Sima Salahshor, B.Sc., M.Sc. PMP, PhDAdjunct Professor, University of Toronto, Faculty of MedicineFounder, ScienceHA, Inc.

Diagnostics -the ability to define a disease state.

o Complementary Diagnosticso Companion Diagnostics (CoDx)

Theranostics -the ability to affect therapy or treatment of a disease state.

In vitro diagnostics from screening to disease monitoring:

Reference: Business Inside, Roche Diagnostics (http://www.roche.com/diagnosticsbrochure.pdf)

IVD (in vitro diagnostics) accounts for only 2% of health care spending but influences over 60% of clinical decision making!

Companion diagnostic device can be:o in vitro diagnostic device oro an imaging tool that provides information that is essential for the

safe and effective use of a corresponding therapeutic product.

Example of drug approved as a biomarker-directed therapyo Erbitux (cetuximab) in combination with chemotherapy has

been approved by Health Canada as an initial treatmentoption for Canadians with metastatic colorectal cancerwhose tumors have a non-mutated KRAS gene.

o KRAS companion diagnostic assay

Reference: Drug and Health product, Health Canada (http://bit.ly/1O6WZIr)

Candidate for Cetuximub or Panitumumab treatment

Colorectal cancer mutation panel gene testing

Mutation notdetected

Mutation found

Reference:Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Jolien Tol et al. European Journal of Cancer, July 2010

More likely that patient would respond to Anti-EGFR therapy

Unlikely patient would respond to Anti-EGFR therapy

Mutation testing results predict response to Anti-EGFR in patients with metastatic colorectal cancer (companion diagnostics)

Reference: Acquired/intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesisKazunori Otsuka et al. Oncology Letters. Dec 2011

Drug name Gene Detection MethodKeytruda (pembrolizumab) PD-L1 IHCIressa (gefitinib) EGFR PCR kitErbitux (cetuximab) KRAS PCR/SequencingVectibix (panitumumab) KRAS PCR/SequencingLynparza(olaparib) BRCA PCR/SequencingGleevec/Glivec (imatinib mesylate) c-Kit IHCHerceptin (trastuzumab) HER-2 FISHTarceva (erlotinib) EGFR RT-PCRZelboraf (vemurafenib) BRAF Q-RT-PCRXalkori (crizotinib) ALK FISH

Reference: FDA, List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)http://1.usa.gov/1whiCOt

Reference:Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. Edward B. Garon et al. N Engl J Med 2015; 372:2018-2028 May 21, 2015

Detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue

Patient’s Tissue

PD-L1 IHC 22C3 pharmDx

Qualitative immunohistochemical assay using Anti-PD-L1 in the detection of PD-L1 protein

EnVision FLEX visualization system

PD-L1 protein expression is determined by using Tumor Proportion Score (TPS). The specimen considered PD-L1 positive if TPS ≥ 50% of the viable tumor cells exhibit membrane staining at any intensity.

Approved companion diagnostic device for

Treatment selection

References:

Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. Edward B. Garon et al.N Engl J Med 2015; 372:2018-2028 May 21, 2015

PD-L1 Testing in Cancer: Challenges in Companion Diagnostic Development. Aaron R. Hansen and Lillian L. Siu. JAMA Oncology Online Nov 2015.

If TPS ≥ 50% of the viable tumor cells exhibit membrane staining at any intensity >> PD-L1 Positive >> Specimen Positive >> Aid in identifying NSCLC patients for treatment with KEYTRUDA (pembrolizumab)

Reference:Targeting the human EGFR family in esophagogastriccancerOkines, A. et al. (2011). Nat. Rev. Clin. Oncology

Mutation detection of KRAS, EGFR, HER2 (companion diagnostics)

Patient tumor sample

IHC

FISH/CISH

+2 +30 +1

HerceptinTherapy

+-

FISH/CISH

HerceptinTherapy

HerceptinTherapy

+-

IHC = ImmunohistochemistryFISH = Fluorescence in situ hybridisationCISH = Chromogenic in situ hybridization

Reference: Adrian M. Senderowicz and Otmar Pfaff. Clin Cancer Res 2014; 20:1445-1452

IVD cancer tests in situ hybridization (ISH) Immunohistochemistry (IHC) FOB (Faecal Occult Blood) and Other Rapid Tests PSA (Prostate-specific antigen), CEA and Other Markers Flow Cytometry Pap (Papanicolaou ) Testing Molecular Oncology Assays Tissue Microrrays Methylated DNA Circulating Tumor Cells Next-Generation Sequencing Technologies Tissue Function Tests Companion Testing, CDX Products

Reference: Partnering on Novel Technologies for Companion DiagnosticsVolume XVII, Issue 24, 2015 , Brian Baranick, Alex Vadas

Most personalized medicine strategies have been deployed in oncology.

One-drug, one-test approach for therapy selection!

Complementary diagnostics will provide additionalinformation about:

o how a drug might be used, oro whether someone should receive a class of drugs.

This type of test is not essential for determining who shouldreceive the drug, but can give doctors an idea of how welltheir patients might respond to treatment.

Companion diagnostics are required for the safe and effective useof a drug.

The “PD-L1 IHC 28-8 pharmDx” diagnostics test measures the level ofPD-L1, and is now approved by the FDA to be used prior to treatmentwith Opdivo.

Anti-PD-1 drug Opdivo (nivolumab) approved for all advanced non-smallcell lung cancer (NSCLC) patients who have progressed despite platinum-based chemotherapy.

References :Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. Borghaei H et al. N Engl J Med. 2015 Oct 22;373(17):1627-39

FDA expands approved use of Opdivo in advanced lung cancer. FDA News Release, October 2015

Opdivo, is a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody Opdivo disrupts PD-1-mediated signaling and may restore antitumor immunity.

One biomarker (e.g. HER2)

One device that detect biomarker (e.g. PATHWAY™ Her 2 or PathVysion Kit or INFORM HER-2/NEU Test)

One tailored treatment (e.g. Herceptin)

Theranostics combines diagnostic and therapeutic capabilities into a singleagent, and could facilitate assessment of safety, toxicity and real-timetherapeutic efficacy leading to personalized treatment strategies.

Reference:Macrophage Targeted Theranostics as Personalized Nanomedicine Strategies for Inflammatory DiseasesSravan Kumar Patel, Jelena M. Janjic. Theranostics 2015

Global cancer diagnostic market (tumor biomarker tests, endoscopy, imaging, and biopsy) valuated over $168 Billion by 2020

Global health care industry shifts towards: › point-of-care diagnostics› cost-effective treatment modalities› personalized medicine

Reference: Cancer Diagnostics Market - Global Industry Analysis, Size, Share, Growth, Trends and Forecast, 2014 - 2020”. Transparency Market Research (TMR)

Is required for the safe and effective use of a specific drug.

CoDx provides information that is essential for the safe and effective use of a corresponding therapeutic product.

CD is not essential for determining who should receive the drug.

But provides information about how a drug might be used, and how well the drug might respond.

Companion diagnostics (CoDx)

Complementary diagnostics(CD)

Summary

Email: salahshor@ScienceHA.com || URL: www.ScienceHA.comEmail: s.salahshor@utoronto.ca || U of T: http://bit.ly/1hTp48a || Twitter: @SSalahshor

For seminar, workshop or presentation on this or other topics contact:Info@ScienceHA.com

Sima Salahshor PhD, PMP