Transcript Document

Targeted Adjuvant Systemic
Therapy of Breast Cancer
Current & Future Role of Trastuzumab
NSABP Annual Group Meeting
9/ 17/ 05
Peter A. Kaufman MD
Norris Cotton Cancer Center
Dartmouth-Hitchcock Medical Center
CALGB
Doxorubicin and Cyclophosphamide Followed by
Weekly Paclitaxel +/- Trastuzumab as Adjuvant
Treatment for Women with HER-2/neu
Overexpressing Node (+) or High Risk Node (-)
Breast Cancer
NCCTG N9831
May 2005 Update
Perez EA, Suman VJ, Davidson N, Martino S, Kaufman PA
on Behalf of
NCCTG, ECOG, SWOG, & CALGB
Clinical Research Goals
• Evaluate whether trastuzumab adds to
the benefit of adjuvant AC  paclitaxel in
resected HER-2 (+) breast cancer
• Evaluate impact of trastuzumab schedule
– Sequential to paclitaxel
– Concurrent with paclitaxel
• Evaluate cardiac safety
AC=doxorubicin & cyclophosphamide
Study Schema
Arm A: AC q3w x 4
R
A
N
D
O
M
I
Z
E
Arm B: AC q3w x 4
Arm C: AC q3w x 4
Paclitaxel qw x 12
Paclitaxel qw
x 12
H qw x 52
Paclitaxel qw x 12
+
H qw x 12
H qw x 40
Radiation and/or hormonal therapy as indicated
Perez E et al. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by
2mg/kg); doxorubicin dose 60mg/m2; cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2
q3w=every 3 weeks; qw=weekly
Eligibility
• Resected invasive breast cancer
• Node (+)
• High risk node (-)
– >1.0 cm if ER (-) or >2.0 cm if ER (+)
• HER-2 (+) by central testing
– Protein overexpression (IHC 3+)
– Gene amplification (FISH+)
• Cardiac eligibility
– Normal left ventricular ejection fraction
– No prior MI or CHF
ER=estrogen receptor; HER2=human epidermal growth factor 2; IHC=immunohistochemistry;
FISH=fluorescence in situ hybridization; MI=myocardial infarction; CHF=congestive heart failure
Clinical Endpoints
• Disease-free survival
– Local/regional/distant recurrence
– Contralateral breast disease
(including DCIS*)
– Second primary invasive cancers
– Death due to any cause
• Overall survival
* DCIS=ductal carcinoma in situ
Statistical Plan
Addition of H to AC  T
•
Two pairwise comparisons
Sequential
AC  T  H
Concurrent
AC  T + H  H
•
Control: AC  T
vs
Control: AC  T
Goal
–
•
vs
To detect a 33% increase in median DFS
from 6.3 to 8.4 years
Final analysis
–
–
At 663 events for A vs C comparison
At 789 events for A vs B comparison
T=paclitaxel; DFS=disease free survival
Statistical Plan
Timing of H Initiation
• Pairwise comparison
Sequential
AC  T  H
vs
Concurrent
AC  T + H  H
• Goal
– To detect a 29% increase in median DFS
from 7.3 to 9.4 years
• Final analysis
– At 590 events for B vs C comparison
Cardiac Testing
R
A
N
D
O
M
I
Z
E
Arm A: AC x 4

