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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
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
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)
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 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
1 year trastuzumab1 year trastuzumab
ObservationObservation
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
1 year trastuzumab1 year trastuzumab
ObservationObservation
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.