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Herceptin® Pivotal Studies
Nuhad K Ibrahim, MD, FACP
Associate Professor of Medicine
Breast Medical Oncology Department
MD Anderson Cancer Center
Houston, TX, USAE-mail:
Herceptin® (trastuzumab): History and Introduction
Phase
III
Human
HER2 gene
cloned
trastuzumab
FDA approval
9/25/98
Phase II Phase I IND
for rhuMAb
HER2
muMAb
4D5
1992 1993 1994 1997 1995 1996 1998 1985 1991 1990
1981 1987
Association
of HER2 with
poor clinical
outcome
Murine
HER2/neu
gene
cloned
Targets HER2 protein
High affinity (Kd = 0.1 nM)
and specificity
95% human, 5% murine
– Decreases potential
for immunogenicity
– Increases potential for
recruiting immune effector
mechanisms
HER2 epitopes recognized by
hypervariable murine
antibody fragment
Human
IgG-1
Herceptin®: Humanized Anti-HER2 Antibody
Baselga. Satellite Symposium, 23rd Annual San Antonio Breast Cancer Symposium 2000.
Baselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35.
Potential Mechanisms of Action of Trastuzumab: Preclinical Studies
Cytostatic
– Inhibits tumor cell proliferation by downregulating HER2 expression
and blocking heterodimerization with other HER members
– Induces G1 arrest and p27 cell cycle inhibitor
– Blocks HER2 cleavage/constitutive activation
Cytotoxic
– Initiates Fc-receptor–mediated antibody-dependent cellular
cytotoxicity and complement-mediated cytolysis
– Potentiates chemotherapy (promotes apoptosis)
• N = 469
• MBC
• HER2 positive
• No prior CT for MBC
• Measurable disease
• KPS ≥ 60%
AC = doxorubicin (60 mg/m2) [or epirubicin (75 mg/m2)] + cyclophosphamide (600 mg/m2) q3w for 6 cycles;
Taxol (175 mg/m2 x 3 h) q3w for 6 cycles; Herceptin (4 mg/kg) loading dose, 2 mg/kg qw until progression.
Slamon et al. N Engl J Med. 2001;344:783.
Herceptin® Combination Pivotal Trial in First-Line MBC: Schema
No prior adjuvant AC Prior adjuvant AC
Taxol (n = 96)
Herceptin + Taxol® (n = 92)
AC (n = 138)
Herceptin + AC (n = 143)
STRATIFY
RANDOMIZE RANDOMIZE
Herceptin Herceptin Herceptin + AC AC + Taxol® Taxol + CT CT Parameter (n = 143) (n = 138) (n = 92) (n = 96) (n = 235) (n = 234)
ORR (%) 56 42 41 17 50 32
p value < 0.02 < 0.001 < 0.001
Median DR (mo) 9.1 6.7 10.5 4.5 9.1 6.1
p value 0.005 < 0.01 < 0.001
Median TTP (mo) 7.8 6.1 6.9 3.0 7.4 4.6
p value < 0.001 < 0.001 < 0.001
Median survival (mo) 26.8 21.4 22.1 18.4 25.1 20.3
p value 0.16 0.17 0.046
Subgroup Overall
Herceptin® Combination Pivotal Trial: Efficacy Summary
Herceptin Package Insert 2000.
Slamon et al. N Engl J Med. 2001;344:783.
Herceptin Herceptin + CT CT + CT CT Parameter (n = 180) (n = 180) (n = 55) (n = 54)
Response rate (%) 94 (52) 59 (33) 24 (44) 15 (28) p value < 0.001 < 0.01
Median survival (mo) 26 23 19 14 Risk reduction 0.85 0.64 95% CI 0.66–1.09 0.41–0.99
60 Years 60 Years
Update of Fyfe et al. Proc Am Soc Clin Oncol. 2001;20:48a. Abstract 189.
Herceptin® Combination Pivotal Trial: Results (Age 60 vs 60 y)
• Compared with CT alone, Herceptin + CT significantly improved response rate, regardless of age;
median survival was improved in both age groups, with the greatest improvement in patients
> 60 years old
Herceptin Herceptin
+ CT CT + CT CT
Parameter (n = 97) (n = 87) (n = 98) (n = 106)
Response rate (%) 51 (53) 29 (33) 53 (54) 35 (33)
p value NS NS
Median TTP (mo) 7.4 4.7 7.4 4.5
p value NS NS
Risk reduction, survival 0.90 0.81
(range) (0.65–1.25) (0.56–1.16)
ER+ ER–
Update of Bolton et al. Proc Am Soc Clin Oncol. 2001;20:44a. Abstract 172.
