2. The Role of Personalized Medicine in our Future Delivery System Moderator: Edward Abrahams, Ph.D., President, Personalized Medicine Coalition Panelists: Christine Cournoyer, Chief Executive Officer, N- of-One Maurie Markman, M.D., Senior Vice President for Clinical Affairs, Cancer Treatment Centers of America Catherine A. McCarty, Ph.D., MPH, Principal Research Scientist, Essentia Health David Nixon, Chief Executive Officer, InformedDNA Timothy Thompson, Chief Executive Officer, Intervention Insights

3. The Role of Personalized Medicine in our Future Delivery System Christine Cournoyer, Chief Executive Officer, N-of-One

4. Challenges NCCN Guidelines address the treatment needs of limited number of patients Knowledge of additional markers and therapies isn’t readily available to the physician at the point of care Reimbursement for additional testing and therapies is a key challenge Access to the drugs and clinical trials can be time consuming and difficult Broader testing and guided therapy can offer improved alternatives to cancer patients failing the standard of care

5. Evidence to support exploration of additional therapies Both the literature and N-of-One experience reflect the high percentage of actionable biomarkers that are not included in NCCN guidelines. Expanded testing and clinical interpretation of results can guide physicians to more biomarker-directed therapies Larger patient studies are beginning to support improved clinical outcome of individualized strategies based on molecular test results for cancer treatment Integration of more molecular testing could transform individualized cancer care.

6. NCCN Guidelines impact only about 14% of Caucasians who test positive for EGFR (10-15%) and ALK (4%) leaving a large population of lung cancer patients (~80%) without access to targeted therapy options. Does this matter? A growing number of studies, N-of-One data and patient cases in lung cancer support the premise that access to additional targeted therapies beyond the NCCN guidelines may lead to improved outcomes. Lung adenocarcinoma as an example of the need for expanded testing and personalized cancer care

7. Lung Cancer Mutation Consortium Protocol: evidence for biomarker- directed therapy in lung cancer Oncogenic drivers were identified in 466 of 733 patients tested for 10 biomarkers (64%) from 2009-2012. (KRAS, EGFR, ALK, ERBB2, BRAF, PIK3CA, MET, NRAS, MEK, AKT1) Oncogenic drivers were identified in 578 of 938 patients tested for at least 1 biomarker (62%). 260 with actionable biomarker Biomarker- directed therapy 3.5 yr median survival 318 with actionable biomarker No biomarker- directed therapy 2.4 yr median survival p=0.006 Kris et al, JAMA May 2014

8. Legend: A = drug available on-labelB = drug available off-label C = clinical trial availableD = not actionable % Patients with actionability level N-of-One Data collected over a 1-year period supports biomarker testing in lung adenocarcinoma Clinical actionability in lung adenocarcinoma (n=211)

9. New Models Emerging to bring Precision Medicine to the Community: Example: Intermountain Personalized Medicine Clinic Intermountain, with the help of N-of-One, can offer physicians consulting on the appropriate use of molecular testing to guide additional diagnostic testing with evidence to support reimbursement Intermountain will provide the testing and clinical interpretation and present the results to their Molecular Tumor Board (MTB) for discussion Intermountain’s MTB can provide an analysis of the results and knowledge of available targeted therapies indicated for any actionable mutations. Intermountain can work with the patient on reimbursement and can provide drug procurement of the targeted therapy for the patient Benefit: Patient receives precision medicine options in their community

10. The Role of Personalized Medicine in our Future Delivery System Catherine A. McCarty, Ph.D., MPH, Principal Research Scientist, Essentia Health

11. Personalized Medicine Within Research Networks and in Rural America Challenges Opportunities Cathy McCarty, PhD, MPH Essentia Institute of Rural Health

12. Essentia Health Care Delivery System

13. NCI Community Oncology Research Program

14. HMO Research Network Cancer Research Network

15. Common Challenges Electronic health record usability and interoperability – Data storage – Decision support – Data portability Reimbursement Models for return of results

16. The Role of Personalized Medicine in our Future Delivery System Maurie Markman, M.D., Senior Vice President for Clinical Affairs, Cancer Treatment Centers of America

17. Maurie Markman, M.D. President, CTCA Medicine & Science Clinical Professor of Medicine, Drexel University College of Medicine “Precision Medicine” “The Future of Cancer Care”

18. “Targeted”, “Personalized”, or (most recently) “Precision” therapy Not a new concept Hormonal therapy of breast/prostate cancer: Earliest systemic anti-neoplastic strategy ER receptor discovered 40 years ago HER-2 over-expression in breast cancer CML/GIST (profoundly different pathology but similar molecular abnormalities resulting in essentially identical highly effective therapy) Resulting over-simplification of complex biology © 2011 Rising Tide 18

19. “The difficult path forward …..” Inhibition of EGFR in lung cancer – unique mutation vs. simple over-expression Inhibition of EGRF in colon cancer – role of KRAS mutation defining lack of utility Small patient subsets – Difficulty proving clinical benefit, including for regulatory approval Evidence required for molecular markers Insurers willingness to pay © 2011 Rising Tide 19

20. But …. The future is here It is possible today to sequence the entire genome of a tumor and the corresponding normal genome (pharmacogenomics) of an individual cancer patient for < $5,000 (12-15 years ago this would have cost $6,000,000,000) So, the issue is not whether the data will be available to patients, but rather how to optimally convert this massive quantity of raw data into information of genuine value in individual patient management © 2011 Rising Tide 20

21. © 2011 Rising Tide 21 Declining Cost of Sequencing a Human Genome

22. “The STEPS” Discovering the “code” in an individual patient– (“sequencing”) (easy) Attempting to break the “code” – (“bio- informatics) (difficult - extremely difficult) Exploring the relevance of the proposed solution (“clinical validation with a targeted therapeutic”) in individual patients (unknown difficulty) Proving the relevance of the solution (“n of one” research) (soon-to-be the new paradigm in clinical cancer therapeutic research) © 2011 Rising Tide 22

23. Pharmacogenomics in Cancer Management Well-recognized variations in the severity of toxicities of anti-neoplastic agents between individuals and ethnic groups impacting: (1) quality of life; (2) survival outcomes (ability to deliver a sufficient concentration and total dose over time to produce the desired/optimal cytotoxic effect) © 2011 Rising Tide 23

24. Proposed future research strategy Web-based national/international registry of outcomes (history, validated treatment results) from therapy based on molecular-based management – (“n-of-one” research) (“CancerLinQ”– ASCO (Schilsky; Nat. Rev. Clin. Oncol.) ) Results made available to all interested parties (public, patients, regulatory agencies, 3 rd party payers, employers, research community) When robust data available, publication in peer- reviewed literature © 2011 Rising Tide 24

25. The Role of Personalized Medicine in our Future Delivery System David Nixon, Chief Executive Officer, InformedDNA

26. The Role of Personalized Medicine in our Future Delivery System Timothy J. Thompson, CEO, Intervention Insights

27. Molecular Testing & Implications for the Care Delivery Model in Oncology Clinical research program established with clearly defined end points Payer covers cost of routine care Study Sponsor covers cost of study-related care Clinical Trial Referral Clinical utility has not been established. Pre-clinical, biologic plausibility data Master protocol Informed consent Structured data capture with a plan to publish Industry Funding? Government/Grant funding? Research (Trial & Error) Marker Panel Funding Considerations Other considerations Care Setting Evidentiary Standard Clinical utility has been established in published literature Payer Reimbursement for total cost of care Routine Clinical Care Marker panel to expand based upon evolving medical evidence © 2014 Intervention Insights. All Rights Reserved.