New Technologies and New Technologies and ChallengesChallenges

Targeted Therapies in Targeted Therapies in CancerCancer

Ian Olver Ian Olver MD PhDMD PhDCEO The Cancer Council CEO The Cancer Council AustraliaAustralia

Changing of the GuardChanging of the Guard

There is a paradigm shift in the There is a paradigm shift in the treatment of cancertreatment of cancer

Conventional cytotoxic drugs interact Conventional cytotoxic drugs interact with DNA to prevent cell replication with DNA to prevent cell replication but are not specific to cancer cellsbut are not specific to cancer cells

We are moving to targeted therapies We are moving to targeted therapies which specifically target cancer cells which specifically target cancer cells as evidenced by the many as evidenced by the many presentations at this meetingpresentations at this meeting

Side EffectsSide Effects of of ChemotherapyChemotherapy

Immediate Early Delayed Immediate Early Delayed LateLate

(hours - days) (days - weeks) (weeks- months) (hours - days) (days - weeks) (weeks- months) (months - yrs)(months - yrs)

Extravasation Extravasation Myelosuppression Myelosuppression Cardiotoxicity Cardiotoxicity Second CancerSecond Cancer

EmesisEmesis Mucositis Lung fibrosis Mucositis Lung fibrosis EncephalopathyEncephalopathy

HypersensitivityHypersensitivity Alopecia Alopecia P. Neuropathy SterilityP. Neuropathy SterilityTumour lysisTumour lysis Cystitis Cystitis Hepatotoxicity Hepatotoxicity

TeratogenicityTeratogenicity NephrotoxicityNephrotoxicity

Targeted therapiesTargeted therapies

With targeted therapy the specific With targeted therapy the specific mechanism of action of the drug results in mechanism of action of the drug results in an increase in its therapeutic indexan increase in its therapeutic index

However, the advantages of the specificity However, the advantages of the specificity and safety of the are offset by the smaller and safety of the are offset by the smaller number of susceptible tumour typesnumber of susceptible tumour types

Increasing numbers of these innovative Increasing numbers of these innovative and expensive anti-cancer drugs may and expensive anti-cancer drugs may exceed the capacity of the public purse to exceed the capacity of the public purse to pay for thempay for them

The Need to Identify The Need to Identify the Targetthe Target

Appropriate use of newly approved Appropriate use of newly approved and expensive targeted therapies for and expensive targeted therapies for cancer first depends on the cancer first depends on the pathologist identifying the target for pathologist identifying the target for treatment in the tumour sampletreatment in the tumour sample

Currently the two major classes of Currently the two major classes of targeted therapy are the small targeted therapy are the small molecule tyrosine kinase inhibitors molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (TKIs) and monoclonal antibodies (mAbs)(mAbs)

Potential mechanisms Potential mechanisms of Glivec of Glivec

Glivec may inhibit tyrosine kinases in Glivec may inhibit tyrosine kinases in many tumours, but this will be many tumours, but this will be effective therapy only where tumour effective therapy only where tumour stem cells depend on these enzymes stem cells depend on these enzymes for survival, growth or metastasisfor survival, growth or metastasis

Tyrosine kinases are part of the Tyrosine kinases are part of the signalling pathways of cells which tell signalling pathways of cells which tell them to growthem to grow

PET Before and after PET Before and after Glivec for GISTGlivec for GIST

7/12/007/12/00 9/1/019/1/01

STI 571 (Glivec)STI 571 (Glivec)

Specific inhibitor for BCR-ABL, PDGF Specific inhibitor for BCR-ABL, PDGF receptor and c-kit tyrosine kinases receptor and c-kit tyrosine kinases produced by these genes produced by these genes which are which are responsible for growthresponsible for growth in CML and GIST in CML and GIST

Effective in chronic myeloid leukaemiaEffective in chronic myeloid leukaemia Effective in GIST Gastrointestinal stroma Effective in GIST Gastrointestinal stroma

tumours which over express c-kittumours which over express c-kit Side effectsSide effects

– Nausea, myalgia oedema, diarrhoea, Nausea, myalgia oedema, diarrhoea, myelosuppression, LFT’s early “storm”myelosuppression, LFT’s early “storm”

Monoclonal AntibodiesMonoclonal Antibodies

Action of the mAbs, rituximab Action of the mAbs, rituximab (Mabthera®) for NHL and (Mabthera®) for NHL and trastuzumab (Herceptin®) for trastuzumab (Herceptin®) for breast cancer depend on the breast cancer depend on the targets CD20 expression and targets CD20 expression and erbB2 erbB2 gene being amplified gene being amplified and and responsible for growthresponsible for growth

