Transcript No Slide Title

ASCO 2005
Adjuvant Breast Cancer
Update
Lori J. Goldstein, MD
Director, Breast Evaluation Center
Leader, Breast Cancer Research Program
Fox Chase Cancer Center
Philadelphia, PA
ASCO 2005
Breast Cancer Update
Abstract #/ Session
512
513
MoAB Ed
MoAB Ed
MoAB Ed
Title/ Subject
E2197: Adjuvant AT vs. AC
ECTO: A->CMF vs AT->CMF
N9831/ NSABP B31 Joint
Analysis – Adjuvant Trastuzumab
N9831 – Adjuvant Trastuzumab
HERA: Adjuvant Trastuzumab
MoAB Ed
E2100: T +/- bevacizumab MBC
E2197: Phase III AT vs. AC in the
Adjuvant Treatment of Node
Positive and High Risk Node
Negative Breast Cancer
Goldstein LJ, O’Neill A, Sparano JA,
Perez EA, Shulman LN, Martino S,
Davidson NE.
E2197 Rationale
Phase II Studies Anthracyline + Taxane
Study
A/Por D mg/m2
RR %
CHF %
Gianni/
60/P200
80-90
20
50/P150
60/P200
47
57
9.8
6
60/D60
60/D60
50/D75
57
63
81
6
10
0
Dombernowsky
Sledge E1193
Sparano E4195
Sparano E1196
Cresta
Misset
E2197 Rationale
Phase III Studies:Anthracyline + Docetaxel
Phase III Studies:
MBC
AT (50/75)
RR%
60
TTPwk
37.1
CHF %
2
FN%
33
No difference OS
AC (60/600)
47
p=.012
31.9 p=.015
4
10
Nabholtz JCO 2003
TAC vs. FAC MBC
Mackey ASCO 2002
Increase RR with TAC; no difference in TTP or OS
TAC vs. FAC Adjuvant: Nabholtz ASCO 2002
TAC increase DFS/ OS
E2197: Schema
T1-3 N0-1 M0
No then
T> 1.0cm
R
A
N
D
O
M
I
Z
E
Adriamycin 60mg/m2
Docetaxel (T) 60mg/m2
IV q 3wk x 4
Cipro 500mg
po. bid D8 x 10d
Adriamycin 60mg/m2
IV q 3wk x 4
2
Cyclophosphamide 600mg/m
Tamoxifen 20mg daily x 5 years
post chemotherapy for ER and/or
PR positive tumor
*G-CSF per ASCO guidelines
Stratified:
•Nodal Status
•HR Status (ER+PR+,ER+PR-,
ER-PR+,ER- PR-,ER/PR unknown)
•Menopausal Status
E2197: Objectives
• To determine whether AT will
improve DFS and OS
• To compare toxicity of AT vs. AC
No difference in LVEF between AT
and AC reported ASCO 2003.
E2197: Study Design
• Primary endpoint: DFS-recurrences, new breast
primaries, or death without recurrence whichever
comes first.
• Design: 83% power to detect a 25% reduction of
the DFS failure hazard rate
(5% absolute improvement in 5 yr DFS from 78%
to 83% by using AT)
• Sample size: 2778 including an estimated 10%
ineligible
• Primary Analysis: Intent-to-treat analysis on
eligible patients.
E2197:Results
• Opened 7/30/98; closed 1/21/00
• 2952 entered through the
collaborative effort of ECOG, CALGB,
NCCTG, SWOG and EPP.
• 3% Ineligibility rate
• 2885 eligible and analyzable
E2197: Patient Characteristics
• Balanced for age, HR, menopause,
nodes, surgery, grade and size
• Age range 24-85 yo, Median age 51
• 64% ER +
• 65% LN• Grade: 10% low, 38% int., 46% high
• Size: 0.1 – 12.5 cm; Median – 2.0 cm
E2197: Toxicity Summary
Feb/Infxn/N
AML/MDS
Lethal Events
Related
Unrelated
AT
28%
7
AC
10%
7
4
2
2
E2197 Cardiac Safety
Grade
3
AT
4
5
CHF
15
2
1
AC
3
4
10
Total
18
10
%
.01
.006
No statistically significant difference
E2197: DFS
• Fall 2004 DMC (409/ 420 DFS failures)
• O’Brien-Fleming boundary had not been
crossed, there was not enough evidence
to suggest a significant difference
• April 2005 - Median follow-up = 59 months
• 432/ 2885 (15%) recurred, developed
second breast cancer or died.
