Transcript No Slide Title

European Cooperative Trial in
Operable Breast Cancer(ECTO):
Improved freedom from
progression from adding
paclitaxel(T) to doxorubicin(A)
followed by CMF
Luca Gianni
Abstract 513
ECTO: Schema
Tumors > 2 cm randomized to :
A. SURG ->A 75 mg/m2 x 4 -> CMF x 4
B. SURG ->AT 60/ 200 x 4 -> CMF x 4
C. AT 60/ 200 x 4 -> CMF x 4 -> SURG
Tam for HR +
Analysis: FFP
A vs B
B vs C
ECTO at 5 years
Analysis A vs. B
A-CMF
AT-CMF
Pts.
453
451
Events
91
63
HR
.66
p
0.01*
Analysis B vs. C
S-AT-CMF
451 63
1.22 0.24
AT-CMF-S
451 78
Data super imposable so far, no significant
difference, however pCR had improved FFP.
ECTO: Main Treatment Outcomes
A(%)
B(%)
Total FFP
pCR
no pCR
NN + 1-3
N +>3
C(%)
89
75
81
79
58
89
86
65
86
71
59
OS
82
91
90
No significant difference in OS.
No significant difference in cardiac toxicity
Doxorubicin and Cyclophosphamide
Followed by Paclitaxel
with or without Trastuzumab
as Adjuvant Therapy for Patients with
HER-2 Positive Operable Breast Cancer
Combined Analysis of
NSABP-B31/NCCTG-N9831
Romond EH, Perez EA, Bryant J, Suman V, Geyer CE,
Davidson N, Tan-Chiu E, Martino S, Swain SM, Kaufman
P, Fehrenbacher L, Pisansky T, Vogel V, Kutteh LA,
Yothers G, Visscher D, Brown AM, Jenkins R, Seay TE,
Mamounas E, Abrams J, Wolmark N
NSABP B-31
Control: ACT
Arm 1
Arm 2
NCCTG N9831
Arm A
Investigational: ACT+H
Arm B
Arm C
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4
= paclitaxel (T) 175 mg/m2 q 3 wk x 4
= paclitaxel (T) 80 mg/m2/wk x 12
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
Patient Eligibility
• HER-2 positive by FISH or +++ by IHC verified
centrally (N9831) or by approved reference lab (B-31)
• Normal left ventricular ejection fraction
• No past or active cardiac disease including:
•
•
•
•
•
•
•
•
History of myocardial infarction
History of congestive heart failure
Angina pectoris requiring medication
Arrhythmia requiring medication
Clinically significant valvular disease
Uncontrolled hypertension
LVH
Cardiomegaly on CXR
LVEF Evaluation Schedule
B-31 Arm 2 / N9831 Arm C
AC
Paclitaxel + Trastuzumab
0
mo.
3
mos.
6
mos.
9
mos.
18
mos.
9
mos.
18
mos.
B-31 Arm 1 / N9831 Arm A
AC
Paclitaxel
0
mo.
3
mos.
6
mos.
Asymptomatic Patients
Rules for Trastuzumab Continuation
Based on Serial LVEFs
Absolute
Decrease
of < 10%
Absolute
Decrease
of 10 - 15%
Absolute
Decrease
of  16%
Within Normal Limits
Cont.
Cont.
Hold *
1- 5 % below LLN
Cont.
Hold *
Hold *
 6 % below LLN
Cont.*
Hold *
Hold *
Relationship of
LVEF to LLN
* Repeat LVEF assessment after 4 weeks
- If criteria for continuation met – resume trastuzumab
- If 2 consecutive holds, or total of 3 holds occur – discontinue
trastuzumab
B-31: Trastuzumab Discontinuation Due to
Asymptomatic or Symptomatic
Cardiac Dysfunction by Quarter
25
20
15
10
5
7.7
7.2
2.9
2.1
0
1st Quarter
2nd Quarter
3rd Quarter
4th Quarter
Patient and Tumor Characteristics (%)
AC  Paclitaxel
AC  Paclitaxel
+ Trastuzumab
872
B-31
807
N9831
864
B-31
808
N9831
<50
50-59
≥60
52
34
15
51
34
15
51
32
16
50
32
18
No. Pos Nodes
0
1-3
4-9
10+
0
57
29
14
13
48
25
15
0
57
29
14
11
50
25
14
Hormone Receptors
ER+
ERPR+
PR-
53
47
41
58
52
46
41
57
51
48
39
60
51
48
39
60
Tumor Size
≤2.0 cm.
