ASCO 2005 Adjuvant Breast Cancer Update

1
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

2
ASCO 2005 Breast Cancer Update

• Abstract / Session Title/ Subject
• 512 E2197 Adjuvant AT vs. AC
• 513 ECTO A-gtCMF vs AT-gtCMF
• MoAB Ed N9831/ NSABP B31 Joint Analysis
  Adjuvant Trastuzumab
• MoAB Ed N9831 Adjuvant Trastuzumab
• MoAB Ed HERA Adjuvant Trastuzumab
• MoAB Ed E2100 T /- bevacizumab MBC

3
E2197 Phase III AT vs. AC in the Adjuvant
Treatment of Node Positive and High Risk Node
Negative Breast Cancer

• Goldstein LJ, ONeill A, Sparano JA, Perez EA,
  Shulman LN, Martino S, Davidson NE.

4
E2197 RationalePhase II Studies Anthracyline
Taxane

• Study A/Por D mg/m2 RR CHF
• Gianni/ 60/P200 80-90 20
• Dombernowsky
• Sledge E1193 50/P150 47 9.8
• Sparano E4195 60/P200 57 6
• Sparano E1196 60/D60 57 6
• Cresta 60/D60 63 10
• Misset 50/D75 81 0

5
E2197 RationalePhase III StudiesAnthracyline
Docetaxel

• Phase III Studies
• MBC AT (50/75) AC (60/600)
• RR 60 47 p.012
• TTPwk 37.1 31.9 p.015
• CHF 2 4
• FN 33 10
• No difference OS 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

6
E2197 Schema
IV q 3wk x 4 Cipro 500mg po. bid D8 x 10d
T1-3 N0-1 M0
No then Tgt 1.0cm
IV q 3wk x 4
Tamoxifen 20mg daily x 5 years post chemotherapy
for ER and/or PR positive tumor

• Stratified
• Nodal Status
• HR Status (ERPR,ERPR-,
• ER-PR,ER- PR-,ER/PR unknown)
• Menopausal Status

G-CSF - per ASCO guidelines
7
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.

8
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.

9
E2197Results

• 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

10
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

11
E2197 Toxicity Summary

• AT AC
• Feb/Infxn/N 28 10
• AML/MDS 7 7
• Lethal Events
• Related 4
• Unrelated 2 2

12
E2197 Cardiac Safety

• AT AC
• Grade 3 4 5 3 4
• CHF 15 2 1 10
• Total 18 10
• .01 .006
• No statistically significant difference

13
E2197 DFS

• Fall 2004 DMC (409/ 420 DFS failures)
• OBrien-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.

14
E2197 DFS/OSHazard Ratio

• HR gt 1 favors AT
• HR (adjusted)
• DFS 1.03 (0.86-1.25), p0.70
• OS 1.09 (0.85-1.40), p0.49
• As of 4/4/05, 242 deaths

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17
E2197 DFSSubgroup Analysis

• No significant effect within any of the following
  subgroups
• Nodes
• Size
• Age
• Menopausal Status
• Grade
• Type of Surgery
• Race

18
E2197 Disease-Free SurvivalER-/PR-
E2197 Disease-Free SurvivalER-/PR
100
90
80
70
60
Percent
Percent
50
40
30
20
10
0
0
12
24
36
48
60
72
0
12
24
36
48
60
72
Months
Months
N
Events
4-Yr
(S.E.)
N
Events
4-Yr
(S.E.)
AT
454
85
83
(2)
83
(2)
83
(2)
AT
52
14
77
(6)
AC
463
109
79
(2)
79
(2)
79
(2)
79
(2)
79
(2)
79
(2)
79
(2)
79
(2)
AC
38
3
95
(4)
E2197 Disease-Free SurvivalER/PR-
E2197 Disease-Free SurvivalER/PR
100
100
90
90
80
80
70
70
60
60
Percent
Percent
50
50
40
40
30
30
20
20
10
10
0
0
0
12
24
36
48
60
72
0
12
24
36
48
60
72
Months
Months
N
Events
4-Yr
(S.E.)
N
Events
4-Yr
(S.E.)
AT
162
22
90
(2)
AT
767
91
90
(1)
90
(1)
90
(1)
90
(1)
90
(1)
90
(1)
90
(1)
AC
164
34
83
(3)
81
(3)
81
(3)
AC
770
73
92
(1)
92
(1)
92
(1)
92
(1)
92
(1)
92
(1)
92
(1)
19
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
0.5
1
2
5
Favors AC
Favors AT
20
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.

