Tissue Biomarkers in Oncology Tissue Biomarkers in Oncology Clinical Development Clinical Development The Digital AdvantageThe Digital Advantage

Christopher UngChristopher UngVP Strategic Business & Operations, OncologyVP Strategic Business & Operations, Oncology

TMD – A Quintiles LaboratoryTMD – A Quintiles Laboratory

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The Targeted Therapy ContinuumThe Targeted Therapy Continuum

Non-TargetedNon-Targeted Targeted (Somewhat)Targeted (Somewhat) Personalized Med.Personalized Med.

1998

(HER2)

Herceptin

2002

(bcr/abl)

(c-kit)

(PDGFR)

Gleevec

2003

(EGFR)

Erbitux

Iressa

Time Consuming Clinical Endpoints (TTP, OS)

“More is better” (MTD Approach)

No target population

Earlier decisions based on Biological Endpoints

Efficacy without Toxicity (Biologically Effective Dose)

Targeted Population

Chemotherapies

Biomarker-Driven Single or Combination

Therapy

Treat Based on Treat Based on

HistologyHistology

Treat Based on “some” Treat Based on “some”

BiomarkersBiomarkers

Treat Based on Molecular Treat Based on Molecular

ProfileProfile

(KRAS)

Vectibix

Erbitux

2008

(HER2) (pHer2) (pHer3)

Tykerb

2008

Predictive Biomarkers for Response To Predictive Biomarkers for Response To LapatinibLapatinib

3Johnston, et al. (2008). Phase II Study of Predictive Biomarker Profiles for Response Targeting Human HER-2 in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy. JCO 26(7): 1066-72.

Observations of Predictive Biomarkers:

•Most patients in Cohort A (HER2 overexpressing) had high p-HER2

•However, co-expression of p-HER2 AND p-HER3 predicted for response to lapatinib

•High IGF-1R expression does not appear to play a role in drug resistance, nor does PTEN deficiency

Pre-Treatment Post-TreatmentArm A Biomarker Analysis

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Quintiles – Solid Tumor Oncology Quintiles – Solid Tumor Oncology ServicesServices

Biomarker Driven Spans Discovery

through Clinical Development for Oncology

Science Differentiator

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CAP CLIA GLP/GCP

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Our Biomarker Tool SetOur Biomarker Tool Set

Real-Time PCR (Mutation Analysis & Gene

Expression)

Immunohistochemistry (IHC)Immunofluorescence (IF)

Fluorescent in situ hybridization (FISH)

Chromogenic in situ hybridization (CISH)

Tissue Microarray (TMA)FFPE Tissue Xenografts

Digital Pathology & Image Analysis

Frozen Tissue

Biomarkers for Oncology Drug Biomarkers for Oncology Drug Development: An ExampleDevelopment: An Example

Biomarkers to Analyze “Activation” Status of PI3K Pathway PI3KCA mutation, PI3KCA amplification PTEN expression by IHC (advantages over sequencing)

Other Biomarkers KRAS and/or BRAF mutation (depending on tumor type) EGFR, HER2, c-Met amplification (depending on tumor

type) IGF-1R, p-EGFR, p-HER2, p-HER3

Biomarkers for PD/Target Modulation p-S6, p-4EBP1, p-mTOR, Cleaved Caspase 3, Ki67

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The Challenges of IHCThe Challenges of IHC

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Broken SlidesBroken Slides

Lost SlidesLost Slides

Expensive to shipExpensive to ship

Hard to move tissue Hard to move tissue in and out of Chinain and out of China

Turnaround time Turnaround time and cost can be and cost can be high if testing is high if testing is

“over-centralized”“over-centralized”

Images are hard to Images are hard to transmittransmit

Outsourcing to Outsourcing to independent labs is independent labs is

tricky especially tricky especially with data with data

integrationintegration

IHC is subjectiveIHC is subjective

Interpretation Interpretation between between

pathologists can be pathologists can be inconsistentinconsistent

Non-numerical Non-numerical biomarker biomarker

representation is representation is difficult to use difficult to use

Atlanta United States

EdinburghScotland

PretoriaSouth Africa

Singapore

MumbaiIndia

Buenos Aires, Argentina

Sao PauloBrazil

Owned Facility

Anatomic Pathology

Affiliated Facility

Support Services

BeijingChina

TokyoJapan

QWES Chicago

Quintiles Labs Global CoverageQuintiles Labs Global Coverage

Regional Labs Allow for Rapid TAT and Lower Shipping Costs

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Tissue Biomarker Assay Development Tissue Biomarker Assay Development ModelModel

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Proof or Robustness. Full development & validation at TMD.

SOPs in place Teams trained at TMD Both platform and

technology are reviewed Performance qualification

at global labs TMD inspects global labs Extensive use of digital

pathology platform to maintain quality and consistency

Develop Centrally, Perform Globally

IHC Assay Validation with Image IHC Assay Validation with Image AnalysisAnalysis

PTEN

Actin

MWM

MC

F-7

T47

D

ZR

75-1

DU

145

PC

3

LN

Cap

T47D (Wild-type PTEN)

PC3 (PTEN Homozygous Deletion)

Du145 (1 Wild-type Allele, 1 Mutant Allele)

No tumor PTEN staining, high stromal cell staining

Stroma

Tumor

Moderate tumor PTEN staining, high stromal cell staining

Tumor

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Stroma

Numerical Data May Enable Further Resolution in Analyses

Multi-site Integration in a Global Environment

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Multisite Integration in a Global Environment Pete Tearle

Sep 15. 7:00 pm – 9:00 pm Atlanta Room

Quintiles Digital Pathology Applications Quintiles Digital Pathology Applications for Drug Developmentfor Drug Development

Image Analysis & Technology Transfer for Image Analysis Algorithms

Collaboration & education – Digital Pathology conferencing

Global review of tumor presence prior to genotyping of solid tumors

Simultaneous biomarker review of patient data Tissue Micro Array and Cell Micro Array analysis Digital Slide Scanning

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www.quintiles.com/centrallab

www.quintiles.com/centrallab

Quintiles Global Oncology LaboratoriesQuintiles Global Oncology Laboratories

CAP, CLIA, GLP, GCP Laboratories Anatomic Pathology Services

Basic anatomic pathology (accessioning, microtomy, processing, H&E)

Immunohistochemistry (common signaling pathways), HER2 FISH , EGFR FISH Mutation analysis (Real-Time PCR) High resolution scanning of images (Aperio

ScanScope) Tissue MicroArray prep, staining and reporting Biorepository

Experienced Quintiles histotechnologists Dual platform – DAKO + Ventana

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Leveraging Digital Pathology for the Leveraging Digital Pathology for the Development of Targeted TherapiesDevelopment of Targeted Therapies

Invest in a standardized system for global deployment

Use the platform to increase collaboration and learning, internally and with key constituents

Engage the benefits of archiving, secure back up, image management and image retrieval

Use tools such as TMA Lab and image analysis algorithms to create assay development value

Obtain input for additional creativity and solutions

Stay strong in the vision

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