E2197: DFS/OS
Hazard Ratio
HR > 1 favors AT
HR (adjusted)
DFS
1.03 (0.86-1.25), p=0.70
OS
1.09 (0.85-1.40), p=0.49
As of 4/4/05, 242 deaths
E2197 Disease-Free Survival
100
90
80
Percent
70
60
50
40
30
20
10
0
0
12
24
AT
AC
36
Months
N
Events
1444
213
1441
219
48
60
4-Yr % (S.E.)
87 (1)
87 (1)
72
E2197 Overall Survival
100
90
80
Percent
70
60
50
40
30
20
10
0
0
12
24
AT
AC
36
Months
N
Events
1444
117
1441
125
48
60
4-Yr % (S.E.)
94 (1)
93 (1)
72
E2197: DFS
Subgroup Analysis
No significant effect within any of the
following subgroups :
•Nodes
•Size
•Age
•Menopausal Status
•Grade
•Type of Surgery
•Race
E2197 Disease-Free Survival:ER-/PR-
E2197 Disease-Free Survival:ER-/PR+
90
90
80
80
70
70
60
60
Percent
100
Percent
100
50
40
50
40
30
30
20
20
10
10
0
0
0
12
24
36
N
454
463
AT
AC
48
Months
Events
85
109
60
0
72
4-Yr % (S.E.)
83 (2)
79 (2)
24
36
N
52
38
AT
AC
E2197 Disease-Free Survival:ER+/PR-
Months
Events
14
3
48
60
72
4-Yr % (S.E.)
77 (6)
95 (4)
E2197 Disease-Free Survival:ER+/PR+
90
90
80
80
70
70
60
60
Percent
100
100
Percent
12
50
40
50
40
30
30
20
20
10
10
0
0
0
12
24
AT
AC
36
N
162
164
Months
Events
22
34
48
60
4-Yr % (S.E.)
90 (2)
83 (3)
81
72
0
12
24
AT
AC
36
N
767
770
Months
Events
91
73
48
60
4-Yr % (S.E.)
90 (1)
92 (1)
72
Disease Free Survival
ER-/PR-
1.30 (0.96, 1.70)
ER-/PR+
0.30 (0.10, 0.95)
ER+/PR-
1.64 (0.96, 2.80)
ER+/PR+
0.79 (0.58, 1.10)
0.1
0.2
Favors AC
0.5
1
2
Favors AT
5
E2197 Conclusions
• These results show a better than expected
outcome for both regimens.
87%(obs) vs 78% (expected for AC) DFS at 4
yrs.
• At 59 mo median follow-up, there is no
difference in DFS or OS between AT and AC.
• Prespecified stratifications at randomization:
LN, menopause, ER/PR – no significant
difference between the 2 treatment arms.
• In PR negative tumors, a potential benefit to
AT may be suggested.
E2197: Issues for Discussion
Would longer f/u change these results? Unlikely
Observed DFS = 87% at 4 yrs.
Expected DFS = 78% at 4yrs.
Aromatase Inhibitor Affect:
60% on Tam; Median 41 mo; AI info collected; future
analysis
Subset analysis of prespecified ER/PR stratifications:
Hypothesize that the biology of the primary tumor
predicts outcome and benefit to specific therapies.
Central review of ER/PR/Her 2 pending
Genomic Health/ Sanofi-Aventis Analysis:
Oncotype
Genomic profiling
Use as training set for validation with E1199
Pharmacogenomics
PACCT- 1 Trial
Thank You
Patients
Data managers/ CRA’s
CALGB, NCCTG, SWOG, EPP
Anne O’Neill, Deborah Namande, Eric Ross
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.