21
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

22
Thank You

• Patients
• Data managers/ CRAs
• CALGB, NCCTG, SWOG, EPP
• Anne ONeill, Deborah Namande, Eric Ross

23
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

24
ECTO Schema

• Tumors gt 2 cm randomized to
• SURG -gtA 75 mg/m2 x 4 -gt CMF x 4
• SURG -gtAT 60/ 200 x 4 -gt CMF x 4
• AT 60/ 200 x 4 -gt CMF x 4 -gt SURG
• Tam for HR
• Analysis FFP A vs B
• B vs C

25
ECTO at 5 years Analysis A vs. B

• Pts. Events HR p
• A-CMF 453 91 .66 0.01
• AT-CMF 451 63
• 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.

26
ECTO Main Treatment Outcomes

• A() B() C()
• Total FFP
• pCR 89
• no pCR 75
• N - 81 89 86
• N 1-3 79 86 71
• N gt3 58 65 59
• OS 82 91 90
• No significant difference in OS.
• No significant difference in cardiac toxicity

27
Combined Analysis ofNSABP-B31/NCCTG-N9831

• Doxorubicin and Cyclophosphamide Followed by
  Paclitaxel
  with or without Trastuzumab
  as Adjuvant Therapy for Patients with
  HER-2 Positive Operable Breast Cancer
• 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

28
NSABP B-31
Control AC?T
Arm 1
Arm 2
NCCTG N9831
Arm A
Investigational AC?TH
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
29
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

30
LVEF Evaluation Schedule
B-31 Arm 2 / N9831 Arm C AC Paclitaxel
Trastuzumab
0 mo.
18 mos.
3 mos.
6 mos.
9 mos.
B-31 Arm 1 / N9831 Arm A AC Paclitaxel
0 mo.
18 mos.
3 mos.
6 mos.
9 mos.
31
Asymptomatic PatientsRules for Trastuzumab
ContinuationBased on Serial LVEFs
Absolute Decrease of lt 10
Absolute Decrease of 10 - 15
Absolute Decrease of ? 16
Relationship of LVEF to LLN
Cont. Cont. Cont.

• Within Normal Limits
• 1- 5 below LLN
• ? 6 below LLN

Cont. Hold Hold
Hold Hold Hold
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
32
B-31 Trastuzumab Discontinuation Due to
Asymptomatic or Symptomatic Cardiac Dysfunction
by Quarter
33
Patient and Tumor Characteristics ()
AC ? Paclitaxel AC ? Paclitaxel AC ? Paclitaxel Trastuzumab AC ? Paclitaxel Trastuzumab
872 B-31 807 N9831 864 B-31 808 N9831
Age lt50 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 ER- PR 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. gt4.0 cm. 41 43 14 40 46 13 37 44 17 38 47 14
34
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
  p0.0005 (2p0.001)

35
Disease-Free Survival
AC?TH
87
85
AC?T
75

67
N Events AC?T 1679 261 AC?TH 1672 134
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831
36
Forest Plot For Disease-Free Survival
ALL DATA
Age
60 50-59 40-49 39
Positive Negative
Hormone Receptor
4.1cm 2.1- 4.0 cm lt2.0 cm
Tumor Size
No. Positive Nodes
10 4-9 1-3 0
Protocol
N9831 NSABP B-31
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Hazard Ratio
37
Disease-Free Survival
B-31
N9831
AC?TH
AC?TH
87
87
AC?T
85
86
AC?T
78
74

68
66
N Events
N Events
AC?T 807 90
AC?T 872 171
AC?TH 808 51
AC?TH 864 83
HR0.55, 2P0.0005
HR0.45, 2P1x10-9
Years From Randomization
38
Time to First Distant Recurrence
100
AC?TH
AC-gtTH
90
90
90
90
90
90
90
AC?T
AC-gtT
80
81
81
81

