Transcript Slide 1

Should clinicians routinely recommend trastuzumab
(Herceptin) as part of the adjuvant therapy for all
patients with Her2 positive early breast cancer?
A review of recent data, and reflections on how these
results relate to the use of Adjuvant!
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An Interpretation of Adjuvant Herceptin
Results Presented at ASCO May 2005
1) Romond EH, Perez EA, Bryant J, et al.
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
2) Perez EA, Suman VJ, Davidson N, et al.
NCCTG N9831 May 2005 Update
3) Piccart MJ
First Results Of The HERA Trial
NSABP B-31
Arm 1
Arm 2
NCCTG N9831
Arm A
Arm B
Arm C
HERA (Randomization after chemotherapy)
Arm A
Arm B
No Herceptin
(1 yr)
(2 yr)
Arm C
AC q 3 wk * 4
= paclitaxel q 3 wk * 4
= trastuzumab q 1 w
= paclitaxel q 1 wk * 12
= trastuzumab q 3 w
Combined analysis of B31 / N9831
Control
Arm 1 (B31)
Arm A (N9831)
Herceptin
Arm 2 (B31)
Arm C (N9831)
Combined:
n = 3,351; median follow-up 2.0 yr
NSABP B-31: n = 1,736; median follow-up 2.4 yr
N9831:
n = 1,615; median follow-up 1.5 yr
Eligibility
NSABP B-31 / N9841
1) Definitively resected primary adenocarcinoma of
the breast.
2) Axillary node positive (N9841 was amended to allow
high risk node negative).
3) No locally advanced or metastatic disease.
4) Normal hematologic, hepatic, and renal function.
5) No prior anthracycline or taxane therapy.
6) No significant sensory or motor neuropathy.
7) No past or current cardiac history.
8) Normal LVEF.
9) Her2 IHC +++ or FISH + (N9831 by central lab, B31
by approved reference laboratory).
Patient / Tumor: Characteristics
No Imbalances Between Treatment Arms
(numbers shown are % of total)
Age
< 50
50 - 59
> 59
Tumor Size
51
33
16
Nodes
N0
NP (1-3)
NP (4-9)
NP (> 9)
T < 2cm
T 2.1-4.0 cm
T > 4 cm
39
45
15
ER and PgR Status
6
53
27
14
ER +
ER PgR +
PgR -
52
48
40
59
Combined Analysis for DFS of
NSABP B-31 / NCCTG – N9831
ACTH
87%
85%
ACT
75%
%
67%
ACT
ACTH
N
1679
1672
Events
261
134
HR=0.48, 2P=3x10-12
Years From Randomization
Combined Analysis for DFS of
NSABP B-31 / NCCTG – N9831
Subset Analysis For DFS
Herceptin Benefit
In all age subsets
In all tumor size subsets
In all nodal subsets (NN CI very broad)
In ER positive and negative subsets
In both N9831 and B31
Forest Plot For DFS: B31/N9831
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone Positive
Receptor Negative
0.2
0.4
0.6
0.8
1.0
Hazard Ratio
Tumor
Size
≥ 4.1cm
2.1- 4.0 cm
<2.0 cm
No.
Positive
Nodes
10+
4-9
1-3
0
Protocol
N9831
NSABP B-31
1.2
1.4
Combined Analysis for DDFS of
NSABP B-31 / NCCTG – N9831
100
ACTH
AC->T+H
90%
90%
90%
90
90%
90%
90%
ACT
AC->T
80
81%
81%
81%
%
70
N
74%
74%
74%
Events
N Events
ACTH 1672 96
AC->T
1679 194
ACT
1679
AC->T+H 1672194
96
60
HR=0.47, 2P=8x10-10
HR=0.47, 2P=8x10-10
50
0
1
2
3
Years From Randomization
4
5
Annual Hazard of Distant Recurrence
Rate per 1000 Women /Yr
120
100
ACT
80
60
40
ACTH
20
0
0
1
2
Years From Randomization
3
4
Combined Analysis for OS of
NSABP B-31 / NCCTG – N9831
94%
ACTH
91%
ACT
92%
87%
ACT
ACTH
N
1679
1672
Deaths
92
62
HR=0.67, 2P=0.015
Years From Randomization
B31/N9831
Cardiac Monitoring
~ 20% of the patients discontinued Herceptin
because of symptomatic or asymptomatic
heart problems
Herceptin * 12 mns
AC * 4
Taxol * 4
Baseline
3 mns
6 mns
2.1%
9 mns
7.7%
15 mns
18 mns
10.1%
% stopping Herceptin by time period
~ 4 % of patients never got Herceptin because of developing a
low LVEF post AC * 4.
LVEF measurements
This analysis from B31data alone.