Paclitaxel
Arm B: AC x 4

Paclitaxel

H
Arm C: AC x 4

Paclitaxel + H

H
Time (months)
0
LVEF measurement
Pre-AC
6
3
No H if
symptoms or
LVEF ↓ >15%
or ↓ to <LLN
Post-AC
LVEF=left ventricular ejection fraction; LLN=lower limit of normal
9
18–21
Impact of Joint Analysis on
N9831 (April 2005)
• Joint analysis with B-31: Concurrent
approach
AC  T + H  H significantly improves
disease-free and overall survival vs
control: AC  T
• DMC asked for an unplanned interim
analysis comparing Arm B (sequential) vs
Arm C (concurrent)
DMC=data monitoring committee
Patient/Event Status at Time of Joint
Analysis (April 2005)
• Patients
– Enrollment goals met (n: >3300)
• 700 patients on chemotherapy
• 2701 patients entered prior to 1/1/2005
– Median follow up: 1.5 years
• Total disease-free survival events
– A and B: 220 (of 789 needed)
– B and C: 147 (of 590 needed)
Patient and Tumor Characteristics
Race
Caucasian
African American
Other
Age
<40
40ﾐ49
50ﾐ59
60+
Nodal Status
N0
1ﾐ3
4ﾐ9
10+
ER- and/or
PgR-positive
Tumor ｲ2 cm
AC > T, %
(n=979)
AC > T> H, %
(n=985)
AC > T + H > H, %
(n=840)
85
6
9
86
7
7
83
6
11
17
34
34
15
19
32
32
16
16
34
32
18
11
47
27
15
11
47
28
14
12
50
25
13
54
34
55
31
55
31
Results
Disease-Free Survival
Joint Analysis
Pairwise
Comparison
A
C
Number of
events
AC > T
vs AC > T + H > H
395
Log rank
p-value*
ﾐ12
3x10
HR*
(95% CI)
0.48
(0.39-0.60)
*Stratified – nodal status and receptor status
N9831 Analysis
Pairwise
Comparison
Number of
events
Log rank
p-value*
HR*
(95% CI)
AC > T
220
0.2936
0.87
(0.67-1.13)
AC > T > H
137
0.0114
0.64
(0.46-0.91)
A vs AC > T > H
B (n=1964)**
B vs AC > T + H > H
C (n=1682)**
*Stratified – nodal status and receptor status
**for patients randomized before 1/1/2005
Disease-Free Survival: A vs C
From the Joint Analysis
AC > T + H > H
Events=134
100
90
80
70
60
% 50
40
30
20
10
0
AC > T
Events=261
Hazard ratio=0.48
Stratified logrank 2P=3x10-12
0
1
Number of patients followed
A 1162
689
C 1217
766
2
Years
374
427
3
193
238
4
59
74
Disease-Free Survival: A vs B
N9831
AC >T >H
Events=103
100
90
80
70
60
% 50
40
30
20
10
0
AC > T
Events=117
Hazard ratio=0.87
Stratified logrank 2P=0.2936
0
1
Number of patients followed
A 979
629
B 985
637
2
Years
3
4
353
403
168
169
15
20
Disease-Free Survival: B vs C
N9831
AC > T + H > H
Events=53
100
90
80
70
60
% 50
40
30
20
10
0
AC > T > H
Events=84
Hazard ratio=0.64
Stratified logrank 2P=0.0114
0
1
Number of patients followed
B 842
501
C 840
520
2
Years
3
4
285
285
162
178
20
17
Overall Survival
Joint Analysis Results
Pairwise
Comparison
Number of
events
Log rank
p-value*
HR*
(95% CI)
A AC > T
C vs AC > T + H > H
154
0.015
0.67
(0.48-0.93)
Number of
events
Log rank
p-value*
HR*
(95% CI)
*Stratified – nodal status and receptor status
N9831 Analysis Results
Pairwise
Comparison
A
B
AC > T
vs AC > T > H
79
0.4752
0.85
(0.55-1.33)
B
C
AC > T > H
vs AC > T + H > H
56
0.2696
0.74
(0.43-1.26)
*Stratified – nodal status and receptor status
Other Relevant Factors
for Patient Management
• HER2 testing
• Cardiac tolerability comparisons based on
planned analyses
HER2 Testing in N9831
• Modest level of concordance between local and
central laboratories for both IHC and FISH
– With IHP: 81% (78-83%)
– With FISH:
87% (84-90%)
• High level of agreement between central and
reference laboratory results for HER2
– 94.5% for IHC (0, 1+, 2+)
– 95.1% for FISH (not amplified)
• Accurate HER2 testing is critical given the degree of
trastuzumab benefit as a component of adjuvant
therapy
Updated from Perez EA et al, ASCO 2004 (abstract 567)
Cardiac Monitoring Plan
• Monthly formal review of LVEF, clinical data
• Interim analyses after 100, 300, and 500
patients per arm
– completed AC and followed at least 6 months
• ~ 9 months from registration
Perez EA et al, ASCO 2005 (abstract 556)
Effect of the Introduction of H
on Cardiac Tolerability
• Difference in the incidence of cardiac events
(CHF and cardiac deaths) between non-H and H arms is <4%
• 9 month analysis; 500 per arm with nl LVEF or LVEF decrease 
15% from baseline (after AC)
– 0.0% (95% CI,0.0-0.7%) for control
– 2.2% (95% CI,1.1-3.8%) for sequential therapy
– 3.3% (95% CI,2.0-5.1%) for concurrent* therapy with paclitaxel
* at month 9, concurrent pts have received 3
additional months of H compared to sequential
Perez EA et al, ASCO 2005 (abstract 556)
Effect of Introduction of Traztusumab on
Disease Recurrence
• 52% decreased recurrence with concurrent vs
control treatment (P=3X10-12) (joint analysis
finding)
• 13% decreased recurrence with sequential vs
control treatment (P=0.2936)
• 36% decreased recurrence with concurrent vs
sequential treatment (P=0.0114)
• More follow up is needed to determine whether
this trend continues
N9831 -- Future Plans
• Pre-specified interim analyses at
50%, 67%, and 75% of events still
planned
• Continued exploration of predictive
factors for cardiac toxicity
• Continued patient follow up
NCCTG N9831
Collaborative Team
• Co-investigators
– NCCTG, ECOG, SWOG, CALGB
– Personnel from Operations Offices of
Cooperative Groups
• NCI
• Genentech
• Breast Cancer Research Foundation
• Advocates and our Patients
PI: Edith A. Perez