1. B-31/N9831 First Interim Joint Analysis
NSABP Meeting
Baltimore MD
17 September 2005
Edward H. Romond, M.D.

2. NSABP B-31 NCCTG N9831 Control: ACT Arm 1 Arm 2 Arm A Arm B Arm C
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

3. Joint Analysis Flow Diagram
Trial
Number Registered1
Treatment Arm
Number Randomized
Accepted / Refused Protocol Therapy
(follow-up pending)4
Number with follow-up4
Total per arm with follow-up
Joint Analysis Cohort
B-31
2043
N9831
2766
1006
(142)
864 18
(10) 8
1015
(152)
863 4
(3) 1
806
(3)
803 13
(9) 4
809
(1)
808 5
(5) 1
1024 2
1019 A
819
(A′)2
(152)
(B)3
(981) C
814 / / / /
872
864
807
808
1679
1672
Group 1: ACPTX
Group 2: ACPTX+H
Total in Intent-to-Treat Comparison
3351
1 B-31: as of 2/15/2005; N9831: as of 11/1/2004
2 (A′): 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

4. Patient and Tumor Characteristics (%)
AC  Paclitaxel
+ Trastuzumab
872
B-31
807
N9831
864
808
Age
<50
50-59
≥60 52 34 15 51 32 16 50 18
No. Pos Nodes
1-3
4-9
10+ 57 29 14 13 48 25 11
Hormone Receptors
ER+
ER-
PR+
PR- 53 47 41 58 46 39 60
Tumor Size
≤2.0 cm.
cm.
>4.0 cm. 43 40 37 44 17 38

5. Disease-Free Survival
ACTH
87%
85%
ACT
75% %
67%
N Events
ACT
ACTH
HR=0.48, 2P=3x10-12
Years From Randomization
B31/N9831

6. Forest Plot For Disease-Free Survival
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone
Receptor
Positive
Negative
Tumor
Size
≥ 4.1cm cm
<2.0 cm
No.
Positive
Nodes
10+
4-9
1-3
Protocol
N9831
NSABP B-31
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Hazard Ratio

7. N9831/B-31 Disease Free Survival By Age

8. N9831/B-31 DSF By HR Status 1 2 3 4 5 50 70 90
A. Negative
B. Positive

9. B-31/N9831 Disease Free Survival By Path Tumor Size
A: <= 2.0cm
B: cm 90 90 70 70 50 50 1 2 3 4 5 1 2 3 4 5
C: >= 4.1cm 90 70 50 1 2 3 4 5

10. B-31/N9831 Disease Free Survival By Nodal Status

11. Disease-Free Survival1 2 3 4 5 50 60 70 80 90
100
B-31
N9831
ACTH
ACTH
87%
87%
85%
ACT
86%
ACT
78%
74% %
66%
68%
N Events
N Events
ACT
ACT
ACTH
ACTH
HR=0.45, 2P=1x10-9
HR=0.55, 2P=0.0005
Years From Randomization

12. 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% %
74% 70
74%
74%
N Events
N Events
ACTH
ACT
AC->T 60
AC->T+H
HR=0.47, 2P=8x10-10
HR=0.47, 2P=8x10-10 50 1 2 3 4 5
Years From Randomization
B31/N9831

13. Hazard of Distant Recurrence
120
100
ACT 80
Rate per 1000 Women /Yr 60 40
ACTH 20 1 2 3 4
Years From Randomization
B31/N9831

14. B-31/N9831 Survival HR=0.67, 2P=0.015 ACTH 94% 91% ACT 92% 87%
N Deaths
ACT
ACTH
HR=0.67, 2P=0.015
Years From Randomization
B31/N9831

15. B-31 : HER-2 Retesting at Control Reference Lab (Lab Corp) Initial Test Done at Smaller Volume* Labs
Initial Submitted Result
Central Herceptest not 3+
Central Path Vysion FISH Neg.
Both Central Assays Neg.
Herceptest 3+
Other IHC pos.
10/52
11/23
12/52
9/23
10/52 (19%)
8/23 (35%)
Total
21/75
18/75 (24%)
*Less than 100 assays/month
Paik et al.: J Natl Cancer Inst 94: , 2002

16. Central Herceptest not 3+ Both Central Assays Neg.
HER-2 Retesting at Control Reference Lab (Lab Corp) Initial Test Done at Large Volume* Labs
Initial Submitted Result
Central Herceptest not 3+
Central FISH
(PathVysion) Neg
Both Central Assays Neg.
Herceptest 3+
Other IHC pos.
1/28
0/1
1/28 (4%)
0/1 (0%)
Total
1/29
1/29 (3%)
*More than 100 assays/month
Paik et al.: J Natl Cancer Inst 94: , 2002

17. B-31Central Review of Cases Entered by FISH
* 26/27 cases by PathVysion, 1/27 case by Inform test

18. Central Review of Cases Entered After Amendment (N=240)
* 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)

19. Genentech: Pamela Klein
B 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