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![Page 1: Herceptin ® adjuvant therapy: “a triumphal narrative of translational research” Brian Leyland-Jones McGill University Department of Oncology Montreal,](https://reader030.fdocuments.us/reader030/viewer/2022032806/56649f055503460f94c1ab17/html5/thumbnails/1.jpg)
Herceptin® adjuvant therapy:
“a triumphal narrative of translational research”
Brian Leyland-Jones
McGill University
Department of Oncology
Montreal, Quebec, Canada
Burstein, H. NEJM 2005:353;1652
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NSABP B-31 (US)(n=1960)
Paclitaxel q3w x 4 or qw x 12
Paclitaxel q3w x 4 or qw x 12 + H qw
HERA Trial (ex-US) (n=5090)
Observation
H q3w* x 12 months
H q3w* x 24 months
Any CT ± RT
Intergroup N9831 (US) (n=3046)
Paclitaxel qw x 12
Paclitaxel qw x 12
Paclitaxel qw x 12 + H qw
BCIRG 006 (global)(n=3222)
Carboplatin + docetaxel q3w x 6 + H qw
Herceptin® adjuvant trials (>13,000 patients)
H qw
AC x 4
AC x 4
Docetaxel q3w x 4
Docetaxel q3w x 4 + H qw
*q3w at 6mg/kgH = Herceptin®
H q3w*
H q3w*
AC x 4
AC x 4
AC x 4
AC x 4
AC x 4
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Herceptin® in the adjuvant setting: how four trials complement each other
Covers all currently accepted EU and US treatment strategies
Combinations of a number of regimens and both taxanes
Compares AC followed by H with novel treatment concepts
Investigates optimal treatment duration
Investigates sequential versus combination therapy
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Joint analysis: disease-free survival
Years from randomisation
Romond et al 2005
87% 85%
67%
75%
HR=0.48; p<0.0001
100
90
80
70
60
500 1 2 3 4 5
2-year median follow-up
Patients (%)
AC T
AC TH
n EventsAC TH 1672 133
AC TP 1679 261
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Joint analysis:time to first distant recurrence
N Events
0 1 2 3 4 5
50
60
70
80
90
100
ACTH 1672 96ACT 1679 194
HR=0.47, 2P=8x10-10
ACACTHTH
ACT
Years from randomization
90%90%90%90%
81%
74%
%
Romond et al 2005
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Joint analysis: hazard of distant recurrence
0 1 2 3 4
0
20
40
60
80
100
120
Rat
e p
er 1
000
Wo
men
/Y
r
Years from randomization
ACACTHTH
ACT
Romond et al 2005
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Joint analysis: overall survival
Romond et al 2005
ACTH94%
91%
87%
92%
ACT
N Deaths
ACT 1679 92
ACTH 1672 62 HR=0.67, 2P=0.015
%
100
90
80
70
60
50 0 1 2 3 4 5Years from randomisation
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0.5 0.3 2.6 1472
1.0 0.5 3.6 1202
1.5 0.5 3.9 983
2.0 0.5 4.1 775
2.5 0.8 4.1 595
3.0 0.8 4.1 405
NSABP B-31: cumulative incidence ofcardiac events in the evaluable cohort
Yrs
Po
st D
ay 1
C
yc 5
Cu
m I
nc
Arm
1
(%
)
Cu
m I
nc
Arm
2 (%
)
Nu
mb
er A
t R
isk
Cohort Arm 1 Evaluable CohortArm 2 Evaluable Cohort
%
0
2
4
6
Years Post Day 1 Cyc 50.0 0.5 1.0 1.5 2.0 2.5 3.0
Arm 2: AC→PTX + HN=850, 31 CHFs,No Cardiac Deaths
Arm 1: AC→PTX N=814, 4 CHFs, 1 Cardiac Death
HR=5.94.1%
0.8%
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NSABP-B31: post – AC LVEF and age are independent predictors of Herceptin®-
associated CHF
Age and LVEF were statistically significant predictors of CHF. Careful cardiac monitoring must be done.
