1) Companion diagnostics are tests that are essential for the safe and effective use of a corresponding drug or therapeutic product. Complementary diagnostics provide additional information that may predict treatment response but are not required for determining treatment. 2) Companion diagnostic tests identify biomarkers that indicate whether a patient is likely or unlikely to respond to a targeted drug. For example, the KRAS companion diagnostic predicts response to cetuximab for colorectal cancer. 3) The global cancer diagnostic market, including companion diagnostics, is large and growing as healthcare shifts toward personalized medicine approaches.

1. Sima Salahshor, B.Sc., M.Sc. PMP, PhD
Adjunct Professor, University of Toronto, Faculty of Medicine
Founder, ScienceHA, Inc.

2. Diagnostics -the ability to define a disease state.
o Complementary Diagnostics
o Companion Diagnostics (CoDx)
Theranostics -the ability to affect therapy or treatment of a disease
state.

3. 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!

4. Companion diagnostic device can be:
o in vitro diagnostic device or
o 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 therapy
o Erbitux (cetuximab) in combination with chemotherapy has
been approved by Health Canada as an initial treatment
option for Canadians with metastatic colorectal cancer
whose tumors have a non-mutated KRAS gene.
o KRAS companion diagnostic assay
Reference:
Drug and Health product, Health Canada (http://bit.ly/1O6WZIr)

5. Candidate for Cetuximub or Panitumumab treatment
Colorectal cancer mutation panel gene testing
Mutation not
detected
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)

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

7. Drug name Gene Detection Method
Keytruda (pembrolizumab) PD-L1 IHC
Iressa (gefitinib) EGFR PCR kit
Erbitux (cetuximab) KRAS PCR/Sequencing
Vectibix (panitumumab) KRAS PCR/Sequencing
Lynparza(olaparib) BRCA PCR/Sequencing
Gleevec/Glivec (imatinib mesylate) c-Kit IHC
Herceptin (trastuzumab) HER-2 FISH
Tarceva (erlotinib) EGFR RT-PCR
Zelboraf (vemurafenib) BRAF Q-RT-PCR
Xalkori (crizotinib) ALK FISH
Reference:
FDA, List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)
http://1.usa.gov/1whiCOt

8. 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

9. 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)

10. Reference:
Targeting the human EGFR
family in esophagogastric
cancerOkines, A. et al.
(2011). Nat. Rev. Clin.
Oncology
Mutation detection
of KRAS, EGFR, HER2
(companion
diagnostics)

11. Patient tumor sample
IHC
FISH/CISH
+2 +30 +1
Herceptin
Therapy
+-
FISH/CISH
Herceptin
Therapy
Herceptin
Therapy
+-
IHC = Immunohistochemistry
FISH = Fluorescence in situ hybridisation
CISH = Chromogenic in situ hybridization

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

13.  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

14. Reference: Partnering on Novel Technologies for Companion Diagnostics
Volume 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!

15. Complementary diagnostics will provide additional
information about:
o how a drug might be used, or
o whether someone should receive a class of drugs.
This type of test is not essential for determining who should
receive the drug, but can give doctors an idea of how well
their patients might respond to treatment.
Companion diagnostics are required for the safe and effective use
of a drug.

16. The “PD-L1 IHC 28-8 pharmDx” diagnostics test measures the level of
PD-L1, and is now approved by the FDA to be used prior to treatment
with Opdivo.
 Anti-PD-1 drug Opdivo (nivolumab) approved for all advanced non-small
cell 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.

17.  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 single
agent, and could facilitate assessment of safety, toxicity and real-time
therapeutic efficacy leading to personalized treatment strategies.
Reference:
Macrophage Targeted Theranostics as Personalized Nanomedicine Strategies for Inflammatory Diseases
Sravan Kumar Patel, Jelena M. Janjic. Theranostics 2015

18.  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)

19. 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

20. Email: salahshor@ScienceHA.com || URL: www.ScienceHA.com
Email: 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