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The Killer in Context: A Pathologist's Perspective on Companion Diagnostics Mary T. Padilla, M.D., Medical Director Ventana Companion Diagnostics

Market Conditions Pharma’s & Dia’s need create ideal CDx environment

Targeted Therapy &

Patient Selection

Differentiated Assays &

Medical Value CDx

•  Rising costs vs. lowering program success

•  Regulators mandate improved clinical outcomes

•  Payors mandate better health economics

•  Increasing macro economic pressures drive decreasing reimbursement

•  Low cost competitors drive pricing pressure

•  Maturing business (decline in capital, automation saturation)

Rx - Challenges Dx - Challenges

2

3

3

Prototype Assay Development and CAP/CLIA studies

Ventana Companion Diagnostics Solution

Prototype Assay

AGENDA

Current Case for Tissue

Immunotherapy

Future NGS

Q&A

Tissue context is required for diagnosis, IHC can not be displaced by molecular methods

A DNA test would produce identical results at all three stages

Larvae

5

Cocoon Butterfly

PD-L1 Staining

Tumor -

Rx Effective Rx Effective No Rx Benefit Infiltrate +

Tumor +

Infiltrate +

Tumor +

Infiltrate -

Information embedded in the tissue

6 Intact Extracted

Chemistry in Context

7

Medical Needs The Patient The Lab/The MD What do I have? Diagnosis

What caused it? Etiology: Infections/Genetic

What explains my symptoms? Pathogenesis

What are my prospects? Prognosis

Has it spread? Metastasis

What is my treatment? Therapeutic Targets

Will I be cured? Response Prediction

Will I be hurt? Toxicity Prediction

How will I be followed? Monitoring

Will it return? Relapse

Will others in my family get it? Predisposition Screening

How will you communicate the results? Medical Report

Objectives

Demonstrate how slide-based tissue chemistry innovations will change cancer care

Method

– Describe where we are today – Describe our unsolved problems – Describe innovative solutions

9

The Challenges

–  Deliver more results relevant to patient prognosis and therapy.

–  Deliver more molecular-based assays.

–  Deliver more automated, standardized results.

–  Communicate results better.

10

The Key Scientific Advances

Beyond diagnosis to therapeutics

Beyond single analyte to multiplexing

Beyond protein to gene plus protein assays

Beyond qualitative to quantitative assays

Beyond informatics to cellular informatics

Beyond written reports to patient-centric reports

Utility of Slide-Based Tissue Chemistry Simultaneous analysis of morphology, gene and protein status

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Morphology Gene status Protein status

H&E: Hematoxylin&Eosin (Dye)

ISH: in situ Hybridization) (DNA/RNA Probe)

IHC: Immunohistochemistry

(Antibody)

H&E IHC

Normal Tissue

Carcinoma

The Importance of Tissue Analysis in Morphologic Context Patient 1: 48 year old female with 2 cm invasive ductal breast carcinoma (H&E).

Estrogen Receptor

on normal

cells

Conflicting test results for Estrogen Receptor (IHC ER-neg/PCR ER-pos)

The Importance of Chemistry in Morphologic Context Breast Cancer: Heterogeneity of HER2 Expression

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Objective 4x

3+

2+ 1+

0 Predicts Therapy Failure

Patient 2: female with breast carcinoma and recurrent tumor despite anti hormone therapy.

IHC: HER2-positive Ki67 H&E IHC: ER-positive

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The Importance of Tissue Analysis in Morphologic Context

Applying tests on various biomarkers helps explaining recurrence of HER2 positive tumor and allows appropriate therapy guidance.

Utility of Tissue-Based Chemistry

–  Reveals functional morphology.

–  Reveals microenvironment.

–  Reveals driver events.

IHC Uncovers Heterogeneity and Reveals Functional Morphology Hematoxylin and Eosin Estrogen Receptor Progesterone Receptor

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“ Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing”

Gerlinger et al, NEJM 366:883-92, 2012

The Key Observations

In tumor heterogeneity there is genetic divergence with consequent phenotypic convergence which alters cell function at the protein level which undergoes Darwinian selection and evolutionary adaptation and probable therapy failure.

Gerlinger et al, NEJM

Nagle, et al The Prostate 9999:1-7 (2013)

Loss of PTEN Expression in Prostate Cancer

Coussens et al. Science 339, 286 (2013)

Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet?

AGENDA

Current Case for Tissue

Immunotherapy

Future NGS

Q&A

Immune Cell Modulators – A Class on its Own A number of these receptors can be analyzed by IHC

B7-H3

PD-1/PD-L1: A Critical Immuno Checkpoint Pathway

PD-1/PD-L1: A Critical Immuno Checkpoint Pathway

anti-PD-1; NSCLC 40x anti-PD-L1 (SP); NSCLC 40x

Surface Markers: Critical for Immune Cell Classification

anti-CD3 (SP7); anti-CD16 (SP96) NSCLC 40x

anti-CD3 (SP6) NSCLC 40x

anti-CD8 (SP16) NSCLC 40x

anti-CD3 (SP6) anti-CD8 (SP16) NSCLC 40x

Role of IDO1in Regulating Anti-Tumoral Immunity

anti-IDO1 (SP); NSCLC 10x

Other Immune Modulating Markers: B7H3

anti-B7-H3 (SP206); NSCLC 40x

Zang X , and Allison J P Clin Cancer Res 2007;13:5271-5279

Immunohistochemistry illustrates key interactions –  Summary points for IHC/ISH

–  Morphology

–  Interactions

–  Tumor vs. Infiltrate (or “inflamate”)

“We are leaving the world of commoditized diagnostic, what is it,

and going to higher value tests linked to therapy, what to do.”

Dr. Tom Grogan, Founder Ventana Medical Systems, Inc.

Where we are going …

AGENDA

Current case for Tissue

Immunotherapy

Future NGS

Q&A

Cancer Treatment in the Future?

A. Bacall, The New Yorker

"Here's my sequence”

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Next Generation Cell Signaling Assays PI3k

Measuring Activation Status

–  Personalized medicine utilizing the best available technologies

–  Clinically relevant information

–  Broad patient access

Future of NGS

AGENDA

Current Case for Tissue

Immunotherapy

Future NGS

Q&A

Question and Answer Session From in the room and beyond

-  Your questions first

-  Live Tweet format for additional questions

-  Follow us @ventana

-  Review tweets from the conference at @worldcdx

Thank you.

VENTANA Empowering | Personalized Healthcare www.roche.com www.ventana.com

© 2014 Ventana Medical Systems, Inc.

VENTANA and the VENTANA logo are trademarks of Roche. All other trademarks are the property of their respective owners. Ad-pro # here E5248A-5

Doing now what patients need next

VENTANA Empowering | Personalized Healthcare www.roche.com www.ventana.com

© 2014 Ventana Medical Systems, Inc.

VENTANA and the VENTANA logo are trademarks of Roche. All other trademarks are the property of their respective owners. Ad-pro # here E5248A-5

Doing now what patients need next