From Promise to Practice Precision Medicine From Promise to Practice

PRECISION ONCOLOGY IS THE FUTURE OF CANCER CARE. Most cancers harbor mutations leading to disrupted biological pathways and tumor initiation. Tumor genome data informs cancer treatment and clinical pathways, resulting in better health outcomes. New cancer therapies target the molecular pathways that lead to tumor genesis and progression.

New Approaches: Precision Medicine and Immunotherapy Recent investments in biomedical research have led to major advances in precision medicine and immunotherapy. In 2016, the Food and Drug Administration approved: 16 new and expanded use cancer therapies1 First liquid biopsy diagnostic test for lung cancer mutations 2 First next-generation sequencing diagnostic test to identify patients with advanced ovarian cancer eligible for a particular cancer treatment3 1 US Food and Drug Administration: Hematology/oncology (cancer) approvals & safety notifications. ww.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm 2 US Food and Drug Administration: cobas EGFR Mutation Test v2. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm504540.htm 3 US Food and Drug Administration: Rucaparib. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm533891.htm

Precision Cancer Treatment – a new Paradigm Cancer care is evolving from non-specific cytotoxic drugs that damage both tumor and normal cells to more specific targeted agents and immunotherapy approaches – Personalized Medicine. Targeted agents are directed at unique molecular features of cancer cells and immunotherapeutics modulate the tumor immune response. Both approaches aim to produce greater effectiveness with less toxicity. Molecular testing Standard of Care/NCCN Guidelines for: -Breast Cancer -Lung Cancer -Melanoma -Colorectal Cancer Precision Medicine aims to streamline clinical decision making by using molecular/genetic/genomic information available through biomarker(s) testing and then applying that information based on the patient’s unique profile.

A Three Year Trend In 2016, for the third year in a row, personalized medicines accounted for more than 20 percent of all new molecular entities (NMEs) approved by the Us Food and Drug Administration (FDA). A New Molecular Entity (NME) or New Chemical Entity (NCE) is a drug or chemical that is without precedent among regulated and approved drug products. The NME designation indicates that a drug in development is not a version or derivative of an existing and previously investigated, trialed and approved substance. Being labeled as entirely 'new' or first-in-class molecule dictates that certain types of clinical trials must be run, and that particular attention must be paid to proving a drugs safety. The analysis underlines that nearly one of every four drugs the agency approved from 2014 to 2016 is a personalized medicine. That ratio is a sharp increase from 2005, when Personalized Medicines accounted for just 5% of NME approvals.

Newly Approved Medicines The six personalized medicines approved in 2016 include:   Rubraca (rucaparib) for the treatment of advanced ovarian cancer. The decision to use this product is informed by the BRCA1/2 biomarker status in patients. Exondys 51 (eteplirsen) for the treatment of Duchenne muscular dystrophy. The decision to use this product is informed by the DMD mutation biomarker status in patients. Epclusa (sofosbuvir and velpatasvir) for the treatment of chronic hepatitis C infection. The decision to use this product is informed by the HCV genotype status of the viral infection in patients. Tecentriq (atezolizumab) for the treatment of advanced or metastatic urothelial cancer and metastatic non-small cell lung cancer. The decision to use this product is informed by PD-L1 expression levels in the tumors of patients. Venclexta (venetoclax) for the treatment of chronic lymphocytic leukemia. The decision to use this product is informed by the chromosome 17p deletion biomarker status in patients. Zepatier (elbasvir and grazoprevir) for the treatment of chronic hepatitis C infection. The decision to use this product is informed by the HCV genotype 1 and 4 biomarker status of the viral infection in patients. Personalized Medicine in Oncology Nowhere is the transformation of healthcare toward personalized medicine more clear that in oncology. Of the six personalized NMEs approved in 2016, three are oncology drugs.

Newly Approved Indications FDA also approved several significant new personalized medicine indications for previously approved drugs in 2016. These approvals redefine the drugs’ intended populations and provide patients with effective personalized treatment options. The list of new personalized medicines in 2016 should therefore be complemented with reference to newly approved indications for: Imbruvica (ibrutinib), Opdivo (nivolumab), Keytruda (pembrolizumab) and Tecentriq (atezolizumab) for new molecularly defined subsets of patients.