2.1-4.0 cm.
>4.0 cm.
41
43
14
40
46
13
37
44
17
38
47
14
Age
Statistical Analysis
• Median follow-up: 2.0 years
(2.4 years on B-31/1.5 years on N9831)
• Primary endpoint: DFS
– analyzed by intent-to-treat
• Secondary endpoints: OS and Time to 1st
Distant Recurrence
• Definitive analysis after 710 DFS events
• First interim analysis after 355 DFS
events
• Stop trials only if equivalence is rejected
at p=0.0005 (2p=0.001)
Disease-Free Survival
ACTH
87%
85
%
ACT
75
%
%
N
Events
ACT 1679 261
ACTH 1672 134
67
%
HR=0.48,
2P=3x10-12
Years From Randomization
B31/N983
1
Forest Plot For Disease-Free Survival
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone Positive
Receptor Negative
Tumor
Size
≥ 4.1cm
2.1- 4.0 cm
<2.0 cm
No.
10+
Positive 4-9
Nodes
1-3
0
Protocol N9831
NSABP B-31
0.2
0.4
0.6
0.8
1.0
Hazard Ratio
1.2
1.4
Disease-Free Survival
B-31
100
N9831
100
ACTH
ACTH
90
90
87%
ACT
80
85%
ACT
87%
86%
80
78%
74%
%70
70
68%
66%
60
ACT
ACTH
50
0
1
2
HR=0.45,
60
N Events
ACT
807 90
ACTH 808 51
50
N Events
872 171
864 83
3
4
2P=1x10-9
5
0
1
2
3
4
HR=0.55, 2P=0.0005
Years From Randomization
5
Time to First Distant Recurrence
100
ACTH
AC->T+H
90%
90%
90%
90
90%
90%
90%
ACT
AC->T
80
81%
81%
81%
%
70
N
60
ACTH 1672 96
AC->T
1679 194
ACT
1679
AC->T+H 1672194
96
74%
74%
74%
Events
N Events
HR=0.47, 2P=8x10-10 HR=0.47, 2P=8x10-10
50
0
1
2
3
Years From Randomization
4
5
B31/N9831
Hazard of Distant Recurrence
Rate per 1000 Women /Yr
120
100
ACT
80
60
40
ACTH
20
0
0
1
2
3
Years From Randomization
4
B31/N983
1
B-31/N9831 Survival
ACT
ACTH
94%
91
%
92
%
87
%
N Deaths
ACT 1679 92
ACTH 1672 62
HR=0.67, 2P=0.015
Years From Randomization
B31/N983
1
0.5
0.3
2.5
1412
1.0
0.4
3.5
1168
1.5
0.4
3.9
924
2.0
0.4
4.0
719
2.5
0.6
4.0
532
3.0
0.6
4.0
357
%
No. At Risk
4.0%
Cum Inc Arm2 (%)
Arm 2: AC→T H
N=846, 30 CHFs,
No Cardiac Deaths
4
HR=7.2
Cum Inc Arm 1 (%)
6
Yrs Post Day 1 Cyc 5
B-31: Cumulative Incidence of
Cardiac Events in the Evaluable Cohort
Arm 1: AC→T
N=811, 3 CHFs,
1 Cardiac Death
2
0
0.0
0.5
Cohort
0.6%
1.0
1.5
2.0
2.5
Years Post Day 1 Cyc 5
Arm 1 Evaluable Cohort
Arm 2 Evaluable Cohort
3.0
B-31: Post-AC LVEF and Age
Are Independent Predictors of
Trastuzumab-Associated CHF
LVEF (%)
Age
P(Age)=0.04
P(LVEF)<0.0001
Conclusions
1. For high risk HER-2 positive breast cancer,
trastuzumab given concurrently with paclitaxel
following AC chemotherapy, reduces the risk of
a first breast cancer event at 3 years by 52%.
2. The relative risk reduction benefit was present
and of similar magnitude in all subsets of
patients analyzed. There is not, however,
statistical power to establish efficacy in the
node negative subset.
3. The addition of trastuzumab reduced the
probability of distant recurrence by 53% at 3
years, and the hazard of developing distant
metastases appears, thus far, to decrease over
time.
Conclusions
4. Results at a median follow-up of 2 years
show a statistically significant survival
advantage with a relative risk reduction
of 33%.
5. The combination of trastuzumab and
chemotherapy has a notable risk of
cardiac toxicity. Careful monitoring of
cardiac function is of vital importance if
trastuzumab is to be used in the
adjuvant setting.