Oncology: Approaches to Personalized Therapy

Moscow, 13 May 2011

What is “Precision” or “Personalized” Medicine?

Medicines targeting patient segments that will

have an optimal response to therapy

Building disease understanding to identify the right

pathways and targets

Linking disease understanding

and clinical outcomes

Precision MedicinePrecision Medicine

Segmented, not personalized(5-20%+ patient subgroups,

not individuals)

Segmented, not personalized(5-20%+ patient subgroups,

not individuals)

2

Right TargetRight Target

Genetic validation; Rare phenotypes

What are we trying to accomplish?

Right Drug(or Combinations)

Right Drug(or Combinations)

Selective design and delivery; Combinations for complex diseases

Right PatientRight Patient

Phenotyping and Genotyping

3

HER2+ Luminal BBasal Luminal A

Deletion of p16 and amplification of Cyclin D with wild type retinoblastoma (Rb) predict for sensitivity to CDK4/6 inhibitor

Novel CDK4/6 inhibitor PD 0332991: Proof of Concepts to be performed in Luminal B breast cancer and Multiform Glioblastoma (GBM)

12%

ALLBREASTCANCER

6.3% 36.5%12%14.4%

Precision Medicine today: Oncology is pursuinga novel approach in breast cancer targeting Cyclin D Kinase 4/6 (CDK4/6)

CDK4/6 Program Highlights Opportunity forPatient Segmentation in Breast Cancer

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Finn et al; Breast Cancer Research 11(5); 2009

Right TargetRight Target

Genetic validation; Rare phenotypes

What are we trying to accomplish?

Right Drug and Combinations

Right Drug and Combinations

Selective design and delivery; Combinations for complex diseases

Right PatientRight Patient

Phenotyping and Genotyping

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LINKER Calicheamicin

CMC-544

Internalized

Linker

Hydrolized

Calicheamicin

Released

Intracellularly

DS DNA

BreaksApoptosis

Inotuzumab: Specific mAb-like target bindingallows targeted delivery to cancer cells

• Inotuzumab ozogamicin is an anti-CD22 antibody-calicheamicin conjugate– focused delivery of cytotoxic agent to tumor cells may maximize its

antitumor effect– Major B-cell malignancy currently under study:

– Non-Hodgkin’s Lymphoma (NHL)

– Phase 2 study with Inotuzumab plus Rituximab in refractory NHL demonstrated positive proof of concept, with strong efficacy and favorable tolerability

– Additional opportunity in other NHL types and B-cell leukemias

66

Median Overall Survivalnot reached

Progression Free SurvivalMedian 7.8 months

Inotuzumab – Phase II clinical activity inAggressive Non-Hodgkin’s Lymphoma (NHL)

Outcomes in relapsed, refractory Diffuse Large B-cell Lymphoma or transformed follicular NHL exceeding current Standard of Care

– Median survival not reached in patients who have failed prior chemotherapy

– Proof of Concept Achieved September 2010

Emerging clinical data in combination with rituximab suggests probability of technical success in Phase III is greater than 95%

7

Right TargetRight Target

Genetic validation; Rare phenotypes

What are we trying to accomplish?

Right Drug(or Combinations)

Right Drug(or Combinations)

Selective design and delivery; Combinations for complex diseases

Right PatientRight Patient

Phenotyping and Genotyping

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Molecular Subtypes in Lung CancerAn Evolving Landscape of Medical Need

Seg. 1

K-ras mut

No targeted therapyChemotherapy ineffective

Seg. 4

LKB1

PI3K/mTor

Seg. 2

EML4/Alk

crizotinib

Seg. 3

EGFR

erlotinib

Seg. 5

MYC

No therapy

c-Met amplification/ErbB amplification

EGFR T790M GK mutation

EGFR T790M GK mutation/c-Met amplification

Resistance mechanisms

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1. Shaw AT et al., J Clin Oncol. 2009; 27:4247-42532. Manabu Soda et al., Nature 2007; 448, 561-566

Highly effective therapyOverall response rate = 65%Disease control rate = 84% at a median of ~24 weeks

Accelerated clinical activitiesInitiated Phase 3 trial based on Phase 1 results, bypassing Phase 2 and accelerating development timeline

Highly effective therapyOverall response rate = 65%Disease control rate = 84% at a median of ~24 weeks

Accelerated clinical activitiesInitiated Phase 3 trial based on Phase 1 results, bypassing Phase 2 and accelerating development timeline

Crizotinib: A potent and selective oral inhibitor of

MET and ALK

Crizotinib: A potent and selective oral inhibitor of

MET and ALK

... initially being developed for MET mechanism

... initially being developed for MET mechanism

Academic discovery of new patient segment redefined lung cancer

10-15%1 of non small cell lung cancer (NSCLC) patients with fusion oncogene ELM4-ALK2 are unresponsive to conventional EGFR inhibitor1 treatment

New Phase I trial targeting advanced NSCLC patients

harboring ALK rearrangement

New Phase I trial targeting advanced NSCLC patients

harboring ALK rearrangement

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Targeting Lung Cancer Treatments in PatientSubsets to Improve Outcomes

Note: Patients in trial composed of 2nd to 4th line. 1st line response to Standard of Care: ~50%, 2nd line: ~10%, 3rd line: 3-5%

Clinical Outcome for NSCLC Patients After Crizotinib Treatment

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Pre-Treatment

(FLT-PET)

After 4 weeks of Crizotinib

43-yr old Male Non-smoker with NSCLCALK Fusion

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Thank you for your attention!