Herceptin® Combination Pivotal Trial: Effect of ER Status
Similar Herceptin benefit was seen in both ER+ and ER– patients
60
50
40
30
20
10
0
% o
f p
ati
en
ts im
pro
ved
p = 0.003
p = 0.07
p = 0.08
p = 0.03
Global Physical Role Fatigue Social Emotional
QOL
p = NS
p = NS
Herceptin + CT CT
Update of Osoba et al. Proc Am Soc Clin Oncol. 2000;19:436a. Abstract 1710.
Herceptin® Combination Pivotal Trial: QOL Improvements (QLQ-C30)
Months
0.2
0
0.4
0.6
0.8
1.0
FISH+
Months
0.2
0
0.4
0.6
0.8
1.0 Herceptin + CT (n = 176)
CT (n = 169)
Pro
ba
bil
ity o
f su
rviv
al
RR = 0.71 p = 0.007
0 10 20 30 40 50
20.0 mo
26.2 mo
FISH–
RR = 1.11 p = NS
0 10 20 30 40 50
19.8 mo
24.0 mo
Herceptin + CT (n = 50)
CT (n = 56)
Herceptin® Combination Pivotal Trial: Overall Survival
Update of Mass et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.
Herceptin® after adjuvant chemotherapy
significantly improves disease-free survival
in HER2-positive early breast cancer
Michael Untch
Ludwig-Maximilians-Universität
München, Germany
on behalf of the HERA Study Team
HERA trial
HER2 and Herceptin
HER2-positive breast cancer is associated with early progression and poor overall prognosis
20-25% of women with breast cancer have HER2-positive disease
Targeting HER2 with Herceptin is associated with significant survival benefits in women with metastatic breast cancer
Early and accurate determination of HER2 status has prognostic and therapeutic importance
IHC
FISH or CISH
FISH or CISH
Herceptin
therapy
Herceptin
therapy
0 1+ 2+ 3+
Patient tumour sample
– +
Herceptin
therapy
– +
Bilous et al 2003
IHC, immunohistochemistry; FISH, fluorescence in situ
hybridisation; CISH, chromogenic in situ hybridisation
Importance of HER2 testing
Surgery + (neo)adjuvant CT ± RT
Stratification
Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region
Randomisation
2 years Herceptin
8 mg/kg 6 mg/kg
3 weekly schedule
1 year Herceptin
8 mg/kg 6 mg/kg
3 weekly schedule
Observation
Women with HER2-positive invasive
early breast cancer (IHC 3+ or FISH+
centrally confirmed)
HERA, HERceptin Adjuvant; CT, chemotherapy; RT, radiotherapy
HERA trial design
Key inclusion criteria
Centrally confirmed HER2 overexpression
(IHC 3+) or amplification (FISH+)
Node-positive or (sentinel) node-negative with >T1c
Completed >4 cycles of approved adjuvant or neoadjuvant CT
Baseline LVEF >55% (Echo or MUGA scan) after completion of (neo)adjuvant CT
and RT
Known hormone receptor status (ER / PgR or
ER alone)
LVEF, left ventricular ejection fraction;
ER, oestrogen receptor; PgR, progesterone receptor
100
80
60
40
20
0
Patients
(%)
Months from randomisation
6 12 18 24
1693 1108 767 445 224
1694 1172 885 532 268
127 127
220 220
1 year Herceptin
Observation
0
No.