NCCTG N9831
May 2005 Update
Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P,
on Behalf of
NCCTG, ECOG, SWOG, CALGB
NCCTG N9831 Schema
R
A
N
D
O
M
I
Z
E
Arm A: AC q3w x 4
Paclitaxel qw x 12
Arm B: AC q3w x 4
Paclitaxel qw x 12
H qw x 52
Arm C: AC q3w x 4
Paclitaxel qw x 12
+
H qw x 12
H qw x 40
Radiation and/or hormonal therapy as indicated
Perez E. 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
Statistical Plan
Addition of H to AC  T
• Two pairwise comparisons
Sequential
AC  T  H
Concurrent
AC  T + H  H
vs
Control: AC  T
vs
Control: AC  T
• Goal
– 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
MI
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) to assist in patient
management
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)
Results
Disease-Free Survival
Joint Analysis
Pairwise
Comparison
AC → T
vs AC → T + H → H
Number of
events
395
Log rank
p-value*
–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)
A
B
AC → T
vs AC → T → H
(n=1964)**
220
0.2936
0.87
(0.67-1.13)
B
C
AC → T → H
vs AC → T + H → H
(n=1682)**
137
0.0114
0.64
(0.46-0.91)
*Stratified – nodal status and receptor status
**for patients randomized before 1/1/2005
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)
154
0.015
0.67
(0.48-0.93)
Number of
events
Log rank
p-value*
HR*
(95% CI)
AC → T
vs AC → T + H → H
*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 HercepTest™: 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 control vs sequential
– 3.3% (95% CI,2.0-5.1%) for control vs 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 H on
Disease Recurrence
Conclusions
• 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
NCCTG N9831
Next Steps
• 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
ASCO, Scientific Session, May 16, 2005
FIRST RESULTS OF THE HERA
TRIAL
A randomized three-arm multi-centre comparison
of:
• 1 year Herceptin®
• 2 years Herceptin®
• or no Herceptin®
in women with HER-2 positive primary breast
cancer who have completed adjuvant
chemotherapy
Martine J. Piccart-Gebhart, MD, PhD on behalf of:
The Breast International Group (BIG), NON-BIG participating
groups, Independent sites, F. Hoffmann – La Roche Ltd.
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 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
1 year trastuzumab
100
% alive
and
90
disease free
80
70
60
50
40
30
20
10
0
Observation
2-yr
Events DFS % HR
0
No.
at risk
1694
1693
[95% CI]
p value
127
85.8 0.54 [0.43, 0.67] <0.0001
220
77.4
5
10
15
20
Months from randomization
1472
1428
1067
994
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
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
• Trastuzumab therapy is associated with a low incidence of
severe symptomatic congestive heart failure; longer
follow-up is needed to better quantify this risk
• All patients continue to be followed for long-term safety:
patients in the observation arm will be offered trastuzumab
(guidelines in preparation)
• Results regarding optimal trastuzumab duration (1 versus 2
years) should be available by 2008
HERA Study Design Elements
•Randomized following ctx
•DFS was primary endpoint
•Most patients did not receive taxane
•In contrast to the Joint analysis,
HERA included a large percentage of
node negative pts(About 1/3).
•Very short median follow-up
Adjuvant Trastuzumab
Summary and Conclusions
•Does adjuvant trastuzumab improve
DFS? YES!
•Should we give trastuzumab with or
following CTX?
•What is the appropraite duration of
trastuzumab?
•What is the price of trastuzumab?
Should we give Trastuzumab
before or after CTX?
•Preclinical data suggest that trastuzumab
may amplify ctx’s pro-apoptotic effects.
•Synergistic activity in preclinical models
for some ctx
•Cardiotoxicity concerns when
trastuzumab is given in proximity to
anthracyclines.
What is the appropriate
duration of Trastuzumab?
•Unknown (HERA 1 vs. 2 yr pending)
•Current data supports one year of therapy
•Current data supports initiation of therapy
for up to 6 months following completion of
chemotherapy or radiation therapy
•Could we get by with less trastuzumab?
( ie. only with chemo?)
What is the price of
Trastuzumab?
