A randomized threearm multicentre comparison of:

1
ASCO, Scientific Session, May 16, 2005
FIRST RESULTS OF THE HERA TRIAL

• A randomized three-arm multi-centre comparison
  of
• 1 year Herceptin
• 2 years Herceptin
• or no Herceptin
• in women with HER-2 positive primary breast
  cancer who have completed adjuvant chemotherapy

Martine J. Piccart-Gebhart, MD, PhD on behalf
of The Breast International Group (BIG),
NON-BIG participating groups, Independent sites,
F. Hoffmann La Roche Ltd.
2
ACCRUAL 5090 WOMEN 478 centers from 39
countries (2002-2005)
NORDIC COUNTRIES
EASTERN EUROPE ? 11
CANADA
71.5
EU

• JAPAN
• ? 12
• ASIA PACIFIC

CENTRAL SOUTH AMERICA
5.5
AUSTRALIA NEW ZEALAND
SOUTH AFRICA
3
HERA TRIAL DESIGN
Women with HER2 POSITIVE invasive breast cancer
IHC3 or FISH centrally confirmed
Surgery (neo)adjuvant chemotherapy (CT) ?
radiotherapy
Stratification
Nodal status, adjuvant CT regimen, hormone
receptor status and endocrine therapy, age, region
Randomization
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
4
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

5
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)
SAFETY
EFFICACY

• Tolerability
• Incidence of cardiac dysfunction.

Primary endpoint DFS Secondary endpoints RFS,
DDFS, OS, 2 years vs 1 year trastuzumab
Three interim analysis of cardiac endpoints
aftern 300 n 600 n 900 pts
Stopping rule ? 4 absolute increase in primary
cardiac events
One interim efficacy analysis (n 475
events) One primary core analysis (n 951 events)
6
HERA FLOW CHART
5090 Women enrolled
5081 with available data 1 year median follow-up
Efficacy Analysis N3387
2y trastuzumab N1694
Observation N1693
1y trastuzumab N1694
N20
N3
N26
Safety Analysis N3413
N 1677 1y trastuzumab
N1736 Observation
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PATIENT/TUMOR CHARACTERISTICS
Age ()
Observation (n 1693)
1 year trastuzumab (n 1694)
7.3
7.6
44.3
43.7
31.8
32.7
16.2
16.2
0.2
0.2
Adjuvant chemotherapy ()
6.2
6.1
68.3
67.9
25.5
26.0
0.1
0.2
Anthracyclines taxanes
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PATIENT/TUMOR CHARACTERISTICS
Menopausal status at randomization ()
Observation (N1693)
1 year trastuzumab (N1694)
Prem
16.1
15.4
37.9
37.2
Uncertain
50.0
47.1
Postmenopausal
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PATIENT/TUMOR CHARACTERISTICS
Observation (N1693)
1 year trastuzumab (N1694)
Nodal Status ()
Any (neoadjuvant)
11.1
10.2
Node neg.
32.1
32.9
1-3 nodes
28.5
28.9
? 4 nodes
28.3
27.9
missing
0.2
0.1
Hormone Receptor ()
HR negative
49.9
49.0
49.0
HR positive
50.0
50.9
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ADJUVANT ENDOCRINE THERAPY
Observation
1 year trastuzumab
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OVERVIEW OF ADVERSE EVENTS
1 year trastuzumab (N1677)
Observation (N1736)

N

N
7.9
132
4.3
75
Patients with at least one grade 3 or 4 AE
7.0
117
4.7
81
Patients with at least one SAE
6 (b)
3 (a)
Fatal AE
8.5
143 (c)
Treatment withdrawals

• Cardiac failure, suicide, unknown
• Cerebral hemorrhage, cerebrovascular accident,
  sudden death, appendicitis, two unknown
• Reason safety in 6, refusal in 2.5