at risk
Events HR 95% CI p value
0.54 0.43, 0.67 <0.001
2-year
DFS
85.8
77.4
Disease-free survival
Median follow-up: 1 year HR, hazard ratio; CI, confidence interval
Cardiac safety
Decrease by >10 EF points
and LVEF <50%a,b
Symptomatic CHF, including
severe CHFc
Severe CHFc
Cardiac deathc
Observation
34 (2.21)
1 (0.06)
0
1 (0.06)
1 year Herceptin
113 (7.08)
29 (1.73)
9 (0.54)
0
No. patients (%)
aMany were single observations not confirmed at subsequent time points bObservation, n=1540; Herceptin, n=1595 cObservation, n=1710; Herceptin, n=1677 CHF, congestive heart failure
p value
<0.001
<0.001
0.002
1.00
Conclusions
Herceptin following adjuvant CT significantly prolongs DFS in women with HER2-positive breast cancer
Herceptin significantly reduces the risk of distant metastases
Herceptin was associated with a low incidence of severe CHF (0.5%)
Long-term follow-up will provide
– clarification of the survival gain
– further safety data
– information on optimum Herceptin treatment duration (1 vs 2 years)
NSABP-B31 / NCCTG N9831: interim combined analysis
Edith Perez
Mayo Clinic, Jacksonville, FL, USA
National Cancer Institute sponsored 2 trials
of adjuvant Herceptin
– NSABP-B31
– NCCTG N9831
Control and concurrent treatment groups similar
– compared standard chemotherapy (AC) followed by paclitaxel with
or without concurrent Herceptin therapy
Joint analysis plan was agreed with the FDA
Rationale for combined analysis
NSABP-B31
NCCTG N9831
Arm 1
Arm 2
Arm A Arm B
Arm C
= doxorubicin / cyclophosphamide (AC) 60 / 600 mg/m2 q3w x 4
= paclitaxel (P) 175 mg/m2 q3w x 4
= P 80 mg/m2 qw x 12
= Herceptin (H) 4 mg/kg loading dose 2 mg/kg qw x 51
NSABP-B31 and NCCTG N9831 trial designs
Control
Herceptin
Arm 1 (B31)
Arm A (N9831)
Arm C (N9831)
n=3351
Median follow-up: 2 years
Arm 2 (B31)
Combined analysis
= doxorubicin / cyclophosphamide (AC) 60 / 600 mg/m2 q3w x 4 = paclitaxel (P) 175 mg/m2 q3w x 4 = P 80 mg/m2 qw x 12 = Herceptin (H) 4 mg/kg loading dose 2 mg/kg qw x 51
Years from randomisation
87% 85%
67%
75%
100
90
80
70
60
50
0
1
2
3
4
5
2-year median
follow-up
Patients
(%)
Combined analysis: DFS
HR=0.48; p<0.0001
ACPH
ACP
Events
133
261
n
1672
1679
Romond et al 2005
Subgroup analyses: DFS
HR
0.2 0.4 0.6 0.8 1.0 1.2 1.4
Protocol N9831
Tumour size, cm >4.1
All data
No. positive nodes 10+
<39
Age, years >60
50-59
40-49
Hormone receptor Positive
Negative
<2.0 2.1-4.0
0
4-9
1-3
B31
Romond et al 2005
194 1679
81%
74%
90% 90%
0 1 2 3 4 5
50
60
70
80
90
100
Years from randomisation
Time to 1st distant recurrence
HR=0.47; p<0.0001
Events n 96 1672
Patients
(%)
ACPH ACP
Romond et al 2005
Hazard of distant recurrence
0
20
40
60
80
100
120 Rate
per 1000
women/
year
0
1
2
3
4
Years from randomisation
ACP ACPH
Romond et al 2005
Overall survival
94% 91%
87% 92%
0 1 2 3 4 5 50
60
70
80
90
100
Years from randomisation
HR=0.67; p=0.015
Deaths n
62 92
1672 1679
Patients
(%)
ACPH
ACP
Romond et al 2005
N9831: DFS
87%
86%
68%
78%
0 1 2 3 4 5 50
60
70
80
90
100
Years from randomisation
HR=0.55; 2p=0.0005
Events n
51 90
808 807
Patients
(%)
ACPH
ACP
Romond et al 2005
Combined analysis: summary of efficacy end points
DFS
Time to distant
recurrence
Overall survival
No. events
H vs obs
HR
(95% CI)
133 vs 261 0.48
(0.39-0.59)
96 vs 193 0.47
(0.37-0.61)
0.67
(0.48-0.93)
62 vs 92
0.0
0.5
1.0
1.5
HR
Median follow-up: 2 years Romond et al 2005
LVEF evaluation schedule
MUGA (B31 and N9831) or echo scan (N9831)
Post-AC LVEF >LLN or decrease <16 points from baseline to initiate
Herceptin
0 months
3 months
(post-AC)
6 months
(post-P or -PH)
9 months
18 months
MUGA, multiple-gated acquisition; LLN, lower limit of normal
N9831: 3-year cumulative
incidence of cardiac events
39 cardiac events were reported in 3 treatment arms over 3 years
– 2 cardiac deaths, 37 CHFs
Cumulative incidence, %
Time since
registration, years
Arm A
ACP
(n=670)
0.0
0.0
0.0
0.3
Arm B
ACPH
(n=718)
0.8
1.4
2.5
2.5
Arm C
ACPH
(n=579)
2.6
3.5
3.5
3.5
0.5
1
2
3
Perez et al 2005
N9831: radiotherapy does not increase the
incidence of cardiac events