74
74
74
70
N Events
N Events
AC?TH 1672 96 AC?T 1679 194
AC-gtT 1679 194
60
AC-gtTH 1672 96
HR0.47, 2P8x10-10
HR0.47, 2P8x10-10
50
0
1
2
3
4
5
B31/N9831
Years From Randomization
39
Hazard of Distant Recurrence
120
100
AC?T
80
Rate per 1000 Women /Yr
60
40
AC?TH
20
0
0
1
2
3
4
B31/N9831
Years From Randomization
40
B-31/N9831 Survival
AC?TH
94
91
AC?T
92
87
N Deaths AC?T 1679 92 AC?TH 1672 62
HR0.67, 2P0.015
Years From Randomization
B31/N9831
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42
B-31 Post-AC LVEF and Age Are Independent
Predictors of Trastuzumab-Associated CHF
Age
LVEF ()
P(Age)0.04 P(LVEF)lt0.0001
43
Conclusions

• 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.
• 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.
• 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.

44
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.

45
NCCTG N9831May 2005 Update
Perez EA, Suman VJ, Davidson N, Martino S,
Kaufman P, on Behalf of NCCTG, ECOG, SWOG,
CALGB
46
NCCTG N9831 Schema
Paclitaxel qw x 12
AC q3w x 4
Arm A
RANDOMIZE
Paclitaxel qw x 12
Arm B
AC q3w x 4
H qw x 52
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. 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
47
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
48
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
49
Cardiac Testing
?
RANDOMIZE
Paclitaxel
Arm A AC x 4
?
?
Arm B AC x 4
Paclitaxel
H
?
?
Arm C AC x 4
Paclitaxel H
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
50
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) to assist in patient management

AC ? T H ? H significantly improves
disease-free and overall survival vs control AC
? T
DMCdata monitoring committee
51
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)

52
Results Disease-Free Survival
Joint Analysis
Stratified nodal status and receptor status
N9831 Analysis
A
B
B
C
Stratified nodal status and receptor
status for patients randomized before 1/1/2005
53
Disease-Free Survival A vs BN9831
AC ? T ? HEvents103
100 90 80 70 60 50 40 30 20 10 0
AC ? 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
54
Disease-Free Survival B vs CN9831
AC ? T H ? HEvents53
100 90 80 70 60 50 40 30 20 10 0
AC ? T ? H Events84

Hazard ratio0.64 Stratified logrank 2P0.0114
0 1 2 3 4 Years
Number of patients followed B 842 501 285 162 20 C
840 520 285 178 17
55
Overall Survival
Joint Analysis Results
Stratified nodal status and receptor status
N9831 Analysis Results
A
B
B
C
Stratified nodal status and receptor status
56
Other Relevant Factorsfor Patient Management

• HER2 testing
• Cardiac tolerability comparisons based on planned
  analyses

57
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)
58
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)
59
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 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)
60
Effect of Introduction of H on Disease
RecurrenceConclusions

• 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

61
NCCTG N9831Next 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

62
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.
63
ACCRUAL 5090 WOMEN 478 centers from 39
countries (2002-2005)
NORDIC COUNTRIES
EASTERN EUROPE ? 11
CANADA
71.5
EU

• JAPAN
• ? 12
• ASIA PACIFIC

CENTRAL SOUTH AMERICA
5.5
AUSTRALIA NEW ZEALAND
SOUTH AFRICA
64
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
65
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

66
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)
SAFETY
EFFICACY

• Tolerability
• Incidence of cardiac dysfunction.

Primary endpoint DFS Secondary endpoints RFS,
DDFS, OS, 2 years vs 1 year trastuzumab
Three interim analysis of cardiac endpoints
aftern 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)
67
HERA FLOW CHART
5090 Women enrolled
5081 with available data 1 year median follow-up
Efficacy Analysis N3387
2y trastuzumab N1694
Observation N1693
1y trastuzumab N1694
N20
N3
N26
Safety Analysis N3413
N 1677 1y trastuzumab
N1736 Observation
68
PATIENT/TUMOR CHARACTERISTICS
Age ()
Observation (n 1693)
1 year trastuzumab (n 1694)
7.3
7.6
44.3
43.7
31.8
32.7
16.2
16.2
0.2
0.2
Adjuvant chemotherapy ()
6.2
6.1
68.3
67.9
25.5
26.0
0.1
0.2
Anthracyclines taxanes
69
PATIENT/TUMOR CHARACTERISTICS
Menopausal status at randomization ()
Observation (N1693)
1 year trastuzumab (N1694)
Prem
16.1
15.4
37.9
37.2
Uncertain
50.0
47.1
Postmenopausal
70
PATIENT/TUMOR CHARACTERISTICS
Observation (N1693)
1 year trastuzumab (N1694)
Nodal Status ()
Any (neoadjuvant)
11.1
10.2
Node neg.
32.1
32.9
1-3 nodes
28.5
28.9
? 4 nodes
28.3
27.9
missing
0.2
0.1
Hormone Receptor ()
HR negative
49.9
49.0
49.0
HR positive
50.0
50.9
71
ADJUVANT ENDOCRINE THERAPY
Observation
1 year trastuzumab
72
OVERVIEW OF ADVERSE EVENTS
1 year trastuzumab (N1677)
Observation (N1736)

