Targeted Adjuvant Systemic Therapy of Breast Cancer Current

1
Targeted Adjuvant Systemic Therapy of Breast
CancerCurrent Future Role of
TrastuzumabNSABP Annual Group Meeting9/ 17/ 05
Peter A. Kaufman MD Norris Cotton Cancer
Center Dartmouth-Hitchcock Medical Center CALGB
2
Doxorubicin and Cyclophosphamide Followed by
Weekly Paclitaxel /- Trastuzumab as Adjuvant
Treatment for Women with HER-2/neu
Overexpressing Node () or High Risk Node (-)
Breast CancerNCCTG N9831May 2005 Update
Perez EA, Suman VJ, Davidson N, Martino S,
Kaufman PA on Behalf of NCCTG, ECOG, SWOG,
CALGB
3
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

ACdoxorubicin cyclophosphamide
4
Study Schema
Paclitaxel qw x 12
Arm A
AC q3w x 4
RANDOMIZE
H qw x 52
Arm B
AC q3w x 4
Paclitaxel qw x 12
Paclitaxel qw x 12 H qw x 12
Arm C
H qw x 40
AC q3w x 4
Radiation and/or hormonal therapy as indicated
Perez E et al. Protocol NCCTG-N9831.
Htrastuzumab (4mg/kg loading dose, followed by
2mg/kg) doxorubicin dose 60mg/m2
cyclophosphamide, 600mg/m2 paclitaxel, 80mg/m2
q3wevery 3 weeks qwweekly
5
Eligibility

• Resected invasive breast cancer
• Node ()
• High risk node (-)
• gt1.0 cm if ER (-) or gt2.0 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

ERestrogen receptor HER2human epidermal growth
factor 2 IHCimmunohistochemistry
FISHfluorescence in situ hybridization
MImyocardial infarction CHFcongestive heart
failure
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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

DCISductal carcinoma in situ
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Statistical PlanAddition of H to AC ? T

• Two pairwise comparisons
• Goal
• To detect a 33 increase in median DFSfrom 6.3
  to 8.4 years
• Final analysis
• At 663 events for A vs C comparison
• At 789 events for A vs B comparison

Sequential AC ? T ? H
Control AC ? T
vs
Concurrent AC ? T H ? H
Control AC ? T
vs
Tpaclitaxel DFSdisease free survival
8
Statistical Plan Timing of H Initiation

• Pairwise comparison
• Goal
• To detect a 29 increase in median DFSfrom 7.3
  to 9.4 years
• Final analysis
• At 590 events for B vs C comparison

Sequential AC ? T ? H
Concurrent AC ? T H ? H
vs
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Cardiac Testing
RANDOMIZE
Paclitaxel
Arm A AC x 4
?
?
?
Arm B AC x 4
Paclitaxel
H
Arm C AC x 4
H
?
?
Paclitaxel H
Time (months)
6
9
1821
0
3
LVEF measurement
No H if symptoms or LVEF ? gt15 or ? to ltLLN
Pre-AC
Post-AC
LVEFleft ventricular ejection fraction
LLNlower limit of normal
10
Impact of Joint Analysis on N9831 (April 2005)

• Joint analysis with B-31 Concurrent approach
• DMC asked for an unplanned interim analysis
  comparing Arm B (sequential) vs Arm C (concurrent)

AC ? T H ? H significantly improves
disease-free and overall survival vs control AC
? T
DMCdata monitoring committee
11
Patient/Event Status at Time of Joint Analysis
(April 2005)

• Patients
• Enrollment goals met (n gt3300)
• ?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)

12
Patient and Tumor Characteristics



o
s
itive

54

55

55

T
u
mo
r

?
2

cm

34

31

31


13
Results Disease-Free Survival
Joint Analysis
P
ai
rw
is
e
N
um
b
e
r
of
Lo
g r
ank
HR

C
om
p
a
r
ison
e
v
ents
p-v
a
lue

(9
5

C
I)
A
AC
gt T
?
1
2
3
9
5
3
x
10
0.
4
8
C
v
s

AC
gt T


H
gt
H
(0.
3
9-0
.
60)
Stratified nodal status and receptor status
N9831 Analysis
P
ai
rw
is
e
N
um
b
e
r
of
Lo
g r
ank
HR

C
om
p
a
r
ison
e
v
ents
p-v
a
lue

(9
5

C
I)
AC
gt T
2
2
0
0.
2
93
6
0.
8
7
A
v
s

AC
gt T

gt
H
(0.
6
7-1
.
13)
B
(n
1
96
4
)

AC
gt
T
gt
H
1
3
7
0.
0
11
4
0.
6
4
B
v
s

AC
gt T


H
gt
H
(0.
4
6-0
.
91)
C
(n
1
68
2
)

Stratified nodal status and receptor
status for patients randomized before 1/1/2005
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Disease-Free Survival A vs CFrom the Joint
Analysis
AC gt T H gt HEvents134
100 90 80 70 60 50 40 30 20 10 0
AC gt T Events261

Hazard ratio0.48 Stratified logrank 2P3x10-12
0 1 2 3 4 Years
Number of patients followed A 1162
689 374 193
59 C 1217 766 427
238 74
15
Disease-Free Survival A vs BN9831
AC gtT gtHEvents103
100 90 80 70 60 50 40 30 20 10 0
AC gt TEvents117

Hazard ratio0.87 Stratified logrank 2P0.2936
0 1 2 3 4 Years
Number of patients followed A 979 629 353 168 15 B
985 637 403 169 20
16
Disease-Free Survival B vs CN9831
AC gt T H gt HEvents53
100 90 80 70 60 50 40 30 20 10 0
100 90 80 70 60 50 40 30 20 10 0
AC gt T gt H Events84


Hazard ratio0.64 Stratified logrank 2P0.0114
0 1 2 3 4 Years
0 1 2 3 4 Years
Number of patients followed B 842 501 285 162 20 C
840 520 285 178 17
17
Overall Survival
Joint Analysis Results
P
ai
rw
is
e
N
um
b
e
r
of
Lo
g r
ank
HR

C
om
p
a
r
ison
e
v
ents
p-v
a
lue

(9
5

C
I)
A
AC
gt T
1
5
4
0.
0
15
0.
6
7
v
s A
C

gt T

H

gt
H
C
(0.
4
8-0
.
93)
Stratified nodal status and receptor status
N9831 Analysis Results
P
ai
rw
is
e
N
um
b
e
r
of
Lo
g r
ank
HR

C
om
p
a
r
ison
e
v
ents
p-v
a
lue

(9
5

C
I)
A
AC
gt T
7
9
0.
4
75
2
0.
8
5
v
s

AC
gt
T
gt
H
(0.
5
5-1
.
33)
B
B
AC
gt
T
gt
H
5
6
0.
2
69
6
0.
7
4
C
v
s

AC
gt
T

H
gt
H
(0.
4
3-1
.
26)
Stratified nodal status and receptor status
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Other Relevant Factorsfor Patient Management

• HER2 testing
• Cardiac tolerability comparisons based on planned
  analyses

19
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)
20
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)
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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 lt4
• 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)
22
Effect of Introduction of Traztusumab on Disease
Recurrence

• 52 decreased recurrence with concurrent vs
  control treatment (P3X10-12) (joint analysis
  finding)
• 13 decreased recurrence with sequential vs
  control treatment (P0.2936)
• 36 decreased recurrence with concurrent vs
  sequential treatment (P0.0114)
• More follow up is needed to determine whether
  this trend continues

23
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

24
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