Cumulative incidence, %
Radiotherapy
Yes
No
Arm B
ACPH
1 year
1.6
0.6
2 years
2.2
2.8
Arm C ACPH
1 year
2.3
4.6
2 years
2.3
4.6
n
508
160
n
399
131
Perez et al 2005
Summary
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 risk of cardiac events was low
– <4% incidence, Herceptin vs non-Herceptin in both trials
– risk of cardiac events may increase with age
Conclusions
Adjuvant Herceptin is recommended for patients with HER2-
positive early breast cancer
– unless a specific contraindication exists
– can be administered concomitantly with radiotherapy
Careful monitoring of cardiac function is essential with adjuvant
Herceptin therapy
BCIRG 006
John Crown
St Vincent’s Hospital,
Dublin, Ireland
Trial design
6 x D and Carbo
1 year Herceptin
ACD
ACDH
DCarboH
1 year Herceptin
HER2 positive (FISH positive)
Node positive or
high-risk node negative
n=3222
Stratified by nodes
and hormonal receptor status
AC, doxorubicin + cyclophosphamide; D, docetaxel; Carbo, carboplatin
4 x AC 4 x D
4 x AC 4 x D
DFS Patients
(%)
Years
100
90
80
70
0
1
2
3
4
5
93%
86% 84%
80% 80%
91%
86%
77% 73%
n
1074
1075
1073
Events
77
98
147
ACDH
DCarboH
ACD
60
50
HR=0.49
HR=0.61
Slamon et al 2005
0
10
20
30
40
50
60
70
80
Grade 3/4 haematological toxicity
Patients
(%)
ACD (n=1050)
ACDH (n=1068)
DCarboH (n=1056)
Slamon et al 2005
Grade 3/4 non-haematological toxicity
0
5
10
15
20
25
30Patients
(%)
ACD (n=1050)
ACDH (n=1068)
DCarboH (n=1056)
Slamon et al 2005
Cardiovascular risk factors ACD
(n=1073)
49
23-74
38
54
20
27
16
638
335
ACDH
(n=1074)
49
22-74
34
45
10
36
16
625
307
DCarboH
(n=1075)
49
23-73
30
43
12
37
17
647
323
Age, years
median
range
Risk factors, no. patients
diabetes
hypercholesterolaemia
hyperlipidaemia
obesity
hypertension
Radiotherapy, no. patients
after chemotherapy
to left chest
Slamon et al 2005
Clinically significant cardiac events
statistical analysis
p=0.016
ACD
(n=1050)
10
0.95
0.46-1.74
ACDH
(n=1068)
25
2.34
1.52-3.44
DCarboH
(n=1056)
14
1.33
0.73-2.21
Patients
%
95% CI
p=0.11
p=0.54
Slamon et al 2005
Clinically significant cardiac events as per
independent review panel
Cardiac death, n
Grade 3/4 cardiac
ischaemia / infarction, n
Grade 3/4 arrhythmia, n
Grade 3/4 CHF, n
ACD
(n=1050)
0
0
7*
3
ACDH
(n=1068)
0
4
4*
17
DCarboH
(n=1056)
0
1
9*
4
*5 / 20 arrhythmias not yet adjudicated by independent
review panel (2 in ACD, 1 in ACDH, 2 in DCarboH) Slamon et al 2005
Mean LVEF: all observations LVEF
66
65
63
62
60
59
0
100
300
400
600
800
Days
200
500
700
64
61
205 pts
290 pts
189 pts
DCarboH
ACD
ACDH
(n=1029)
(n=1012)
(n=1040)
Slamon et al 2005
HER2
core region
17 q 12 17 q 21.1 17 q 21.2
n=2120
1285 pts
(60%)
91 pts
(4%)
Topo II
non-co-
amplified
Topo II
region
744 pts
(35%) Co-amplified
Normal Amplified Deletion
HER2 and topo II in BCIRG 006: 2120 / 3222 patients analysed
Topo II, topoisomerase II
DFS topo II co-amplified vs non-co-amplified: all patients
Patients
(%) 100
90
80
70
60
50
0
1
2
3
4
5
Years
Patients
744
1376
Events
57
191
Topo II
Co-amplified
Non-co-amplified p<0.001
Slamon et al 2005
DFS co-amplified topo II 100
90
80
70
60
50
0
6
24
36
42
54
Months
Patients
265
227
252
Events
13
23
98
ACDH
ACD
DCarboH
12
18
32
48
p=0.24
Patients
(%)
Slamon et al 2005
DFS non-co-amplified topo II 100
90
80
70
60
50
0
6
24
36
42
54
Months
Patients
472
446
458
Events
45
54
92
ACDH
DCarboH
ACD
12
18
32
48
p<0.001
Patients
(%)
Slamon et al 2005
Conclusions
BCIRG 006 has confirmed the benefit of Herceptin in early breast cancer
With a favourable overall safety profile, the
risk : benefit ratio warrants the use of Herceptin
in early breast cancer
Preliminary data on topo IIα status suggest that
not all patients benefit equally from anthracyclines
Cardiac safety improves with DCarboH
Further follow-up is required to determine whether efficacy differs
between ACDH and DCarboH
Neoadjuvant therapy with paclitaxel followed by FEC chemotherapy with
trastuzumab in HER-2 positive operable breast cancer
PI. Aman Buzdar, MD
Who benefits from a particular adjuvant chemotherapy?
