К.Тверской, pfizer
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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%
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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!
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