Transcript No Slide Title

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
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
ACCRUAL: 5090 WOMEN
478 centers from 39 countries (2002-2005)
NORDIC
COUNTRIES
CANADA
71.5%
EU
CENTRAL
&
EASTERN
EUROPE:
 11%
JAPAN
 12%
ASIA
PACIFIC
5.5%
SOUTH
AMERICA
SOUTH
AFRICA
AUSTRALIA –
NEW ZEALAND
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
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
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)
EFFICACY
Primary endpoint: DFS
Secondary endpoints: RFS, DDFS, OS,
2 years vs 1 year trastuzumab
SAFETY
• Tolerability
• Incidence of cardiac
dysfunction.
Three interim analysis of
cardiac endpoints after
n = 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)
HERA FLOW CHART
5090 Women enrolled
5081 with available data
1 year median follow-up
2y trastuzumab
N=1694
N=26
1y trastuzumab
N=1694
N=20
N= 1677
1y trastuzumab
Observation
N=1693
Efficacy
Analysis
N=3387
N=3
N=1736
Observation
Safety
Analysis
N=3413
PATIENT/TUMOR CHARACTERISTICS
Age (%)
Observation (n = 1693)
1 year trastuzumab (n = 1694)
7.3 7.6
< 35 y
43.7
32.7
35- 49 y
50 - 59 y
 60 y
missing
44.3
31.8
16.2
0.2
16.2
0.2
Adjuvant chemotherapy (%)
6.1 6.2
68.3
No anthracyclines,
no taxane
Anthracyclines
Anthracyclines + taxanes
missing
67.9
25.5
26.0
0.1
0.2
PATIENT/TUMOR CHARACTERISTICS
Menopausal status at randomization (%)
Observation (N=1693)
1 year trastuzumab (N=1694)
15.4 Prem 16.1
37.2
47.1
Uncertain
Postmenopausal
37.9
50.0
PATIENT/TUMOR CHARACTERISTICS
Observation (N=1693)
1 year trastuzumab (N=1694)
Nodal Status (%)
Any (neoadjuvant)
Node neg.
32.9
1-3 + nodes
28.9
 4 + nodes
27.9
missing
10.2
11.1
32.1
28.5
28.3
0.1
0.2
Hormone Receptor (%)
HR negative
HR positive
49.9
49.0
49.0
50.0
50.9
ADJUVANT ENDOCRINE THERAPY
1 year trastuzumab
Observation
LHRH ± TAM
LHRH ± TAM
17%
16%
TAM
AI
AI
11%
TAM
9%
64%
TAM
AI
8%
TAM
8%
AI
66%
OVERVIEW OF ADVERSE EVENTS
Observation
(N=1736)
1 year trastuzumab
(N=1677)
N
%
N
%
Patients with at least one
grade 3 or 4 AE
75
4.3
132
7.9
Patients with at least one
SAE
81
4.7
117
7.0
Fatal AE
Treatment withdrawals
3 (a)
6 (b)
143 (c)
8.5
a) Cardiac failure, suicide, unknown
b) Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknown
c) Reason: safety in 6%, refusal in 2.5%
SAFETY ANALYSIS POPULATION
Cardiotoxicity
Decrease by
 10 EF points
and LVEF < 50%
Same LVEF criteria
and symptomatic CHF
NYHA class III/IV,
confirmed by
cardiologist
Cardiac death
Observation
N=1736
1 year trastuzumab
N=1677
2.2 %
7.1 %
0%
(95% CI: 0.00-0.21)
0.5%
(95% CI: 0.25-1.02)
0.1%
0%
DISEASE-FREE SURVIVAL
% alive
and
disease free
100
90
80
70
60
50
40
30
20
10
0
1 year trastuzumab
Observation
Events
0
No.
at risk
1694
1693
2 yr
DFS % HR
127
85.8
220
77.4
5
10
Months from
1472
1428
1067
994
[95% CI]
p value
0.54 [0.43, 0.67] <0.0001
15
20
randomization
629
580
303
280
25
102
87
DISEASE-FREE SURVIVAL
Type of First Event
Observation
n= 220 events
Distant event 70%
1 year trastuzumab
n= 127 events
n=154
Loco regional event
n= 85
23%
n=50 n=27
21%
Contralateral breast Ca
3%
n=7
n=6
5%
Second non breast malignancy
3%
n=6
n=3
2%
n=6
5%
Death as first event
1%
n=3
67%
DFS BENEFIT IN SUBGROUPS
HR: 1 year trastuzumab vs observation
n
All
Nodal status
Any, neo-adjuvant chemotherapy
0 pos, no neo-adjuvant chemotherapy
1-3 pos, no neo-adjuvant chemotherapy
4 pos, no neo-adjuvant chemotherapy
Adjuvant chemotherapy regimen
No anthracycline or taxane
Anthracycline, no taxane
Anthracycline + taxane
Receptor status/endocrine therapy
Negative
Pos + no endocrine therapy
Pos + endocrine therapy
Age group
<35 yrs
35-49 yrs
50-59 yrs
60 yrs
Region
Europe, Nordic, Canada, SA, Aus, NZ
Asia Pacific, Japan
Eastern Europe
Central + South America
0
Favors
trastuzumab
1
Favors
observation
2
Hazard
ratio
3387
0.54
358
1100
972
953
0.53
0.52
0.51
0.53
203
2307
872
0.64
0.43
0.77
1674
467
1234
0.51
0.49
0.68
251
1490
1091
549
0.47
0.52
0.53
0.70
2430
405
364
188
0.58
0.42
0.31
0.90
SECONDARY EFFICACY ENDPOINTS
Intent-to-treat Analysis
RFS
DDFS
OS
0.76
0.51
0.50
No of
events
209
113
95% CI
0.40-0.63
p value (logrank)
< 0.0001
2y outcome (%) 78.6 vs 87.2
179
98
0.40-0.66
< 0.0001
81.8 vs 89.7
37
29
0.47-1.23
<0.26
95.0 vs 96.0
Observation
1 year trastuzumab
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
• Trastuzumab’s clinical benefits are independent of patients’
baseline characteristics (nodal status, hormone receptor
status, ...) and of type of adjuvant chemotherapy received
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
CONCLUSIONS: OVERALL
These data support the use of
trastuzumab as adjuvant treatment
for women with HER-2 positive early
breast cancer
FOLLOW-UP: 1
All patients continue to be followed
for long-term safety: patients in
the observation arm will be offered
trastuzumab
ER-negative; Study 8541
RR=0.64 (Hi v Lo)
p=0.002
0.9
0.8
0.7
0.6
Hi CAF
0.5
0.4
Low CAF
0.3
Mid CAF
0.2
0.1
0.0
0
10
ER-positive; Study 8541
20
Years
1.0
6
Disease-free Survival
Disease-free Survival
1.0
RR=0.86 (Hi v Lo)
p=0.35
0.9
0.8
0.7
Hi CAF
0.6
0.5
Low CAF
0.4
Mid CAF
0.3
0.2
0.1
0.0
0
10
20
Years
10
ER-negative; Study 9741
RR=0.77
p=0.05
0.9
0.8
q2wk
0.7
0.6
q3wk
0.5
0.4
0.3
0.2
0.1
0.0
0
10
ER-positive; Study 9741
20
Years
1.0
8
Disease-free Survival
Disease-free Survival
1.0
q2wk
0.9
0.8
RR=0.90
p=0.44
q3wk
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
20
Years
12
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
FOLLOW-UP: 2
Results regarding optimal trastuzumab
duration (1 versus 2 years) should be
available by 2008