzumab

TAMTAM

64%64%AIAI

TAMTAMAIAI

9%9%

11%11%

LHRH ± TAMLHRH ± TAM

16%16%

TAMTAM

66%66%8%8%

8%8%

17%17%

AIAI

TAMTAMAIAI

LHRH ± TAMLHRH ± TAM

OVERVIEW OF ADVERSE EVENTSOVERVIEW OF ADVERSE EVENTS

7.97.91321324.34.37575Patients with at least Patients with at least one grade 3 or 4 AEone grade 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 Patients with at least one SAEone SAE

%%NN%%NN

1 year trastuzumab1 year trastuzumab

(N=1677)(N=1677)


(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%


N=1677N=1677


N=1736N=1736

0.1% 0%

DISEASE-FREE SURVIVALDISEASE-FREE SURVIVAL

% alive % alive and and

disease disease freefree

Months fromMonths from randomizationrandomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents22--yryr

DFSDFS %% HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54 [0.43, 0.67][0.43, 0.67] <0.0001<0.0001

220220 77.477.4



10010090908080707060605050404030302020101000

No. No. at riskat risk

Months fromMonths from randomizationrandomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents22--yryr

DFSDFS %% HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54 [0.43, 0.67][0.43, 0.67] <0.0001<0.0001

220220 77.477.4



10010090908080707060605050404030302020101000

No. No. at riskat risk

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

n=6n=6 5%5%

DISEASE-FREE SURVIVALDISEASE-FREE SURVIVALType of First EventType 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

CONCLUSIONSCONCLUSIONS

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

• Trastuzumab therapy is associated with a low incidence of Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer severe symptomatic congestive heart failure; longer

follow-up is needed to better quantify this riskfollow-up is needed to better quantify this risk

• All patients continue to be followed for long-term safety: All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab patients in the observation arm will be offered trastuzumab (guidelines in preparation)(guidelines in preparation)

• Results regarding optimal trastuzumab duration (1 versus 2 Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008years) should be available by 2008

CONCLUSIONSCONCLUSIONS

HERA Study Design Elements

•Randomized following ctx

•DFS was primary endpoint

•Most patients did not receive taxane

•In contrast to the Joint analysis, HERA included a large percentage of node negative pts(About 1/3).

•Very short median follow-up

Adjuvant Trastuzumab Summary and Conclusions

•Does adjuvant trastuzumab improve DFS? YES!

•Should we give trastuzumab with or following CTX?

•What is the appropraite duration of trastuzumab?

•What is the price of trastuzumab?

Should we give Trastuzumab before or after CTX?

•Preclinical data suggest that trastuzumab may amplify ctx’s pro-apoptotic effects.

•Synergistic activity in preclinical models for some ctx

•Cardiotoxicity concerns when trastuzumab is given in proximity to anthracyclines.

What is the appropriate duration of Trastuzumab?

•Unknown (HERA 1 vs. 2 yr pending)

•Current data supports one year of therapy

•Current data supports initiation of therapy for up to 6 months following completion of chemotherapy or radiation therapy

•Could we get by with less trastuzumab?

( ie. only with chemo?)

What is the price of Trastuzumab?

Cardiac Toxicity(CHF) can be consequence of using trastuzumab

Rate = 3.3-4.3% AC-TH vs. 0-0.5% AC-T (B31/ N9831)

Rate = 0.5-2.2% post ctx (HERA/N9831)

Degree of reversibility uncertain and requires further follow-up

Long term effects unknown

While benefit far outweighs the risks, the price is real and should be discussed with patients

BCIRG 006Adjuvant Breast Cancer

Node Positive and High Risk Node Negative

HER2 +FISH

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Platinum salts75 mg/m2 75 mg/m2 or AUC 6

1 Year Trastuzumab

N=3150480

centres

1 Year Trastuzumab

ACT

ACTH

TCH

BCIRG 006 LVEF Decline by NYHA Class

AC-T AC-TH TCH

>10 < LLN 9 34 7

>15%< LLN 6 25 4

Grade 3-4 CHF 1 18 1

Implication: Trastuzumab by itself is not cardiotoxic; it becomes so when it keeps company with doxorubicin.

Intergroup Guidelines for N9831

•For women receiving trastuzumab, continue until 1 year is completed.

•For women randomized to 1 yr TH, continue as planned

•For women on Arm A: AC-T and are at most 6 months from completion of paclitaxel, begin weekly trastuzumab and continue until you have completed 1 yr of trastuzumab with cardiac testing.

Intergroup Guidelines for N9831

•For women on Arm A: AC-T and have not started paclitaxel, begin weekly trastuzumab with paclitaxel and continue until 1 yr of trastuzumab is completed, with cardiac testing.

•For women on Arm B: AC-T-H, and you have not begun trastuzumab, begin trastuzumab with paclitaxel and continue for 1 yr. with cardiac testing.

•If ctx completed > 6 mo. and have not received trastuzumab, discuss risks and benefits.

Documents

A randomized three-arm multi-centre comparison of: 1 year Herceptin®1 year Herceptin® 2 years Herceptin®2 years Herceptin® or no Herceptin®or no Herceptin®