Pharmacogenomic Biomarkers in Drub Labeling Total number of FDA - approved drugs with biomarker information provided on their drug label* 2017 165 61 / 165 classified Oncology/Hematology 238 pharmacogenomics biomarkers are included on FDA-approved drug label* Source: https://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm Information last updated 03/14/2017

The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer – “on label”: Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin®), ramucirumab (Cyramza®)  Bladder cancer: Atezolizumab (Tecentriq™), nivolumab (Opdivo®) Brain cancer: Bevacizumab (Avastin®), everolimus (Afinitor®) Breast cancer: Everolimus (Afinitor®), tamoxifen (Nolvadex), toremifene (Fareston®), Trastuzumab (Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), lapatinib (Tykerb®), letrozole (Femara®), pertuzumab (Perjeta®), ado-trastuzumab emtansine (Kadcyla®), palbociclib (Ibrance®), ribociclib (Kisqali®) Cervical cancer: Bevacizumab (Avastin®) Colorectal cancer: Cetuximab (Erbitux®), panitumumab (Vectibix®), bevacizumab (Avastin®), ziv-aflibercept (Zaltrap®), regorafenib (Stivarga®), ramucirumab (Cyramza®) Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec®) Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot), avelumab (Bavencio®) Head and neck cancer: Cetuximab (Erbitux®), pembrolizumab (Keytruda®), nivolumab (Opdivo®)  Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), sunitinib (Sutent®), regorafenib (Stivarga®) Giant cell tumor of the bone: Denosumab (Xgeva®) Kidney cancer: Bevacizumab (Avastin®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), temsirolimus (Torisel®), everolimus (Afinitor®), axitinib (Inlyta®), nivolumab (Opdivo®), cabozantinib (Cabometyx™), lenvatinib mesylate (Lenvima®) Leukemia: Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), rituximab (Rituxan®), alemtuzumab (Campath®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), blinatumomab (Blincyto®), venetoclax (Venclexta™), ponatinib hydrochloride (Iclusig®)  Liver cancer: Sorafenib (Nexavar®) Lung cancer: Bevacizumab (Avastin®), crizotinib (Xalkori®), erlotinib (Tarceva®), gefitinib (Iressa®), afatinib dimaleate (Gilotrif®), ceritinib (LDK378/Zykadia™), ramucirumab (Cyramza®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), osimertinib (Tagrisso™), necitumumab (Portrazza™), alectinib (Alecensa®), atezolizumab (Tecentriq™) Lymphoma: Ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), brentuximab vedotin (Adcetris®), rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib (Velcade®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), siltuximab (Sylvant®), idelalisib (Zydelig®), belinostat (Beleodaq®), obinutuzumab (Gazyva®), nivolumab (Opdivo®), pembrolizumab (Keytruda®) Multiple myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), panobinostat (Farydak®), daratumumab (Darzalex™), ixazomib citrate (Ninlaro®), elotuzumab (Empliciti™)  Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®), ruxolitinib phosphate (Jakafi®) Neuroblastoma: Dinutuximab (Unituxin™) Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin®), olaparib (Lynparza™), rucaparib camsylate (Rubraca™), niraparib tosylate monohydrate (Zejula™) Pancreatic cancer: Erlotinib (Tarceva®), everolimus (Afinitor®), sunitinib (Sutent®) Prostate cancer: Cabazitaxel (Jevtana®), enzalutamide (Xtandi®), abiraterone acetate (Zytiga®), radium 223 dichloride (Xofigo®) Skin cancer: Vismodegib (Erivedge®), sonidegib (Odomzo®), ipilimumab (Yervoy®), vemurafenib (Zelboraf®), trametinib (Mekinist®), dabrafenib (Tafinlar®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), cobimetinib (Cotellic™), alitretinoin (Panretin®), avelumab (Bavencio®) Soft tissue sarcoma: Pazopanib (Votrient®), olaratumab (Lartruvo™), alitretinoin (Panretin®) Systemic mastocytosis: Imatinib mesylate (Gleevec®) Thyroid cancer: Cabozantinib (Cometriq®), vandetanib (Caprelsa®), sorafenib (Nexavar®), lenvatinib mesylate (Lenvima®)   Source: https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet

Drug Development – Biopharmaceutical Companies ARE committed Personalized medicine is rapidly coming of age. Drug development pipelines are full of new targeted therapies that offer the hope of effective new treatment options for patients. Biopharmaceutical companies nearly doubled their R&D investment in personalized medicines over the past five years and expect to increase their investment by an additional 1/3 in the next five years. Biopharmaceutical researchers also predict a 69% increase in the number of personalized medicines in development over the next five years. Source: Tufts Center for the Study of Drug Development, “Personalized Medicine Gains Traction but Still Faces Multiple Challenges,” Impact Report, May/June 2015, Volume 17, Number 3

Genetic/Genomic Diagnostics More than 5,500 new Genetic/Genomic Testing products came to market between April 2015 and September 2016.* Source: Concert Genetics – formerly NextGxDx – The current landscape of genetic testing - 2016

Coverage and Payment Policy Coverage and Payment policies in both the public and private sectors play a critically important role in ensuring patient access and encouraging continued innovation. Healthcare policy leaders have contended that in order “to stimulate the development of a more robust diagnostics pipeline and to harness the benefits of personalized medicine in patient-centered care delivery, policymakers must create an environment that encourages increased investment in diagnostics, enables new advances in patient care that are safe, accurate and reliable, and establishes a viable pathway toward patient access.”* However under pressure to address rising healthcare costs, policymakers and payers are increasingly considering policies that may result in across the board coverage and payment cuts. These decisions may limit and/or discourage continued research and development in personalized medicine. Source: Abernethy, A, Abrahams, E, Barker, A, et al. Turning the tide against cancer through sustained medical innovation: The pathway to progress. Clinical Cancer Research. 2014;20(5): 1081-1086.

Coverage and Payment Policy Evidence Requirements Widespread insurance coverage of diagnostic tests, for example, will likely require practice-based evidence demonstrating value. Obtaining the real-world data necessary for generating this evidence is difficult unless the products and services are covered by payers. Value Assessment Frameworks Tools for supporting health care decision-making by quantifying the value of treatments Many of the frameworks, however, have been criticized for failing to account for the heterogeneity of treatment effects Value-Based Payment Models CMS and private payers are also proposing new, “value-based” payment models, also known as “alternative payment models” (APMs), that seek to drive improvements in care quality and efficiency.

Clinical Integration – Operationalizing Precision Medicine Integrating personalized medicine into health care requires: increasing awareness and understanding of personalized medicine concepts amongst the public and health care workforce; placing a greater emphasis on patient perspectives; recognizing the value of molecular pathways in guiding care; building new infrastructure and information management processes; and reshaping health care delivery to ensure access to personalized medicine technologies and services. To successfully integrate personalized medicine into health care, providers will need to implement a range of programs and processes in each of these areas.

2016 – meaningful progress Despite ongoing challenges in the areas of scientific discovery, diagnostic regulatory policy, reimbursement and integration of new technologies into clinical practice, the commitment witnessed in 2016 anticipates a shift away from one-size-fits-all, trial-and-error medicine and toward a health care system that utilizes molecular information to improve outcomes and make the health care system more efficient.

Demonstrated Real-World Success Better outcomes Lower costs Change in Physician Decision-making More drug reimbursed Workflow efficiencies 23 PFS weeks on precision medicine vs 12 PFS weeks on standard of care1 $4,665 per PFS-week per patient on precision oncology vs. $5,000 on standard of care1 64% of patients had their care management changed1 82% of targeted therapy orders successfully obtained through insurance approval or clinical trials2 4-fold increase in molecular tumor board throughput 1. Proof that this works: Syapse at Intermountain Healthcare [if we think that this story is reasonably solid] a. 2X increase in progression free survival b. 10% decrease in total cost of care per week c. 20x increase in patients receiving precision medicine d. 5x increase in targeted therapy procurement 1. Haslem, Derrick S., et al. "A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression-Free Survival Without Increased Health Care Costs." Journal of Oncology Practice (2016): JOPR011486. 2. Nadauld, Lincoln, et al. "Implementation of a precision cancer program in an integrated health care system." ASCO Annual Meeting Proceedings. Vol. 33. No. 15_suppl. 2015.