Transcript Figure 1: Joint Analysis Flow Diagram

B-31/N9831
First Interim Joint Analysis
NSABP Meeting
Baltimore MD
17 September 2005
Edward H. Romond, M.D.
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
Joint Analysis Flow Diagram
Trial
Number Registered1
Treatment Arm
Number Randomized
Joint Analysis Cohort
2043
2766
(A′)2
(B)3
(152) (981)
2
A
1024
1019
819
872
1015 / 4
806 / 13
(152) (3)
863
1
(3)
803
864
(9)
4
C
814
809 / 5
(1)
808
807
1679
Group 1: ACPTX
Total in Intent-to-Treat Comparison
1
N9831
1
Accepted / Refused
1006 / 18
Protocol Therapy
(follow-up pending)4
(142) (10)
Number with follow-up4 864
8
Total per arm with
follow-up
B-31
808
1672
Group 2: ACPTX+H
3351
B-31: as of 2/15/2005; N9831: as of 11/1/2004
Randomized to Arm A 2/1/1002—9/3/2002 while Arm C was closed to accrual; excluded from joint analysis
3 (B): Excluded from joint analysis
4 B-31: as of 2/15/2005; N9831: as of 3/15/2005
2 (A′):
(5)
0
Patient and Tumor Characteristics (%)
AC  Paclitaxel
AC  Paclitaxel
+ Trastuzumab
872
B-31
807
N9831
864
B-31
808
N9831
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
<50
50-59
≥60
Disease-Free Survival
ACTH
87%
85%
ACT
75%
%
67%
N
ACT
1679
ACTH 1672
Events
261
134
HR=0.48, 2P=3x10-12
Years From Randomization
B31/N9831
Forest Plot For Disease-Free Survival
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone Positive
Receptor Negative
0.2
0.4
0.6
0.8
1.0
Hazard Ratio
Tumor
Size
≥ 4.1cm
2.1- 4.0 cm
<2.0 cm
No.
Positive
Nodes
10+
4-9
1-3
0
Protocol
N9831
NSABP B-31
1.2
1.4
N9831/B-31 Disease Free Survival By Age
0
70
50
50
70
90
B. 40-49
90
A. <=39
1
2
3
4
5
0
1
4
5
4
5
90
70
50
70
50
0
3
D. >=60
90
C. 50-59
2
1
2
3
4
5
0
1
2
3
N9831/B-31 DSF By HR Status
B. Positive
50
50
70
70
90
90
A. Negative
0
1
2
3
4
5
0
1
2
3
4
5
B-31/N9831 Disease Free Survival By Path Tumor Size
B: 2.1-4.0cm
50
50
70
70
90
90
A: <= 2.0cm
0
1
2
3
4
5
4
5
50
70
90
C: >= 4.1cm
0
1
2
3
0
1
2
3
4
5
B-31/N9831 Disease Free Survival By Nodal Status
0
70
50
50
70
90
B. 1-3
90
A. N0
1
2
3
4
5
0
1
4
5
4
5
90
70
50
70
50
0
3
D. 10+
90
C. 4-9
2
1
2
3
4
5
0
1
2
3
Disease-Free Survival
B-31
100
N9831
100
ACTH
87%
90
ACT
ACTH
90
85%
87%
ACT
78%
80
80
86%
74%
%
70
66%
70
N Events
60 ACT
807 90
ACTH 808 51
50 HR=0.55, 2P=0.0005
N Events
ACT
872 171
ACTH 864 83
HR=0.45, 2P=1x10-9
60
50
0
1
2
3
4
68%
5
0
1
Years From Randomization
2
3
4
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
74%
74%
74%
Events
N Events
ACTH 1672 96
AC->T
1679 194
ACT
1679
AC->T+H 1672194
96
60
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
Years From Randomization
3
4
B31/N9831
B-31/N9831 Survival
94%
ACT
ACTH
91%
92%
87%
N
ACT
1679
ACTH 1672
Deaths
92
62
HR=0.67, 2P=0.015
Years From Randomization
B31/N9831
B-31 : HER-2 Retesting at
Control Reference Lab (Lab Corp)
Initial Test Done at Smaller Volume* Labs
Initial Submitted
Result
Herceptest 3+
Other IHC pos.
Total
Central Herceptest not
3+
Central Path Vysion
FISH Neg.
Both Central Assays
Neg.
10/52
11/23
12/52
9/23
10/52 (19%)
8/23 (35%)
21/75
21/75
18/75 (24%)
*Less than 100 assays/month
Paik et al.: J Natl Cancer Inst 94:852-854, 2002
HER-2 Retesting at
Control Reference Lab (Lab Corp)
Initial Test Done at Large Volume* Labs
Initial Submitted
Result
Herceptest 3+
Other IHC pos.
Total
Central Herceptest not
3+
Central FISH
(PathVysion) Neg
Both Central Assays
Neg.
1/28
0/1
1/28
0/1
1/28 (4%)
0/1 (0%)
1/29
1/29
1/29 (3%)
*More than 100 assays/month
Paik et al.: J Natl Cancer Inst 94:852-854, 2002
B-31Central Review of Cases Entered
by FISH
Small volume
lab
Larger volume
lab
Central
Number of
PathVysion
contributing
Not-amplified labs
0/17
15
0/10
6
* 26/27 cases by PathVysion, 1/27 case by Inform test
Central Review of Cases Entered After
Amendment (N=240)
Original assay
used
Assay
failure
Total
6/132* (4.5%)
1
133
IHC
2/104 (2%)
3
107
total
8/236 (3%)
4
240
FISH
Central
PathVysion
Not-amplified
* two cases with increase in both HER2 and CEP17 signals were regarded
as amplified since both PathVysion and Inform HER2 test were allowed
for eligibility
Paik, et al.: Breast Cancer Res Treat 2002; 76(suppl 1): S31 (abstr 9)
B-31
N9831
Edward Romond
John Bryant
Charles Geyer
Elizabeth Tan-Chiu
Soon Paik
Sandra Swain
Louis Fehrenbacher
Victor Vogel
Greg Yothers
Ann Brown
Terry Mamounas
Norman Wolmark
Edith Perez
Vera Suman
Nancy Davidson
Silvana Martino
Peter Kaufman
Thomas Pisansky
Leila Kutteh
Daniel Visscher
Robert Jenkins
Shakir Dakhil
Wilma Lingle
James Ingle
Genentech: Pamela Klein