RituximabRituximab

MabtheraMabthera

Mabthera is an Anti-CD20 Mabthera is an Anti-CD20 monoclonal antibody for monoclonal antibody for lymphomalymphoma

CD20 is a protein on the CD20 is a protein on the surface of malignant surface of malignant lymphoma cellslymphoma cells

CD20 expressed on 90% of B-CD20 expressed on 90% of B-cells in lymphomacells in lymphoma

MabtheraMabthera

Side effects include:Side effects include:– Infusion related fever, chills rigorsInfusion related fever, chills rigors– N + V, urticaria, pruritis, headache, N + V, urticaria, pruritis, headache,

fatigue, bronchospasm, fatigue, bronchospasm, hypersensitivityhypersensitivity

– Rare heart rhythm disturbanceRare heart rhythm disturbance– Low blood counts for up to 30 daysLow blood counts for up to 30 days

HER2 HER2

HER2 gene (neu, c-erb-2) ecodes a HER2 gene (neu, c-erb-2) ecodes a transmembrane gycoprotein receptortransmembrane gycoprotein receptor

HER 2 is over expressed by 1/4 HER 2 is over expressed by 1/4 human breast cancer and correlates human breast cancer and correlates with poorer outcome with poorer outcome

MoAb against the receptor inhibits MoAb against the receptor inhibits the growth of overexpressing cellsthe growth of overexpressing cells

HER 2HER 2

As a single agent 15% chance of As a single agent 15% chance of shrinking metastatic breast cancer, shrinking metastatic breast cancer, 4% chance of a complete shrinkage 4% chance of a complete shrinkage in heavily pretreated patientsin heavily pretreated patients

Duration of response can be 9 Duration of response can be 9 months which is at least as good as months which is at least as good as single chemotherapy agentssingle chemotherapy agents

Can combine with chemotherapyCan combine with chemotherapy

Disease-Free SurvivalDisease-Free SurvivalRomond H et al.Romond H et al. Trastuzumab plus Adjuvant Chemotherapy Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer NEJM 2005; for Operable HER2-Positive Breast Cancer NEJM 2005; 353:1673-1684353:1673-1684

87%87%85%85%

67%67%

75%75%

NN EventsEventsACACTT 16791679 261261ACACTHTH 16721672 134134

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HR=0.48, 2P=3x10-12

ACACTHTH

ACACTT

Years From RandomizationB31/N9831

The Paradigm ShiftThe Paradigm Shift

The use of these drugs is giving The use of these drugs is giving clinicians a glimmer of the clinicians a glimmer of the paradigm shift that will occur in paradigm shift that will occur in the treatment of cancerthe treatment of cancer

One or several new targeted One or several new targeted therapies offer the prospect of therapies offer the prospect of cancer being treated as a chronic cancer being treated as a chronic disease.disease.

Brain TumoursBrain Tumours

The optimal use of temozolomide The optimal use of temozolomide chemotherapy for the treatment of chemotherapy for the treatment of primary brain tumours may depend primary brain tumours may depend on knowing the DNA repair enzyme on knowing the DNA repair enzyme status of the tumourstatus of the tumour

Hegi ME et al. MGMT gene silencing and benefit from Hegi ME et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. New Engl J Med 2005; temozolomide in glioblastoma. New Engl J Med 2005; 352:997-1003352:997-1003

Dramatic response in Dramatic response in female, non-smoking female, non-smoking patient with Broncho-patient with Broncho-Alveolar CarcinomaAlveolar Carcinoma

Courtesy Dr T. Lynch, MGH

Patient demographic factors Patient demographic factors associated with outcome in associated with outcome in Gefitinib Phase II studiesGefitinib Phase II studies

GenderGender – Females ORR 25% (CI 19-33%)Females ORR 25% (CI 19-33%)– Males ORR 8% (CI 5-12%)Males ORR 8% (CI 5-12%)

EthnicityEthnicity – Japanese ORR 27% (CI 19-37%)Japanese ORR 27% (CI 19-37%)– Caucasian ORR 11% (CI 6-19%)Caucasian ORR 11% (CI 6-19%)