Mo n th s
Cu
mu
lati
ve
pro
po
rtio
n s
urv
ivin
g d
ise
as
e-f
ree
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 10 20 30 40 50 60 70 80 90 100 110
p C R
< p C R
P = 0.0005
Kuerer H et al. J Clin Oncol 1999
Those who have a complete eradication of their breast cancer
(pCR) by preoperative chemotherapy benefit !
Phase II Trials of Trastuzumab Neoadjuvant Therapy for
Breast Cancer
*42% of patients had <5 mm residual tumors.
Mohsin et al. J Clin Oncol. 2005;23:epub ahead of print; Gennari et al. Clin Cancer Res. 2004;10:5650;
Burstein et al. J Clin Oncol. 2003;21:46; Bines et al. Breast Cancer Res Treat. 2003:82:S56. Abstract 243;
Harris et al. Proc Am Soc Clin Oncol. 2003;22:22. Abstract 86; Limentani et al. Breast Cancer Res Treat.
2003;83:S58. Abstract 251.
Percent
Study (N) Regimen ORR cCR pCR
Mohsin 2005 T qw × 3, T + D qw × 12
Gennari 2004 (11) T qw × 4 36 0 9
Burstein 2003 (40) T qw × 12 + P qw × 4 75 30 18
Bines 2003 (33) T qw × 12 + D q3w × 4 70 24 12
Harris 2003 (42) T qw × 12 + V qw × 12 88 38 19
Limentani 2003 (45) T qw × 12 + DV q2w × 6 100 59 31*
*Paclitaxel 225 mg/m2 q3w.
FEC = 5-fluorouracil 500 mg/m2 d1, 4 + epirubicin 75 mg/m2 d1 +
cyclophosphamide 500 mg/m2 d1, all q3w.
T = trastuzumab 4 mg/kg d1, then 2 mg/kg qwx24 weeks
Buzdar et al. J Clin Oncol. 2005;23:3676-85
Phase III Trial of Neoadjuvant Trastuzumab +
Chemotherapy for Operable Breast Cancer
ARM 1
Paclitaxel 4 +
T 12
ARM 2
Paclitaxel 4
FEC 4 +
T 12
FEC 4
Local and
adjuvant
therapy
R
HER2+
(IHC 3+/FISH+)
N=42*
Additional 22
patients
N=19
N=23
Current Clinical Practices for Herceptin® Patient Selection
Significant false-positive with HercepTest™ suggests in some
cases retesting with FISH may be warranted
High
overexpressors
3+ 2+ 0/1+
IHC FISH
Amplified Nonamplified
Treat with
Herceptin Other
therapies
HER2 results
inconsistent
with clinical
profile
Possible benefit
Sco
re
In current clinical practice, either IHC or FISH is used
for primary testing
Guidelines on HER2 Testing
NCCN Clinical Practice Guideline (2004):
– Recommends HER2 testing for all invasive breast cancer
cases, using IHC and/or FISH
– FISH retesting of IHC 2+ recommended
ASCO Practice Guideline for Tumor Markers (2000):
– HER2 overexpression should be evaluated on every
primary breast cancer either at the time of diagnosis or at
the time of recurrence. Measures of HER2 amplification
may also be of value.
www.nccn.org
www.asco.org
Guidelines on HER2 Testing (cont.)
College of American Pathologists consensus statement (2003):
– Laboratories should calculate their FISH/IHC concordance
rates
– If FISH-neg/IHC 0 and FISH-pos/IHC 3+ concordance is
>95%:
OK to use IHC as screening test
All IHC 1+ and 2+ should be retested by FISH
– If FISH-neg/IHC 1+ concordance is also >95%, OK to not
retest IHC 1+ with FISH, but should document in a path
report comment
– If do not wish to check concordance, or concordance
<95%, consider performing both IHC and FISH on all
samples
Zarbo & Hammond, Arch Pathol Lab Med, 2003
Thank You