Cardiac Monitoring
Rules for action for asymptomatic patients
Absolute Decrease in LVEF
< 10 %
10-15%
> 15%
Normal LVEF
Continue
Continue
Hold *
1-5% below LLN of LVEF
Continue
Hold *
Hold *
> 5% below LLN or LVEF
Continue *
Hold *
Hold *
* Repeat LVEF assessment in 4 weeks
If criteria for continuation met restart
If 2 consecutive holds of a total of 3 holds, discontinue Herceptin
Cardiac Safety
Age and Post AC LVEF were predictors of the
risk of developing CHF
Risk of CHF (%)
Age younger
than 50
Age 50 and
older
Initial LVEF 50 - 54
6.3 %
19.1 %
Initial LVEF 55 - 64
2.2 %
5.2 %
Initial LVEF > 65
0.6 %
1.3 %
In both age groups about 10% of the patients had a LVEF of 50-54,
about 50% of the patients had a LVEF of 55-64, and 35% had a LVEF of
> 65%. Average risk of early CHF for patient younger than 50 is 2 %
and older than 50 is ~ 5%
This analysis from B31data alone.
Risk of Cardiac Events
(no strong evidence of an major delayed toxicity)
% Risk of Cardiac Event
End of Herceptin treatment period
5
4
3
Control
Herceptin
2
1
0
0
1
2
3
Years Since Starting Herceptin
The only cardiac death that occurred during this study occurred in a
control patient.
This analysis from B31 data alone.
NSABP B-31
Cardiac Safety Analysis For First 1000 Patients
Baseline all patients normal LVEF (median 63%)
After 3 months of AC
LVEF median 61% (lower, p<0.001)
4.2% of patients with LVEF < 50%
Patients with low LVEF did not go on to get Herceptin.
Total symptomatic cardiac events during Herceptin
4.28 % in Herceptin group
of these 33% had LVEF < 30%, 52% LVEF 30-39%
0.78 % in Control group
NSABP B-31
Cardiac Safety Analysis For First 1000 Patients
Herceptin Related Fall In LVEF Was Largely Reversible
In Patients With A Cardiac Event (n=27)
60
50
40
During Event
On Recovery
30
20
10
0
< 30 30-39 40-49 50-59 60-69
~ 68% of the patients had symptoms resolve within 6 months
Analysis of Three Arms of N9831
NCCTG N9831
Arm A
Arm B
Arm C
n = 2,804; median follow-up 1.5 yr
N9831 Disease-Free Survival
Control vs Concurrent
AC → T + H → H
100
90
80
70
60
% 50
40
30
20
10
0
AC → T
Hazard ratio = 0.55
Stratified logrank 2P = 0.0005
0
1
2
Years
3
4
N9831 Disease-Free Survival
Control vs Sequential
AC → T → H
100
90
80
70
60
% 50
40
30
20
10
0
AC → T
Hazard ratio = 0.87
Stratified logrank 2P = 0.29
0
1
2
Years
3
4
N9831 Disease-Free Survival
Sequential vs Concurrent
AC → T + H → H
100
90
80
70
60
% 50
40
30
20
10
0
AC → T → H
Hazard ratio = 0.64
Stratified logrank 2P = 0.0114
0
1
2
Years
3
4
Cardiac Safety in 9831
• Difference in the incidence of cardiac events
(CHF and cardiac deaths) between non-H and H arms
is < 4%
• 9 month (post finishing AC * 4) analysis; 500 per arm
with normal LVEF or LVEF decrease  15% from
baseline (after AC)
– 0.0% with events (95% CI,0.0-0.7%) for control
– 2.2% with events (95% CI,1.1-3.8%) for control vs sequential
– 3.3% with events (95% CI,2.0-5.1%) for control vs concurrent*
therapy with paclitaxel
* at month 9, concurrent pts have received 3 additional months of
Herceptin compared to sequential
HERA Trial
HERA (Randomization after chemotherapy)
Arm A
Arm B
Arm C
No Herceptin
(1 yr)
(2 yr)
Only Arms 1 and 2 analyzed in this interim analysis
n = 3,307, median follow-up ~ 1 year
Eligibility
HERA Trial
1) Definitively resected primary adenocarcinoma of
the breast.
2) Received and completed neoadjuvant and/or
adjuvant chemotherapy. Chemotherapy must have
been at least 4 cycles of an approved regimen.
3) If node negative tumor size must have been T1c or
larger (for adjuvant patients).
4) Normal LVEF by MUGA or echo of > 55%.
5) Her2 IHC +++ or FISH + by central lab.
6) Known (and centrally reviewed ER status).