Smoking historySmoking history – Non-smokers ORR 31% (CI 23-40%)Non-smokers ORR 31% (CI 23-40%)– Smokers ORR 8% (CI 5-12%)Smokers ORR 8% (CI 5-12%)

Patient demographic factors Patient demographic factors associated with outcome in associated with outcome in Gefitinib Phase II studiesGefitinib Phase II studies

HistologyHistology– Adenocarcinoma Adenocarcinoma n=275 ORR 19% n=275 ORR 19% – SquamousSquamous n=75n=75 ORR 7% ORR 7% – UndifferentiatedUndifferentiated n=35n=35 ORR 3% ORR 3%– MixedMixed n=26n=26 ORR 4% ORR 4%– Large cellLarge cell n=11n=11 ORR 9% ORR 9%– UnrecordedUnrecorded n=3n=3 ORR 0% ORR 0%

EGFR Mutations and EGFR Mutations and ResponseResponse Lynch TJ et al New Engl J Med 350, May 20 2004 Lynch TJ et al New Engl J Med 350, May 20 2004

Hypothesis was that a mutation of Hypothesis was that a mutation of EGFR EGFR accounts for the response of accounts for the response of some patients with NSCLC to gefitinibsome patients with NSCLC to gefitinib

They sequenced the entire coding They sequenced the entire coding region of region of EGFR EGFR in tumors from patients in tumors from patients with a response to gefitinib and in with a response to gefitinib and in tumors from those without a responsetumors from those without a response

Use of Molecular Use of Molecular MethodsMethods

Increase diagnostic accuracy and thereby Increase diagnostic accuracy and thereby improve prognosticationimprove prognostication

Identify clinically distinct patient subsets to Identify clinically distinct patient subsets to facilitate rational clinical trial designfacilitate rational clinical trial design

Help to optimize current treatments by Help to optimize current treatments by increasing their specificity and improving increasing their specificity and improving their safetytheir safety

Identify signaling pathways that define cancer Identify signaling pathways that define cancer vulnerabilities and thus create drug targetsvulnerabilities and thus create drug targetsBrown M, Buckley M, Rudzki B, Olver I. How can we turn cancer Brown M, Buckley M, Rudzki B, Olver I. How can we turn cancer into a chronic disease that we can afford to treat? J Intern Med into a chronic disease that we can afford to treat? J Intern Med 2006 in press2006 in press

Practical Uses of Practical Uses of Molecular Pathology and Molecular Pathology and TargetingTargeting The decision to treat metastatic breast The decision to treat metastatic breast

cancer depends on the state of the diseasecancer depends on the state of the disease The need for additional treatment after The need for additional treatment after

surgery relies on predicting its behavior, surgery relies on predicting its behavior, which still relies on anatomic stagingwhich still relies on anatomic staging– Tumor sizeTumor size– Nodal statusNodal status

These are prognostic but not predictive of These are prognostic but not predictive of treatment outcometreatment outcome

However hormone status and HER2 status However hormone status and HER2 status have been shown to be both prognostic and have been shown to be both prognostic and predictive and we have had targeted predictive and we have had targeted hormonal therapy for decadeshormonal therapy for decades

Molecular Molecular ClassificationClassification With technology that can rapidly With technology that can rapidly

measure multiple gene expression measure multiple gene expression profiles it has been found that: profiles it has been found that: – They correlate with microscopic observed They correlate with microscopic observed

difference e.g. one pattern of genes difference e.g. one pattern of genes correlates with grade correlates with grade (Perou CM et al (Perou CM et al Nature, 2000, 406: letter 749-52, 2000)Nature, 2000, 406: letter 749-52, 2000)

– They differ across tumors defined by They differ across tumors defined by hormone and HER2 statushormone and HER2 status

– Breast Cancer can be subtyped Breast Cancer can be subtyped

Sorlie T et al Proc Natl Acad Sci U S A. 2001, 98:10869–10874.

85 samples gene expression patterns analyzed by hierarchical clustering. Green is normal breast, red is the basal poor prognosis group

Can use to predict prognosis and outcome of therapy and can target the therapy

ConclusionsConclusions

Targeted therapies which improveTargeted therapies which improve

the therapeutic index are the futurethe therapeutic index are the future

of anti-cancer therapyof anti-cancer therapy Advances in molecular pathology will Advances in molecular pathology will

provide the means to identify the provide the means to identify the targets and will be used to subtype targets and will be used to subtype tumours and will provide predict tumours and will provide predict response to therapy and provide response to therapy and provide prognostic informationprognostic information