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SAFETY ANALYSIS POPULATION Cardiotoxicity
1 year trastuzumab N1677
Observation N1736
7.1
2.2
Decrease by ? 10 EF points and LVEF lt 50
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
0.1
0
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DISEASE-FREE SURVIVAL
alive and disease free
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DISEASE-FREE SURVIVALType of First Event
Observation n 220 events
1 year trastuzumab n 127 events
70
n154
n 85 67
Distant event
23 n50
n27 21
Loco regional event
n6 5
3 n7
Contralateral breast Ca
n3 2
3 n6
Second non breast malignancy
n6 5
1 n3
Death as first event
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DFS BENEFIT IN SUBGROUPS HR 1 year trastuzumab
vs observation
Hazard
Hazard
ratio
ratio
n
n
All
All
3387
0.54
3387
0.54
Nodal
status
Nodal
status
Any, neo
-
adjuvant chemotherapy
358
0.53
Any, neo
-
adjuvant chemotherapy
358
0.53
0 pos, no neo
-
adjuvant chemotherapy
1100
0.52
0 pos, no neo
-
adjuvant chemotherapy
1100
0.52
1
-
3 pos, no neo
-
adjuvant chemotherapy
1
-
3 pos, no neo
-
adjuvant chemotherapy
972
0.51
972
0.51
³
4 pos, no neo
-
adjuvant chemotherapy
953
0.53
³
4 pos, no neo
-
adjuvant chemotherapy
953
0.53
Adjuvant chemotherapy regimen
Adjuvant chemotherapy regimen
203
0.64
No anthracycline or taxane
203
0.64
No anthracycline or taxane
2307
0.43
Anthracycline, no taxane
2307
0.43
Anthracycline, no taxane
872
0.77
Anthracycline taxane
872
0.77
Anthracycline taxane
Receptor status/endocrine therapy
Receptor status/endocrine therapy
Negative
Negative
1674
0.51
1674
0.51
Pos no endocrine therapy
467
0.49
Pos no endocrine therapy
467
0.49
1234
0.68
1234
0.68
Pos endocrine therapy
Pos endocrine therapy
Age group
Age group
lt35 yrs
251
0.47
lt35 yrs
251
0.47
35
-
49 yrs
35
-
49 yrs
1490
0.52
1490
0.52
50
-
59 yrs
50
-
59 yrs
1091
0.53
1091
0.53
³
60 yrs
³
60 yrs
549
0.70
549
0.70
Region
Region
Europe, Nordic, Canada, SA, Aus, NZ
Europe, Nordic, Canada, SA, Aus, NZ
2430
0.58
2430
0.58
Asia Pacific, Japan
405
0.42
Asia Pacific, Japan
405
0.42
Eastern Europe
364
0.31
Eastern Europe
364
0.31
Central South America
188
0.90
Central South America
188
0.90
Favors
Favors
Favors
Favors
0
1
2
0
1
2
trastuzumab
observation
trastuzumab
observation
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SECONDARY EFFICACY ENDPOINTS Intent-to-treat
Analysis
RFS
DDFS
OS
No of events
209
113
179
98
37
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95 CI p value (logrank) 2y outcome ()
0.40-0.63 lt 0.0001 78.6 vs 87.2
0.40-0.66 lt 0.0001 81.8 vs 89.7
0.47-1.23 lt0.26 95.0 vs 96.0
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CONCLUSIONS

• 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 significantly reduces the risk of
  distant metastases
• Trastuzumabs clinical benefits are independent
  of patients baseline characteristics (nodal
  status, hormone receptor status, ...) and of
  type of adjuvant chemotherapy received

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CONCLUSIONS

• Trastuzumab therapy is associated with a low
  incidence of severe symptomatic congestive heart
  failure longer follow-up is needed to better
  quantify this risk
• All patients continue to be followed for
  long-term safety patients in the observation
  arm will be offered trastuzumab (guidelines in
  preparation)
• Results regarding optimal trastuzumab duration
  (1 versus 2 years) should be available by 2008

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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

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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?

21
Should we give Trastuzumab before or after CTX?

• Preclinical data suggest that trastuzumab may
  amplify ctxs pro-apoptotic effects.
• Synergistic activity in preclinical models for
  some ctx
• Cardiotoxicity concerns when trastuzumab is given
  in proximity to anthracyclines.

22
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?)

23
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

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BCIRG 006 Adjuvant Breast Cancer Node Positive
and High Risk Node Negative
4 x Docetaxel 100 mg/m2
4 x AC60/600 mg/m2
AC?T
AC?TH
HER2 FISH
1 Year Trastuzumab
N3150 480 centres
6 x Docetaxel and Platinum salts 75 mg/m2 75
mg/m2 or AUC 6
TCH
1 Year Trastuzumab
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BCIRG 006 LVEF Decline by NYHA Class

• AC-T AC-TH TCH
• gt10 lt LLN 9 34 7
• gt15lt 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.

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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.

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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 gt 6 mo. and have not received
  trastuzumab, discuss risks and benefits.