N

N
7.9
132
4.3
75
Patients with at least one grade 3 or 4 AE
7.0
117
4.7
81
Patients with at least one SAE
6 (b)
3 (a)
Fatal AE
8.5
143 (c)
Treatment withdrawals

1. Cardiac failure, suicide, unknown
2. Cerebral hemorrhage, cerebrovascular accident,
   sudden death, appendicitis, two unknown
3. Reason safety in 6, refusal in 2.5

73
SAFETY ANALYSIS POPULATION Cardiotoxicity
1 year trastuzumab N1677
Observation N1736
7.1
2.2
Decrease by ? 10 EF points and LVEF lt 50
0.5 (95 CI 0.25-1.02)
0 (95 CI 0.00-0.21)
Same LVEF criteria and symptomatic CHF NYHA class
III/IV, confirmed by cardiologist Cardiac death
0.1
0
74
DISEASE-FREE SURVIVAL
alive and disease free
75
DISEASE-FREE SURVIVALType of First Event
Observation n 220 events
1 year trastuzumab n 127 events
70
n154
n 85 67
Distant event
23 n50
n27 21
Loco regional event
n6 5
3 n7
Contralateral breast Ca
n3 2
3 n6
Second non breast malignancy
n6 5
1 n3
Death as first event
76
DFS BENEFIT IN SUBGROUPS HR 1 year trastuzumab
vs observation
Hazard
Hazard
ratio
ratio
n
n
All
All
3387
0.54
3387
0.54
Nodal
status
Nodal
status
Any, neo
-
adjuvant chemotherapy
358
0.53
Any, neo
-
adjuvant chemotherapy
358
0.53
0 pos, no neo
-
adjuvant chemotherapy
1100
0.52
0 pos, no neo
-
adjuvant chemotherapy
1100
0.52
1
-
3 pos, no neo
-
adjuvant chemotherapy
1
-
3 pos, no neo
-
adjuvant chemotherapy
972
0.51
972
0.51
³
4 pos, no neo
-
adjuvant chemotherapy
953
0.53
³
4 pos, no neo
-
adjuvant chemotherapy
953
0.53
Adjuvant chemotherapy regimen
Adjuvant chemotherapy regimen
203
0.64
No anthracycline or taxane
203
0.64
No anthracycline or taxane
2307
0.43
Anthracycline, no taxane
2307
0.43
Anthracycline, no taxane
872
0.77
Anthracycline taxane
872
0.77
Anthracycline taxane
Receptor status/endocrine therapy
Receptor status/endocrine therapy
Negative
Negative
1674
0.51
1674
0.51
Pos no endocrine therapy
467
0.49
Pos no endocrine therapy
467
0.49
1234
0.68
1234
0.68
Pos endocrine therapy
Pos endocrine therapy
Age group
Age group
lt35 yrs
251
0.47
lt35 yrs
251
0.47
35
-
49 yrs
35
-
49 yrs
1490
0.52
1490
0.52
50
-
59 yrs
50
-
59 yrs
1091
0.53
1091
0.53
³
60 yrs
³
60 yrs
549
0.70
549
0.70
Region
Region
Europe, Nordic, Canada, SA, Aus, NZ
Europe, Nordic, Canada, SA, Aus, NZ
2430
0.58
2430
0.58
Asia Pacific, Japan
405
0.42
Asia Pacific, Japan
405
0.42
Eastern Europe
364
0.31
Eastern Europe
364
0.31
Central South America
188
0.90
Central South America
188
0.90
Favors
Favors
Favors
Favors
0
1
2
0
1
2
trastuzumab
observation
trastuzumab
observation
77
SECONDARY EFFICACY ENDPOINTS Intent-to-treat
Analysis
RFS
DDFS
OS
No of events
209
113
179
98
37
29
95 CI p value (logrank) 2y outcome ()
0.40-0.63 lt 0.0001 78.6 vs 87.2
0.40-0.66 lt 0.0001 81.8 vs 89.7
0.47-1.23 lt0.26 95.0 vs 96.0
78
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
• Trastuzumabs clinical benefits are independent
  of patients baseline characteristics (nodal
  status, hormone receptor status, ...) and of
  type of adjuvant chemotherapy received

79
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

80
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

81
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?

