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

10 Kitasato-Harvard Symposium

10/03/2002

Detection of Gene Amplification by FISH

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.