Cardiac Toxicity(CHF) can be consequence of using
trastuzumab
Rate = 3.3-4.3% AC-TH vs. 0-0.5% AC-T (B31/ N9831)
Rate = 0.5-2.2% post ctx (HERA/N9831)
Degree of reversibility uncertain and requires further followup
Long term effects unknown
While benefit far outweighs the risks, the price is real and
should be discussed with patients
BCIRG 006
Adjuvant Breast Cancer
Node Positive and High Risk Node Negative
4 x AC 4 x Docetaxel
60/600 mg/m2
100 mg/m2
ACT
HER2 +
ACTH
FISH
1 Year Trastuzumab
N=3150
480 centres
6 x Docetaxel and Platinum salts
75 mg/m2
75 mg/m2 or AUC 6
TCH
1 Year Trastuzumab
BCIRG 006 LVEF Decline by NYHA Class
>10 < LLN
AC-T
9
AC-TH
34
TCH
7
>15%< LLN
6
25
4
Grade 3-4 CHF
1
18
1
Implication: Trastuzumab by itself is not cardiotoxic; it
becomes so when it keeps company with doxorubicin.
Intergroup Guidelines for N9831
•For women receiving trastuzumab, continue until 1 year
is completed.
•For women randomized to 1 yr TH, continue as planned
•For women on Arm A: AC-T and are at most 6 months
from completion of paclitaxel, begin weekly trastuzumab
and continue until you have completed 1 yr of
trastuzumab with cardiac testing.
Intergroup Guidelines for N9831
•For women on Arm A: AC-T and have not started
paclitaxel, begin weekly trastuzumab with paclitaxel and
continue until 1 yr of trastuzumab is completed, with
cardiac testing.
•For women on Arm B: AC-T-H, and you have not begun
trastuzumab, begin trastuzumab with paclitaxel and
continue for 1 yr. with cardiac testing.
•If ctx completed > 6 mo. and have not received
trastuzumab, discuss risks and benefits.
E2100
A Randomized Phase III Trial of Paclitaxel
versus Paclitaxel plus Bevacizumab as FirstLine Therapy for Locally Recurrent or
Metastatic Breast Cancer
KD Miller, M Wang, J Gralow, M Dickler,
MA Cobleigh, EA Perez, TN Shenkier,
NE Davidson
Indiana University Cancer Center, Dana Farber Cancer Institute,
Pudget Sound Oncology Consortium, Memorial Sloan Kettering
Cancer Center, Rush-Presbyterian-St. Luke’s Medical Center,
Mayo Clinic, British Columbia Cancer Agency, Vancouver
Cancer Center, Johns Hopkins Oncology Center
Rationale
• Tumor growth is dependent on
angiogenesis
• Bevacizumab is a humanized
monoclonal antibody directed against
VEGF
• Recognizes all VEGF-A isoforms
• Active in patients with refractory MBC
• 9% response rate as monotherapy
• Increases ORR but not PFS in combination with
capecitabine
• Greater activity expected in less
heavily pre-treated patients
Study Design
Stratify:
• DFI < 24 mos. vs. > 24 mos.
• < 3 vs. > 3 metastatic sites
• Adjuvant chemotherapy yes vs. no
• ER+ vs. ER- vs. ER unknown
R
A
N
D
O
M
I
Z
E
Paclitaxel + Bevacizumab
Paclitaxel
28-day cycle:
Paclitaxel 90 mg/m2 D1, 8 and 15
Bevacizumab 10 mg/kg D1 and 15
Key Eligibility Criteria
• Locally recurrent or metastatic breast
cancer
– HER2+ only if prior treatment with
trastuzumab or contraindication
• No prior chemo regimens for MBC
– Adjuvant taxane allowed if DFI > 12 months
•
•
•
•
ECOG PS 0 or 1
No anti-tumor therapy within 21 days
No CNS mets (head CT or MR required)
No significant proteinuria (> 500 mg/24
hr)
• No therapeutic anticoagulation
Statistical Design Efficacy
• Primary endpoint: Progression-Free
Survival
– 85% power for a 33% improvement
• 6 vs. 8 months
– One-sided type I error  2.5%
– Requires 650 eligible patients
• Final analysis after 546 PFS events
– Interim analyses after 270 and 425 events
– Asymmetric boundaries to stop early either for
demonstrated benefit or for lack of benefit
– O-Brien-Fleming boundaries and repeated
confidence interval analyses at each interim
Statistical Design - Safety
• Type I event: Grade 4 hemorrhage
or HTN
– Acceptable rate: 1%
• Type II event: Grade 3/4 thrombosis
or embolism
– Acceptable rate: 5%
Current Analysis
• Study activated Dec 21, 2001
• Closed March 24, 2004
– 715 eligible patients
• First planned interim analysis
• Data cut-off February 9, 2005
• 355 events
– Progression – 291
– Death without documented progression - 64
Patient Characteristics
Treated
Paclitaxel
(n=350)
346
Pac. + Bev.