82
Should we give Trastuzumab before or after CTX?

• Preclinical data suggest that trastuzumab may
  amplify ctxs pro-apoptotic effects.
• Synergistic activity in preclinical models for
  some ctx
• Cardiotoxicity concerns when trastuzumab is given
  in proximity to anthracyclines.

83
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?)

84
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 follow-up
• Long term effects unknown
• While benefit far outweighs the risks, the price
  is real and should be discussed with patients

85
BCIRG 006 Adjuvant Breast Cancer Node Positive
and High Risk Node Negative
4 x Docetaxel 100 mg/m2
4 x AC60/600 mg/m2
AC?T
AC?TH
HER2 FISH
1 Year Trastuzumab
N3150 480 centres
6 x Docetaxel and Platinum salts 75 mg/m2 75
mg/m2 or AUC 6
TCH
1 Year Trastuzumab
86
BCIRG 006 LVEF Decline by NYHA Class

• AC-T AC-TH TCH
• gt10 lt LLN 9 34 7
• gt15lt 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.

87
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.

88
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 gt 6 mo. and have not received
  trastuzumab, discuss risks and benefits.

89
(No Transcript)
90
E2100A Randomized Phase III Trial of Paclitaxel
versus Paclitaxel plus Bevacizumab as First-Line
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. Lukes Medical
  Center, Mayo Clinic, British Columbia Cancer
  Agency, Vancouver Cancer Center, Johns Hopkins
  Oncology Center

91
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

92
Study Design

• Stratify
• DFI lt 24 mos. vs. gt 24 mos.
• lt 3 vs. gt 3 metastatic sites
• Adjuvant chemotherapy yes vs. no
• ER vs. ER- vs. ER unknown

28-day cycle Paclitaxel 90 mg/m2 D1, 8 and
15 Bevacizumab 10 mg/kg D1 and 15
93
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 gt 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 (gt 500 mg/24 hr)
• No therapeutic anticoagulation

94
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

95
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

96
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

97
Patient Characteristics
Paclitaxel (n350) Pac. Bev. (n365)
Treated 346 365
Median age 55 (27-85) 56 (29-84)
DFI lt 24 months 41 41
gt 3 sites 29 28
Adjuvant chemo. 64 65
ER 63 64
98
Response
34.3
28.2
16.4
14.2
316
236
330
250
99
Progression Free Survival
100
Overall Survival
101
Bevacizumab ToxicityNCI-CTC Grade 3 and 4
Paclitaxel (n330) Paclitaxel (n330) Pac. Bev. (n342) Pac. Bev. (n342)

Grade 3 Grade 4 Grade 3 Grade 4
HTN 0 0 13 0.3
Thromboembolic 0.3 0.9 1.2 0
Bleeding 0 0 0.6 0.3
Proteinuria 0 0 0.9 1.5
plt0.0001 p0.0004
NCI-CTC v3.0, worst per patient
102
Other ToxicitiesNCI-CTC Grade 3 and 4
Paclitaxel (n330) Paclitaxel (n330) Pac. Bev. (n342) Pac. Bev. (n342)

Grade 3 Grade 4 Grade 3 Grade 4
Neuropathy 13.6 0.6 19.9 0.6
Fatigue 2.7 0 4.7 0.3
Neutropenia 0 3 0.9 4.4
? LVEF 0 0 0.3 0
p0.01
NCI-CTC v3.0, worst per patient
103
Ongoing Correlative Studies

• Quality of Life (FACT-B)
• Circulating markers
• Serum VCAM-1
• Urine VEGF
• Analysis of primary tumor samples
• VEGF expression

104
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

105
Adjuvant Pilot TrialRationale

• 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

106
E2104 Schema
Arm A ddBAC gtBT gtB
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 gtBT gtB
Hormone therapy and radiation per standard care