2. Edward Abrahams, Ph.D., President, Personalized Medicine Coalition

3. “Variability is the law of life, and as now no two bodies are alike and behave alike under abnormal conditions, which we know as disease.” - Sir William Osler

4. Challenges in Building a Precision Medicine Program Richard L. Schilsky, MD, FACP, FASCO Chief Medical Officer American Society of Clinical Oncology

5. Precision Medicine Impacts All Aspects of Cancer Care Meric-Bernstam F et al. JCO 2013;31:1849-1857

6. Hallmarks of Cancer: Therapeutic Implications Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

7. Targeted Therapy Superior to Chemotherapy Gefitinib Vemurafenib CrizotinibGefitinib In Biomarker Selected Populations

8. Schema of Personalized Medicine MacConaill L E, Garraway L A JCO 2010;28:5219-5228 ©2010 by American Society of Clinical Oncology

9. Schema of Personalized Medicine MacConaill L E, Garraway L A JCO 2010;28:5219-5228 ©2010 by American Society of Clinical Oncology Repeat each time a new clinical decision needs to be made.

10. Implementing Personalized Cancer Care

11. Problem: Tissue Collection and Testing No established guidelines for tissue collection and processing for molecular profiling Proliferation of testing facilities Few established standards for molecular work-up of tumors, i.e., appropriate testing platforms, standardized nomenclature and variant annotation, description of the limitations of the test, reporting of results

12. Problem: Increasing Complexity of Molecular Testing Li T et al. JCO 2013;31:1039-1049

13. Problem: Are You Confident in the Test You Order? Analytic validity –Sensitivity, specificity, NPV, PPV (relative to “gold standard”) –Technical reproducibility –Assay stability over time Clinical validity –Does the assay identify a specific population? Clinical utility –Does the use of the assay lead to better clinical outcome (improved OS, less toxicity, less cost, improved PFS) ? Febbo PG,, et al. NCCN task force report: evaluating the clinical utility of tumor markers in oncology. J Natl Compr Canc Netw 2011; 9:S1–32 Parkinson DR, et al. Evidence of clinical utility: an unmet need in molecular diagnostics for patients with cancer. Clin Cancer Res 2014; 20:1428–44.

14. CLIA Certified CAP Accredited FDA approved (?) Regular proficiency testing Standard nomenclature for test reporting Open access variant annotation for decision support Record test used, test results, clinical decisions and patient outcomes in national registry Proposed Solution: Guidelines and Certification

15. Genomic Landscape of 5000 Human Cancers MacConaill, L, et. al., J Mol Diagn 2014, 16: 660-672

16. What is “Actionable”? Van Allen E M et al. JCO 2013;31:1825-1833

17. Oncologist Confidence in Assessing Genomic Test Results Gray, S, et. al., JCO epub March 24, 2014.

18. Matching Drugs and Genomics Meric-Bernstam, F., et. al. : JNCI 2015

19. How Useful Is It? Kurzrock, Et. al., JNCCN 13:1337-46, 2015

20. Nearly 60% of respondents said genomic profiling informed clinical decisions less than 30% of the time! How Useful Is It?

21. Why Wasn’t it Helpful? Kurzrock, R. al., JNCCN 13:1337-46, 2015

22. Genomic-Driven Cancer Medicine Opportunities and Challenges “…oncology has served as a proving ground for the genomics- driven framework that is unique among medical specialties.” “A well-recognized pitfall of genomics-driven cancer medicine centers on the risk that large-scale genomic data generation could emerge without an evidence-based clinical approach to data analysis and interpretation.” Garraway L A JCO 2013;31:1806-1814 Parkinson DR et al Clin Cancer Res 2014;20:1428-1444 Selected tumor molecular assays available/used in clinical practice

23. Health Systems Considerations Genome sequencing: use a commercial lab vs. build a CLIA certified sequencing lab? NGS testing will likely soon be regulated by FDA. More than the lab, building/curating the knowledge base is essential but expensive. Do you have the necessary teams of clinicians, bioinformaticians and molecular pathologists to interpret/report results? If you build it, who will pay for it? Provider and patient education is key Investment in genetic counselors necessary Data storage (security) requirements are huge. The field is rapidly moving and requires continuous attention and updating.

