Tissue Biomarkers in Oncology Clinical Development The Digital Advantage Christopher Ung VP Strategi

1
Tissue Biomarkers in Oncology Clinical
Development The Digital AdvantageChristopher
UngVP Strategic Business Operations,
OncologyTMD A Quintiles Laboratory
2
The Targeted Therapy Continuum
Non-Targeted
Targeted (Somewhat)
Personalized Med.
(bcr/abl) (c-kit) (PDGFR) Gleevec
(HER2) (pHer2) (pHer3) Tykerb
(KRAS) Vectibix Erbitux
(EGFR) Erbitux Iressa
(HER2) Herceptin
Chemotherapies
1998
2002
2003
2008
2008
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
Biomarker-Driven Single or Combination Therapy
Treat Based on Histology
Treat Based on some Biomarkers
Treat Based on Molecular Profile
3
Predictive Biomarkers for Response To Lapatinib
Post-Treatment
Pre-Treatment
Arm A Biomarker Analysis

• 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

Johnston, 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.
4
Quintiles Solid Tumor Oncology Services

• Biomarker Driven
• Spans Discovery through Clinical Development for
  Oncology
• Science Differentiator

CAP
CLIA
GLP/GCP
4
5
Our Biomarker Tool Set
FFPE Tissue
Tissue Microarray (TMA)
Xenografts
Frozen Tissue
Fluorescent in situ hybridization
(FISH) Chromogenic in situ hybridization (CISH)
Real-Time PCR (Mutation Analysis Gene
Expression)
Immunohistochemistry (IHC) Immunofluorescence (IF)
Digital Pathology Image Analysis
5
6
Biomarkers for Oncology Drug Development 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

7
The Challenges of IHC
Hard to move tissue in and out of
China Turnaround time and cost can be high if
testing is over-centralized
IHC is subjective Interpretation between
pathologists can be inconsistent Non-numerical
biomarker representation is difficult to use
8
Quintiles Labs Global Coverage
Edinburgh Scotland
Beijing China
QWES Chicago
Tokyo Japan
Atlanta United States
Mumbai India
Singapore
Sao Paulo Brazil
Support Services
Pretoria South Africa
Owned Facility Anatomic Pathology Affiliated
Facility
Buenos Aires, Argentina
Regional Labs Allow for Rapid TAT and Lower
Shipping Costs
9
Tissue Biomarker Assay Development Model

• 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
9
10
IHC Assay Validation with Image Analysis
Stroma
ZR75-1
LNCap
MCF-7
DU145
T47D
MWM
PC3
Tumor
T47D (Wild-type PTEN)
No tumor PTEN staining, high stromal cell staining
PTEN
Actin
Stroma
Du145 (1 Wild-type Allele, 1 Mutant Allele)
Tumor
Moderate tumor PTEN staining, high stromal cell
staining
PC3 (PTEN Homozygous Deletion)
10
Numerical Data May Enable Further Resolution in
Analyses
11

• Multi-site Integration in a Global Environment

Multisite Integration in a Global Environment
Pete Tearle Sep 15. 700 pm 900 pm Atlanta
Room
12
Quintiles Digital Pathology Applications for 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

12
13
(No Transcript)
14
www.quintiles.com/centrallab
www.quintiles.com/centrallab
15
Quintiles Global Oncology Laboratories

• CAP, CLIA, GLP, GCP Laboratories
• Anatomic Pathology Services
• Basic anatomic pathology (accessioning,
  microtomy, processing, HE)
• 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

15
16
Leveraging Digital Pathology for the Development
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