HERA Trial:
Patient / Tumor: Characteristics
No Imbalances Between Treatment Arms
(numbers shown are % of total)
Age
< 50
50 - 59
> 59
Adjuvant Regimen
51
32
16
Nodes
N0
NP (1-3)
NP > 4
NeoAdj
Anthracyclines
68
Anathra + Taxane 26
No A or Taxane6
ER and PgR Status
33
29
28
11
ER +
ER -
51
49
DFS: HERA Trial
% alive and 100
disease free 90
80
70
60
50
40
30
20
10
0
Trastuzumab 1 yr
Observation
2-yr
Events DFS % HR
0
[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
25
1694
1472
1067
629
303
102
1693
1428
994
580
280
87
No.
at risk
DFS In Patient Subsets: HERA Trial
n
Hazard
ratio
All
3387
0.54
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
358
1100
972
953
0.53
0.52
0.51
0.53
Adjuvant chemotherapy regimen
No anthracycline or taxane
Anthracycline, no taxane
Anthracycline + taxane
203
2307
872
0.64
0.43
0.77
Receptor status/endocrine therapy
Negative
Pos + no endocrine therapy
Pos + endocrine therapy
1674
467
1234
0.51
0.49
0.68
Age group
<35 yrs
35-49 yrs
50-59 yrs
60 yrs
251
1490
1091
549
0.47
0.52
0.53
0.70
0
Trastuzumab
Better
1
Observation
Better
2
Cardiac Safety in HERA
(very early 1 year median follow-up report)
Observation
N=1736
1 Year trastuzumab
N=1677
LVEF < 50% and
decrease by  10
EF points
2.2 %
7.1 %
CHF grade III/IV,
and / or cardiac
death
0%
(95% CI: 0.000.21)
0.5%
(95% CI: 0.25-1.02)
BCIRG 006 (n ~ 3000)
Will Arm 3 (a non-anthracycline adjuvant regimen)
be the answer ?
BCIRG 006
Arm 1
Arm 2
Arm 3
Expected efficacy report SABCS December 2005
Current reported cases of Grade 3/4 CHF
Arm 1 / Arm 2 / Arm 3 = 1, 18, 1
Current reported cases LVEF 15% < LLN
Arm 1 / Arm 2 / Arm 3 = 6, 25, 4
AC q 3 wk * 4
= docetaxel q 3 wk * 4
= trastuzumab q 1 w
= docetaxel/platinum q 3 wk * 6
= trastuzumab q 1 w
So Is Adjuvant Herceptin For All Breast Cancer
Patients? Informed Speculation !
60 Year Old Women. ER +, Her2 +, average comorbidity.
Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w.
Her2 FISH +. Additional RR conferred by Her2 1.5.
Baseline 10 With Tam
Year OS
and Chemo
Added
Herceptin
Benefit
Due to
Herceptin
NP (1-3) T2
45 %
64 %
72 %
8%
NN T2
59 %
74 %
79 %
5%
NN T1c
81 %
86 %
88 %
2%
NN T1ab
88 %
90 %
91 %
1%
Risk of developing CHF 5%, 2/3 have symptoms resolve
in 6 months. Cardiac status at 10 years??
CA * 4 then T * 4
Results of 9344, 9741, and B-31 /N9831
9344
9741
B31/
N9831
Age < 50
60
49
51
NN (0)
0
0
6
NP (1 – 3)
46
59
53
NP (4 – 9)
42
29
27
NP >10
12
1
14
T>2
65
60
61
ER +
59
65
52
79 %
81%
75 %
DFS (3yr)
Her2+++
No major difference in outcome of this arm between trials.
Early Results
Triumphs and Cautionary Tales
Tam vs Obs
(Overview)
Her vs Obs
(B31/N9831)
Proportional risk reductions at 2 Years for DFS
53 %
52%
Proportional risk reductions at 10 years for DFS
39 %
???
Durable but
Late Toxicity
Durable ?
Late Toxicity ?
Early Results Do Not Always Reflect
Late Results In Adjuvant Therapy
Proportional Risk Reduction
During Time Interval
Poly Chemotherapy
50
Tamoxifen (5 yrs)
70
60
40
50
30
40
20
30
20
10
10
0
0
0-2
2-5
5 - 10
Time Periods (yrs)
Recurrence
0-2
2-5
5 - 10
Time Periods (yrs)
Breast Cancer Specific Mortality
NSABP/Intergroup Recommendations For
Control Patients
The recommendations were covered in letters to the
patients and clinicians. The recommendations were
complex because the letter had to deal with the
spectrum of possible treatment points that the patient
might be at. Of special relevance to patients who were
not trial participants were the following:
Patients in the control (non-trastuzumab) arms with
adequate cardiac function, and within 6 months of
finishing chemotherapy were offered trastuzumab.
The NSABP suggested that trial patients who had not yet
started the paclitaxel/trastuzumab, who were > 50 years
old and who had a post AC *4 LVEF of 50-54%, consider
the option of starting the trastuzumab only after
completing the paclitaxel.
Should clinicians routinely recommend
trastuzumab (Herceptin) as part of the adjuvant
therapy for all patients with Her2 positive early
breast cancer?
Adjuvant Herceptin should only recommended
as a part of a process that includes both
information about the early gains and warns the
patient that she faces some increased risk of
developing CHF. Although early results are very
encouraging, information about long term
benefits and risks is not yet available.