LVEF Age < 50 Age ≥ 50
50 – 54 3/48 (6.3%) 9/47 (19.1%)
55 – 64 5/229 (2.2%) 10/194 (5.2%)
65+ 1/160 (0.6%) 2/159 (1.3%)
P(Age) = 0.04
P(LVEF) < 0.001
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Joint analysis: conclusions Herceptin® given concurrently with paclitaxel
following AC – significantly reduces the risk of DFS events by 52%– significantly reduces the risk of distant recurrence
by 53%– significantly improves overall survival, with a 33%
reduced risk of mortality
The number of cardiac events was low– <4% incidence, Herceptin® versus non-Herceptin® in
both trials
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HERA: key inclusion criteria Centrally confirmed HER-2 overexpression or Centrally confirmed HER-2 overexpression or
amplificationamplification
Node-positive or (sentinel) node-negative with Node-positive or (sentinel) node-negative with T1c T1c
Completed Completed 4 cycles of approved (neo)adjuvant 4 cycles of approved (neo)adjuvant chemotherapy regimenchemotherapy regimen
Baseline LVEF Baseline LVEF 55% (Echo or MUGA) 55% (Echo or MUGA)
Known hormone receptor statusKnown hormone receptor statusPiccart-Gebhart et al 2005
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HERA: patient and tumour characteristics (%)
Observation(n=1,693)
1-year Herceptin
(n=1,694)
Age (years)
<3535–49
50–59
≥60
7.3
43.7
32.7
16.2
7.6
44.3
31.8
16.2
Adjuvant CT (%)
No AC, no T
AC
AC + T
6.1
68.3
25.5
6.2
67.9
26.0
Nodal status
Any (neoadjuvant)
Node-negative
1–3 +
≥4 +
10.2
32.9
28.9
27.9
11.1
32.1
28.5
28.3
Hormone Receptor (%)
HR-negative
HR-positive
49.9
50.0
49.0
50.9AC=anthracycline; T=taxane Piccart-Gebhart et al 2005
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HERA: endpoints and analysis plan Target accrual was 4,482 patients, 5,090 enrolled
– HR=0.77 (80% power two sided α=0.025) for nil versus 1 year, nil versus 2 years
Primary endpoint DFS
Secondary endpoints RFS, DDFS, OS, 2 years versus 1-year Herceptin®
One interim efficacy analysis (n=475 events), 1 year median follow up
One primary core analysis (n=951 events)
Safety – tolerability, incidence of cardiac dysfunction
Three safety interim analyses of cardiac endpoints after n=300, 600, 900 patients. Stopping rule ≥4% increase in cardiac events
Piccart-Gebhart et al 2005
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100
80
60
40
20
0
Patients(%)
Months from randomisation6 12 18 24
1693 1108 767 445 2241694 1172 885 532 268
127
220
1 year Herceptin®
Observation
0
No. at risk
Events HR 95% CI p value
0.54 0.43, 0.67 <0.0001
2-yearDFS
85.8
77.4
HERA: disease-free survival
Median follow-up: 1 year; DFS, disease-free survival;HR, hazard ratio; CI, confidence interval Piccart-Gebhart et al 2005
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HERA: efficacy endpoints
0
50
100
150
200
250
HR95% CIp value 2-year outcome, %
0.490.38, 0.63<0.0001
82.8 vs 90.6
0.760.47, 1.23
0.2695.1 vs 96.0
Distant recurrence
Overall mortality
No. events
171 89 37 29
Observation 1 year Herceptin®
Piccart-Gebhart et al 2005
0.540.43, 0.67<0.0001
77.4 vs 85.8
DFSDFS
220 127
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HERA: cardiac safety Cardiac events have been manageable and reversible
Decrease by >10 EF points and LVEF <50%a
Symptomatic CHF, including severe CHF
Severe CHF
Cardiac death
Observation
2.2
0.06
0
0.06
1 year Herceptin
7.1
1.7
0.5
0
% patients
aMany were single observations not confirmed at subsequent time points
p value
<0.001
<0.001
0.002
1.0
Piccart-Gebhart et al 2005CHF = congestive heart failure
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HERA: conclusions At 1-year follow up, Herceptin® given after
chemotherapy – significantly reduces the risk of DFS events
by 46%– significantly reduces the risk of distant recurrence
by 51%– is associated with a low incidence of severe
CHF (0.5%)
Piccart-Gebhart et al 2005
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BCIRG 006: disease-free survival
% D
ise
as
e F
ree
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Year from randomization
77%
86%
80%
73%
84%
80%86%
93%
91%
Patients Events
1073 147 AC->T
1074 77 AC->TH
1075 98 TCH
HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001
HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002
Slamon et al SABCS 2005
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BCIRG 006: mean LVEF - all observations
59
60
61
62
63
64
65
66
0 100 200 300 400 500 600 700 800
Days
LV
EF
AC->T (N=1012) AC->TH (N=1040) TCH (N=1029)
AC->T
TCH
AC->TH
189 pts
290 pts
205 pts
Slamon et al SABCS 2005
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BCIRG 006: HER2 and TOPO II
HER2core region
17q 12 17q 21.1 17q 21.2
60%
n=2120
4%
Topo IINonco-amplified
Slamon et al 2005
Normal Amplified Deletion
TOPO II region
35% Co-amplified
2120 of 3222 patients analysed
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BCIRG 006: disease-free survival non-amplified Topo II by
arm
% D
ise
as
e F
ree
Months
0.0
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 54
Patients Events Treatment
458 92 AC->T472 45 AC->TH446 54 TCH
Logrank P= <0.001
TCHAC->TH
AC->T
Press et al SABCS 2005
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BCIRG 006: disease-free survival amplified Topo II by arm
% D
ise
as
e F
ree
Months
0.5
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 54
Patients Events Treatment
227 23 AC->T
265 13 AC->TH252 21 TCH
Logrank P= 0.24
TCH
AC->TH
AC->T
Press et al SABCS 2005
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BCIRG 006: conclusions Herceptin® provided a significant DFS benefit in
both regimens– in combination with docetaxel after AC (HR=0.49)– in combination with docetaxel and carboplatin
without an anthracycline (HR=0.61)
It is too early to tell whether a non-anthracycline-containing Herceptin® regimen has efficacy comparable to anthracycline-based regimens
Cardiac safety appears to be higher with non-anthracycline-based therapy
Slamon et al 2005
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FinHER: trial design
502 pts.Docetaxel
507 pts.Vinorelbine1010 pts.