(n=365)
365
Median age
55 (27-85)
56 (29-84)
DFI < 24 months
41%
41%
> 3 sites
29%
28%
Adjuvant chemo.
64%
65%
ER+
63%
64%
Response
Overall Response Rate
P<0.0001
P<0.0001
40
34.3%
28.2%
30
20
16.4%
14.2%
10
316
330
250
236
0
All patients
Measurable Disease
Paclitaxel
Pac + Bev
Progression Free
Survival
1.0
Pac. + Bev. 10.97 months
0.9
Paclitaxel
PFS Proportion
0.8
6.11 months
0.7
0.6
0.5
HR = 0.498 (0.401-0.618)
0.4
Log Rank Test p<0.001
0.3
0.2
0.1
0.0
0
10
20
Months
30
Overall Survival
1.0
Pac. + Bev.
0.9
Paclitaxel
OS Proportion
0.8
0.7
0.6
0.5
0.4
0.3
0.2
HR = 0.674 (0.495-0.917)
0.1
Log Rank Test p=0.01
0.0
0
10
20
Months
30
40
Bevacizumab Toxicity
NCI-CTC Grade 3 and 4
Paclitaxel
(n=330)
Pac. + Bev.
(n=342)
%
Grade Grade Grade Grade
3
4
3
4
HTN*
0
0
13
0.3
0.3
0.9
1.2
0
Bleeding
0
0
0.6
0.3
Proteinuria**
0
Thromboembolic
NCI-CTC v3.0, worst per patient
0
0.9
1.5
*p<0.0001; **p=0.0004
Other Toxicities
NCI-CTC Grade 3 and 4
Paclitaxel
(n=330)
Pac. + Bev.
(n=342)
%
Grade 3
Neuropathy*
13.6
Grade
4
0.6
Fatigue
2.7
0
4.7
0.3
Neutropenia
0
3
0.9
4.4
 LVEF
0
0
0.3
0
NCI-CTC v3.0, worst per patient
Grade
3
19.9
Grade
4
0.6
*p=0.01
Ongoing Correlative Studies
• Quality of Life (FACT-B)
• Circulating markers
– Serum VCAM-1
– Urine VEGF
• Analysis of primary tumor samples
– VEGF expression
Conclusions and Future
Directions
• Addition of bevacizumab to paclitaxel
– Significantly prolongs progression free
survival
– Increases objective response rate
– Longer follow-up required to assess impact on
OS
• Further studies should
– Explore the role of Bevacizumab in the
adjuvant setting
– Develop methods to identify patients who are
most likely to benefit from VEGF-targeted
therapies
Adjuvant Pilot Trial
Rationale
• Most successful use of anti-angiogenic
therapy predicted to be in adjuvant setting
– Require large trial for proof of concept
• Limitations of metastatic trials
–
–
–
–
Chronic therapy in only a few patients
Different tolerance for toxicity
Different metabolism (?)
Less concern for rare but potentially fatal
toxicities
E2104 Schema
Arm A: ddBAC >BT >B
R
E
G
I
S
T
E
R
Doxorubicin 60 mg/m2 plus
Cyclophosphamide 600 mg/m2
Bevacizumab 10 mg/kg
every 14 days x 4
Paclitaxel 175 mg/m2
Bevacizumab 10 mg/kg
every 14 days x 4
Bevacizumab
10 mg/kg every
14 days x 18
Doxorubicin 60 mg/m2 plus
Cyclophosphamide 600 mg/m2
every 14 days x 4
Paclitaxel 175 mg/m2
Bevacizumab 10 mg/kg
every 14 days x 4
Bevacizumab
10 mg/kg every
14 days x 22
Arm B: ddAC >BT >B
*Hormone therapy and radiation per standard care