HERA: KEY DESIGN ELEMENTS, RESULTS AND FUTURE PLANS

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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

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

• 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

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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
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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
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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

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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

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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)
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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
1 year trastuzumab
alive and disease free
100
90
80
Observation
70
60
50
2
yr
40
DFS

Events
HR
95 CI
p value
30
85.8
127
0.54
0.43, 0.67
lt0.0001
20
220
77.4
10
0
0
5
10
15
20
25
Months from
randomization
No.
at risk
1694
1472
1067
629
303
102
280
1693
1428
994
580
87
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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 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 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 2
Trastuzumab therapy is associated with a low
incidence of severe symptomatic congestive heart
failure longer follow-up is needed to better
quantify this risk
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CONCLUSIONS OVERALL
These data support the use of trastuzumab as
adjuvant treatment for women with HER-2 positive
early breast cancer
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FOLLOW-UP 1

• All patients continue to be followed for
  long-term safety patients in the observation
  arm will be offered trastuzumab

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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
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FOLLOW-UP 2

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