EBCpN+ or
pN0 (tumour >2 cm,
PR-)
R115 pts.HER2 +
392 pts.HER2 -
116 pts.HER2 +
386 pts.HER2 -
R
R
57 pts. + Herceptin®
58 pts.
58 pts. + Herceptin®
58 pts.
392 pts.HER2 -
386 pts.HER2 -
1010 patients were recruited and after 2 randomisations allocated to 6 treatment arms (1 patient excluded from efficacy analyses)
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FinHER: recurrence-free survival in HER2-positive subgroup
100
80
60
40
20
0
Rec
urr
ence
-fre
e su
rviv
al (
%)
0 1 2 3 4Time (years)
89.3%
77.6%
HerceptinEvents=12
No HerceptinEvents=27
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FinHER: cardiac safety in HER2-positive subgroup
Cardiac failure
LVEF decrease >15% from baseline
Joensuu et al 2005
Herceptin®
0 (0%)
4 (3%)
No Herceptin®
1 (1%)
7 (6%)
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FinHER: conclusions
Compared with vinorelbine, adjuvant docetaxel
– improves DFS
– results in more adverse events
Brief use of adjuvant Herceptin® administered concomitantly with docetaxel or vinorelbine was well-tolerated and effective for HER2-positive breast cancer and warrants further study
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Summary: Herceptin® in EBC
0 1 2
HERA 1 year
Combined analysis 2 years
Median follow-up
FavoursHerceptin®
Favours noHerceptin®
HR
BCIRG 006 DCarboH 2 years
2 yearsBCIRG 006 AC DH
FinHER VH / DH CEF 3 years
Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005
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Summary: Herceptin® in EBC
Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Tan-Chiu et al 2005
Trial
HERA
NSABPB-31
NCCTG N9831
BCIRG006
FinHER
Arm
H 1 yearNil
ACPACPH
ACP ACPH
ACDACDH
DCarboH
HNo H
BaselineLVEF, %
>55
>50
>50
>50
CHF,n (%)
09 (0.5)
4 (0.8)a 31 (4.1)a
0a
20 (2.9)a
3 (0.3)17 (1.6) 4 (0.4)
0 (0)1 (1)
aCumulative percent
Cardiacdeath, n
10
10
000
00
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Herceptin® adjuvant therapy:conclusions and future prospects
Benefits seen with Herceptin® are independent of chemotherapy and patient characteristics
Radiotherapy can be given before or concurrent with Herceptin®
Data are currently not available on benefit of Herceptin®
– as monotherapy or combined with endocrine agents in patients not indicated for chemotherapy
– in patients with primary tumours <1cm
Five studies have demonstrated a substantial DFS advantage with adjuvant Herceptin® in women with HER2-positive EBC
Optimal duration of treatment is uncertain
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Herceptin® in the news
Herceptin is the cure for early stages of breast cancer?
MedIndia, India, Jan 06
…thanks to Herceptin, breast cancer
sufferers could now look
forward to a long life
The Observer, UK, Jan 06
…superdrug that h
as
changed the face of m
odern medicine
The Observer, UK, Jan 06
Cancer wonder drug campaigner gets all clear
Mirror.co.uk, Jan 06
“Herceptin is the best chance for women like me”
Barbara Clarke, Telegraph.co.uk, Jan 06