24. Implementing a Precision Medicine Program Jennifer Levin Carter

25. N-of-One Case Studies: Metastatic Lung Cancer N-of-One all material confidential. Do not distribute. Tumors tested negative for (EGFR, KRAS, ALK) NGS testing pursued. Activating mutations in the ERBB2 gene - encodes the Her2 protein, a well- known breast cancer biomarker Clinical Relevance -FDA Approved Therapy: None approved to target ERBB2/HER2 for NSCLC -Drugs targeting ERBB2/Her2 are approved for treatment of breast cancer and are being tested in clinical trials. -Drug targeting both Egfr and Her2 approved in EGFR-mutant NSCLC 61 yo F non-smoker with recurrent, metastatic non-small cell lung cancer (NSCLC) Clinical Impact – Case 1 - Treated with Herceptin Off-Label - The patient has been progression free for > 5 years ERBB2 YVMA 64 yo F non-smoker newly diagnosed with non-small cell lung cancer (NSCLC) Clinical Impact – Case 2 -Treated with radiation and SOC. - Progressive disease with development of CNS metastases -Switched to afatinib -Stable disease for approximately 6 months then passed away ERBB2 YVMA

26. Why a Cancer Center wants a Precision Medicine Program? Many IDNs are implementing or exploring precision medicine programs – Growing competition for patients – With growing reimbursement clarity, pathology labs can offer NGS testing profitably – Many institutions bringing molecular testing in house to drive revenues Molecular Testing is becoming Standard of Care N-of-One all material confidential. Do not distribute.

27. What is required to Launch a Precision Medicine Program? The Diagnostic Lab N-of-One all material confidential. Do not distribute. Sequencing Data Filtering, Variant Calling Delivery of Relevant Evidence and Therapeuti c Options Bioinformatics Clinical Interpretation LabPathologist Analysis and Sign Out ValidationCLIA/CAP Molecular Tumor Board AccessClinical Trial Access

28. What are the Challenges to Launching a Program? Trends in Molecular Testing Driving Complexity in Interpretation Even small NGS panels can be complex Understanding the full molecular profile to identify drug resistance and sensitivity requires multi-variant analysis Access to relevant Clinical Trials NGS is not the only important molecular test Benefit of incorporating additional clinical information such as prior drugs, relevant labs, co-morbidities etc… N-of-One all material confidential. Do not distribute. To launch and scale their programs, organizations are struggling with the translation of the molecular data such that it can be delivered to the oncologist at the point of care in a high quality, scalable way.

29. Patient-Specific Analysis is Required to Find the Most Relevant Therapeutic Options Patient 1 Disease: Melanoma Gene: BRAF Variant: V600E Mutation Patient 2 Disease: Colorectal Cancer Gene: BRAF Variant: V600E Mutation N-of-One all material confidential. Do not distribute. Conclusion: Gene and Variant Analysis in context of each Patient’s Disease Patient 3 Disease: Colorectal Cancer Gene: BRAF Variant: D594G Mutation Potential Therapeutic Strategy: vemurafenib + cobimetinib or dabrafenib + trametinib Potential Therapeutic Strategy: vemurafenib + cetuximab or trametinib or cobimetinib Potential Therapeutic Strategy: trametinib or cobimetinib or sorafenib or regorafenib

30. How are Health Systems Addressing these Challenges? Some are attempting do everything in-house Some are buying tools Many are working with N-of-One Some send out to another lab or Community Hospitals for comprehensive testing N-of-One all material confidential. Do not distribute.

31. Partnering for Success in the Community: Intermountain Healthcare N-of-One all material confidential. Do not distribute. Partnering for success: Intermountain provides NGS Lab services to other Community Hospitals. N-of-One supports this effort by providing Intermountain with Clinical Interpretation and Clinical Trial Matching Intermountain Healthcare conducted two studies: Treatment changed to targeted therapy in 62% of cases where molecular testing and N-of-One interpretation were available Outcomes progression free survival of 22.9 weeks for precision therapy approach compared to 12.0 weeks for traditional chemotherapy Cost was essentially the same Nadauld et al., J. Clin. Oncol. 33, 2015 (ASCO Abstract e17647, e17641)

32. What Lies Ahead for 2016: Even More Complexity N-of-One all material confidential. Do not distribute. Integrated Molecular Tests More Novel Clinical Trials Novel and Combination Therapies EMR Clinical Data Liquid Biopsies

33. How Does N-of-One Support Precision Medicine Programs? N-of-One all material confidential. Do not distribute. Major Hospital Systems Diagnostic Labs Globally Cancer Treatment Centers N-of-One Clinical Interpretation And Clinical Trial Matching N-of-One Clinical Interpretation And Clinical Trial Matching Pathology Lab Support Collaboration on Research leveraging N-of- One’s database Clinical Trial Pre- Enrollment Services Molecular Tumor Board Support Additional Supporting Services Available

34. THANK YOU! QUESTIONS? Jennifer Levin Carter MD, MPH 617 947-1631 Jennifer.carter@n-of-one.com

35. Michael Kolodziej, M.D., National Medical Director Oncology Solutions, Aetna

37. Moderators: Amy Abernethy, M.D., Ph.D., Senior Vice President and Chief Medical Officer, Flatiron Health Edward Abrahams, Ph.D., President, Personalized Medicine Coalition Panelists: Jennifer Levin Carter, M.D., MPH, Chief Medical Officer and Founder, N-of-One Michael Kolodziej, M.D., National Medical Director Oncology Solutions, Aetna Richard L. Schilsky, M.D., FACP, FASCO, Chief Medical Officer, American Society of Clinical Oncology®