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New Monoclonal Antibody Approved
for Advanced Breast Cancer
Shin-ichi Nihira, Ph.D.
Dept. Clinical Research 3
Chugai Pharmaceutical Co., Ltd.
10/03/2002
Kitasato-Harvard
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Tailor-Made Drug Therapy for Cancer
Identification of
genetic abnormality and molecular mechanism
responsible for generation and exacerbation of cancer
Selection of particular patient population, in which
higher efficacy and safety of the drug therapy is expected.
ex.) Anti-HER2 humanized monoclonal antibody;
Trastuzumab (Herceptin®)
10/03/2002
Kitasato-Harvard
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Trastuzumab (Herceptin®) :
Humanized Anti-HER2 Antibody
Trastuzumab is a humanized monoclonal antibody that binds to the
extracellular domain of the human epidermal growth factor 2 gene (HER2)
• Targets HER2 oncoprotein
• High affinity (Kd = 0.1 nM) and
specificity
• 95% human, 5% murine
- Decrease potential for
immunogenicity
- Increase potential for
recruiting immune-effector
mechanisms
- ADCC
- CDC
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Kitasato-Harvard
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Trastuzumab Therapy
Survival benefit for HER2 overexpressing
metastatic breast cancer (MBC) patients

Offering the alternative option to therapeutic algorithms for MBC
• Hormone therapy
• Chemotherapy
• Antibody therapy

Molecular target drug for HER2 based on genetic abnormality

“Tailor-Made” cancer therapy for solid tumors
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Kitasato-Harvard
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HER2 Overexpression
A Key Strategy for Clinical Development of Trastuzumab

Patient population for Trastuzumab was focused on MBC
patients diagnosed as HER2 amplification/overexpression
in the clinical development (Phase I - III).
 HER2
detection assay had been developed prior to the clinical
studies.
• Clinical Trial Assay (CTA) by Genentech
 Development
of HercepTest® by DAKO
• Know-how and expertise of CTA transferred to DAKO by GNE
 FISH
test
• Confirmation of the concordance have been done by GNE using clinical
trials samples, retrospectively.
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Kitasato-Harvard
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HER2 Receptor Provides an Extracellular
Therapeutic Target
Binding site
Plasma
membrane
Tyrosine
kinase activity
Signal
transduction
to nucleus
Cytoplasm
Nucleus
Gene activation
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Kitasato-Harvard
CELL
DIVISION
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HER2 Overexpression
Amplification / Overexpression
Normal
3
Cytoplasm
C
2
B
A
Nucleus
1
4
Cytoplasmic
membrane
A = HER2 DNA
B = HER2 mRNA
C = HER2 receptor protein
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1=
2=
3=
4=
Kitasato-Harvard
gene copy number
mRNA transcription
cell surface receptor protein expression
release of receptor extracellular domain
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HER2 in Breast Cancer
HER2 oncogene
amplification
Women whose breast cancers are
HER2 positive have a shorter
overall survival
HER2 overexpressing 3 years
HER2 normal
6–7 years
HER2 oncoprotein
overexpression
Slamon et al. 1987
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Kitasato-Harvard
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Methods of Assessing HER2 Status

Gene amplification
 Fluorescence
in-situ hybridisation (FISH)
 Southern hybridisation
 Polymerase chain reaction (PCR)
 in-situ hybridisation (ISH; non-fluorescence)

Protein overexpression
 Immunohistochemistry
(IHC)
 Western
blot
 ELISA (serum) for circulating protein
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Kitasato-Harvard
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Detection of Gene Amplification by FISH
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Kitasato-Harvard
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HER2 Status in IHC & FISH
Normal 0
Normal
Normal 1+
Normal
Abnormal 2+
Abnormal low
amplification
Abnormal 3+
Abnormal high
amplification
IHC Images courtesy of MJ Kornstein, MD, Medical College of Virginia
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Kitasato-Harvard
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The New Biology Comes of Age
Diagnosis of Breast Cancer
Tumour genotype
HER2/neu gene amplification
Tumour phenotype
Selection of therapy
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Kitasato-Harvard
Aggressive
Trastuzumab
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Pivotal Trastuzumab Combination
Multinational Study
D.J Slamon, et al. N Engl J Med 2001; 344: 783-792
Eligible patients (n=469)
No prior anthracyclines
Trastuzumab + AC
AC
(n=143)
(n=138)
10/03/2002





Metastatic breast cancer
HER2 overexpression (HER2 2+&3+)
No prior CT for MBC
Measurable disease
KPS 60%
Prior anthracyclines
Trastuzumab + paclitaxel
(n=92)
Paclitaxel
(n=96)
AC = doxorubicin/epirubicin + cyclophosphamide,
CT = chemotherapy, MBC = metastatic breast cancer
Kitasato-Harvard
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Increasing Efficacy by Level of HER2 Overexpression
- Overall Survival HER2 3+
1.0
Probability of survival
Probability of survival
1.0
0.8
0.6
0.4
0.2
20
0.0
0
10
Trastuzumab + CT
CT alone
0.8
p<0.05
0.6
0.4
0.2
29
20
30
Time (months)
HER2 2+ & 3+
20
0.0
40
50
0
10
25
20
30
40
Time (months)
50
Mass R et al. Proc ASCO 2000;19:Abstract 291
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Kitasato-Harvard
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Increasing Efficacy by Level of HER2 Overexpression
-- all patients (HER2 2+&3+) and HER2 3+ patients -All (HER2 2+&3+): n=469,
H + AC
(n=143)
HER2 3+ : n=349
AC
H+P
(n=138) (n=92)
P
(n=96)
H + CT
(n=235)
CT
(n=234)
Median TTP (months) All
3+
7.8*
8.1*
6.1
6.0
6.9*
7.1*
2.7
3.0
7.4*
7.8*
4.6
4.6
RR (%)
56
60
42
42
41
49
17
17
50
56
32
31
Median DR (months)
9.1
9.3
6.7
5.9
10.5
10.9
4.5
4.6
9.1
10.0
6.1
5.6
Median TTF (months)
7.0*
7.1
5.6
5.1
5.3*
6.7
2.7
2.8
6.6*
7.0
4.5
4.4
Survival (months)
27
31*
21
21
22
25
18
18
25*
29*
20
20
*p<0.05
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Kitasato-Harvard
< Cut-off October 1999 >
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Trastuzumab Efficacy by Level
of HER2 Overexpression
Response Rate (CR+PR)
Percentage responding
(%)
60
IHC
50
2+
3+
40
30
20
10
0
H
Salvage
H
1st line
H+P
H+AC
H0649g H0650g
Monotherapy
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P
AC
H0648g
Combination Therapy
Kitasato-Harvard
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HER2 Testing Algorithm Being Applied for
Breast Cancer Clinical Practice in US
Patient tumour
sample
IHC
–
FISH
2+
3+
+
Retest with
FISH
Trastuzumab
therapy
Trastuzumab
therapy
–
+
Trastuzumab
therapy
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Kitasato-Harvard
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Conclusions

Trastuzumab is a HER2 specific humanised monoclonal antibody,
providing survival benefit for metastatic breast cancer patients with
HER2/neu gene amplification/HER2 overexpression.

Patient population for Trastuzumab should be selected based on
diagnosis of HER2 status, where the efficacy of trastuzumab
correlated with the level of HER2 status.

Development of standardised diagnostic methods for HER2 status
was indispensable for the clinical development of Trastuzumab.

HER2 diagnosis algorithm needs to be implemented in the clinical
practice for breast cancer patients.
10/03/2002
Kitasato-Harvard
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