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Transcript of 1Kitasato-Harvard Symposium 10/03/2002 New Monoclonal Antibody Approved for Advanced Breast Cancer...
1 Kitasato-Harvard Symposium
10/03/2002
New Monoclonal Antibody Approved
for Advanced Breast Cancer
Shin-ichi Nihira, Ph.D.
Dept. Clinical Research 3 Chugai Pharmaceutical Co., Ltd.
2 Kitasato-Harvard Symposium
10/03/2002
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 whichhigher efficacy and safety of the drug therapy is expected.
ex.) Anti-HER2 humanized monoclonal antibody; Trastuzumab (Herceptin®)
3 Kitasato-Harvard Symposium
10/03/2002
Trastuzumab (Herceptin®) : Humanized Anti-HER2 Antibody
• 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
Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor 2 gene (HER2)
4 Kitasato-Harvard Symposium
10/03/2002
Trastuzumab Therapy
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
Survival benefit for HER2 overexpressing metastatic breast cancer (MBC) patients
5 Kitasato-Harvard Symposium
10/03/2002
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.
6 Kitasato-Harvard Symposium
10/03/2002
HER2 Receptor Provides an Extracellular Therapeutic Target
Signaltransductionto nucleus
Nucleus
Binding site
Tyrosinekinase activity
Cytoplasm
Plasmamembrane
Gene activationCELL
DIVISION
7 Kitasato-Harvard Symposium
10/03/2002
HER2 Overexpression
1 = gene copy number2 = mRNA transcription3 = cell surface receptor protein expression4 = release of receptor extracellular domain
A = HER2 DNAB = HER2 mRNAC = HER2 receptor protein
Normal Amplification / Overexpression
Nucleus
Cytoplasm
Cytoplasmicmembrane
1
2
3
4
C
B
A
8 Kitasato-Harvard Symposium
10/03/2002
HER2 in Breast Cancer
Slamon et al. 1987
HER2 oncoprotein overexpression
HER2 oncogeneamplification
HER2 overexpressing 3 yearsHER2 normal 6–7 years
Women whose breast cancers are HER2 positive have a shorter
overall survival
9 Kitasato-Harvard Symposium
10/03/2002
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
11 Kitasato-Harvard Symposium
10/03/2002
HER2 Status in IHC & FISH
IHC Images courtesy of MJ Kornstein, MD, Medical College of Virginia
Abnormal 2+ Abnormal 3+Normal 0 Normal 1+
Normal Normal Abnormal lowamplification
Abnormal highamplification
12 Kitasato-Harvard Symposium
10/03/2002
The New Biology Comes of Age
Diagnosis of Breast Cancer
Tumour genotype HER2/neu gene amplification
Tumour phenotype Aggressive
Selection of therapy Trastuzumab
13 Kitasato-Harvard Symposium
10/03/2002
Pivotal Trastuzumab Combination Multinational Study
No prior anthracyclines Prior anthracyclines
Paclitaxel(n=96)
Trastuzumab + paclitaxel(n=92)
AC(n=138)
Trastuzumab + AC(n=143)
Metastatic breast cancer HER2 overexpression (HER2 2+&3+) No prior CT for MBC Measurable disease KPS 60%
Eligible patients (n=469)
AC = doxorubicin/epirubicin + cyclophosphamide, CT = chemotherapy, MBC = metastatic breast cancer
AC = doxorubicin/epirubicin + cyclophosphamide, CT = chemotherapy, MBC = metastatic breast cancer
D.J Slamon, et al. N Engl J Med 2001; 344: 783-792
14 Kitasato-Harvard Symposium
10/03/2002
Increasing Efficacy by Level of HER2 Overexpression
Trastuzumab + CT
CT alonep<0.05
1.0
0.8
0.6
0.4
0.2
0.020 29
Time (months)
Pro
bab
ilit
y o
f su
rviv
al
Mass R et al. Proc ASCO 2000;19:Abstract 291
0 10 20 30 40 50
1.0
0.8
0.6
0.4
0.2
0.0P
rob
abil
ity
of
surv
ival
20 25
0 10 20 30 40 50 Time (months)
HER2 3+ HER2 2+ & 3+
- Overall Survival -
15 Kitasato-Harvard Symposium
10/03/2002
-- all patients (HER2 2+&3+) and HER2 3+ patients --
H + AC(n=143)
AC(n=138)
H + P(n=92)
P(n=96)
H + CT(n=235)
CT(n=234)
Median TTP (months) All3+
7.8* 8.1*
6.16.0
6.9*7.1*
2.73.0
7.4* 7.8*
4.64.6
RR (%) 5660
4242
4149
1717
5056
3231
Median DR (months) 9.1 9.3
6.75.9
10.5 10.9
4.54.6
9.1 10.0
6.15.6
Median TTF (months) 7.0* 7.1
5.65.1
5.3* 6.7
2.72.8
6.6* 7.0
4.54.4
Survival (months) 27 31*
2121
2225
1818
25*29*
2020
*p<0.05 < Cut-off October 1999 >
All (HER2 2+&3+): n=469, HER2 3+ : n=349
Increasing Efficacy by Level of HER2 Overexpression
16 Kitasato-Harvard Symposium
10/03/2002
Trastuzumab Efficacy by Levelof HER2 Overexpression
0
10
20
30
40
50
60 2+
3+
Pe
rce
nta
ge
res
po
nd
ing
(%
)
H H H+P H+AC P ACSalvage 1st line
IHC
Response Rate (CR+PR)
Combination Therapy
H0649g H0650g
Monotherapy
H0648g
17 Kitasato-Harvard Symposium
10/03/2002
HER2 Testing Algorithm Being Applied for Breast Cancer Clinical Practice in US
Patient tumour sample
IHC FISH
2+ 3+ + –
Retest withFISH
Trastuzumabtherapy
Trastuzumab therapy
– +
Trastuzumab therapy
18 Kitasato-Harvard Symposium
10/03/2002
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.