Tissue Biomarkers in Oncology Clinical Development The Digital Advantage Christopher Ung VP Strategic Business & Operations, Oncology TMD – A Quintiles Laboratory 1

2 The Targeted Therapy Continuum Non-Targeted Targeted (Somewhat) Personalized Med (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 Histology Treat Based on “some” Biomarkers Treat Based on Molecular Profile (KRAS) Vectibix Erbitux 2008 (HER2) (pHer2) (pHer3) Tykerb 2008

Predictive Biomarkers for Response To Lapatinib 3 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): 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-Treatment Arm A Biomarker Analysis

4 Quintiles – Solid Tumor Oncology Services  Biomarker Driven  Spans Discovery through Clinical Development for Oncology  Science Differentiator 4 CAP CLIA GLP/GCP

5 Our 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 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 6

The Challenges of IHC 7 Broken Slides Lost Slides Expensive to ship Hard to move tissue in and out of China Turnaround time and cost can be high if testing is “over-centralized” Images are hard to transmit Outsourcing to independent labs is tricky especially with data integration IHC is subjective Interpretation between pathologists can be inconsistent Non-numerical biomarker representation is difficult to use

Atlanta United States Edinburgh Scotland Pretoria South Africa Singapore Mumbai India Buenos Aires, Argentina Sao Paulo Brazil Owned Facility Anatomic Pathology Affiliated Facility Support Services Beijing China Tokyo Japan QWES Chicago Quintiles Labs Global Coverage Regional Labs Allow for Rapid TAT and Lower Shipping Costs

9 Tissue Biomarker Assay Development Model 9  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 Analysis PTEN Actin MWM MCF-7 T47D ZR75-1 DU145 PC3 LNCap 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 10 Stroma Numerical Data May Enable Further Resolution in Analyses

 Multi-site Integration in a Global Environment 11 Multisite Integration in a Global Environment Pete Tearle Sep 15. 7:00 pm – 9:00 pm Atlanta Room

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

Quintiles 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 15

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 16