OPENING KEYNOTE: PRECISION MEDICINE AT THE INFLECTION POINT. Session PM1, March 5, 2018 Damon Hostin, CEO, Precision Medicine Alliance, LLC

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1 OPENING KEYNOTE: PRECISION MEDICINE AT THE INFLECTION POINT Session PM1, March 5, 2018 Damon Hostin, CEO, Precision Medicine Alliance, LLC 1

2 Conflicts of Interest Damon Hostin Has no real or apparent conflicts of interest to report. 2

3 Agenda Precision Medicine- Scope and Definition of Terms The Ecosystem and Dynamics Data Matters, Context and Value in Workflow Decision Support and Resources State of Reimbursement Closing Thoughts 3

4 Learning Objectives Describe the current state of precision medicine Discuss the precision medicine ecosystem, drivers, emerging technologies, and C&BI tools required for the journey Explain the need for data interoperability, integration into the provider workflow, and data sharing across the care continuum Assess clinical decision support tools for selecting the best targeted therapy and pre-screening of patients for clinical trials Outline the reimbursement strategies for precision medicine treatments 4

5 Precision Medicine- Scope and Definition of Terms Individualized Medicine from Prewomb to Tomb Topol, Eric J. Cell, Volume 157, Issue 1,

6 Contribution of Human Diversity to Health 6

incomplete story Ablate root cells (e.g.

7 Traditional Cancer Therapy Destabilize cell division/ kill all fast growing cells = collateral damage Block growth hormones- incomplete story Ablate root cells (e.g. rituximab anti-cd20) hard to get them all Still a foundation of treatment Chemo Rules 89 7

Human Genome Project (HGP) to the Modern Dawn of Precision Medicine References: 1. https://www.genome.gov/sequencingcosts/ 2.

" Genome Medicine. 2015 September 30; 7:100 3. https://www.forbes.

"The NHGRI-EBI Catalog of published genome-wide association studies." Available at: https://www.ebi.ac.uk/gwas. Accessed 20 Jun, 2017. 5.

8 Human Genome Project (HGP) to the Modern Dawn of Precision Medicine References: Miller NA et al., "A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases." Genome Medicine September 30; 7: "The NHGRI-EBI Catalog of published genome-wide association studies." Available at: Accessed 20 Jun, Chakravarty D et al., "OncoKB: A Precision Oncology Knowledge Base." JCO Precision Oncology May 2017; DOI: /PO

9 Definition of Personalized (Precision?) Medicine Personalized medicine is an evolving field in which care givers use molecular diagnostic tests to determine which medical treatments will work best for the patients. By combining the data from those tests with an individual s medical history, circumstances, and values, health care providers and patients can develop targeted treatment and prevention plans. Adapted from: 9

10 10

may convey resistance to drugs- therefore more information on the patient s tumor is needed Tumor profiles inform the

11 Knowledge of tumor biology targets and Mechanism of Action= PRECISION ONCOLOGY Targeted therapeutics disrupt growth signals, induce cancer cell death, and/or make target cells visible to the immune system Some targets have variants that may convey resistance to drugs- therefore more information on the patient s tumor is needed Tumor profiles inform the clinicians of each patient s tumor armor and weakness Also- epigenetics, proteomics, RNA Source: Adapted from Chambers, UTSW 11

therapy: some lessons from the past decade Huang, Shen, Ding,

12 Hallmarks of Cancer: The Next Generation Hanahan, Douglas et al. Cell, Volume 144, Issue 5, Molecularly targeted cancer therapy: some lessons from the past decade Huang, Shen, Ding, Geng; Shanghai Institute of Materia Medica, Chinese Academy of Sciences

13 2013: Novel Therapeutics = Broader Tumor Sequencing Personalized Medicine, McKinsey & Co

2017: Moving from Molecular Plausibility to STD of Care Implementing Genome-Driven Oncology Cell 168, February 9, 2017 Need data to fill the evidence gap David M. Hyman,1,5 Barry S.

14 2017: Moving from Molecular Plausibility to STD of Care Implementing Genome-Driven Oncology Cell 168, February 9, 2017 Need data to fill the evidence gap David M. Hyman,1,5 Barry S. Taylor,2,3,4 and Jose Baselga1,2,5,* 1Department of Medicine 2Human Oncology and Pathogenesis Program 3Department of Epidemiology and Biostatistics for Molecular Oncology Memorial Sloan Kettering Cancer Center, 5Weill Cornell Medical College 14

15 The Precision Medicine Ecosystem and Dynamics 15

Together CHI and Dignity Impact: ~25% of United States Population (~95 Million lives) At least 70,000 new analytic cancer cases/ year Patients through: Acute Care facilities in 15 states Non-acute

16 Together CHI and Dignity Impact: ~25% of United States Population (~95 Million lives) At least 70,000 new analytic cancer cases/ year Patients through: Acute Care facilities in 15 states Non-acute facilities in 25 states Dozens of underserved communities by providing charitable care and services (~$3.8 Billion 2016) The combined system would have more than $28 billion in operating revenues, more than 700 care sites, about 159,000 employees and more than 25,000 physicians and other advanced practitioners. 16

17 Precision Medicine Alliance Program Elements and Applications Elements Clinician Education, Support and Tools Clinical Workflow and Decision Support Healthcare-centric Diagnostic Tests Clinical Trial Portfolio Access Data Management for Quality/Outcome Research Applications Cancer treatment (tumor profiling)/ risk Pharmacogenomics Cardiovascular (w/ constitutional risks) Pain management Behavioral health Population wellness 17

18 Precision Medicine Alliance Strategy Post-Modern approach to diagnostics Fast Follower/ Shoulders of giants Eschew urges to vertically integrate Highly partnered -Industry friendly Data-centric and Research integrated Sustain a bridge to Precision Medicine Standard of Care Access is Key- avoid ROI diminishing returns Share where appropriate for the common good 18

19 Harmonized Dataset and Workflow Ecosystem Considerations Clinical and Operational Clinical case queries Reference Population Payer evidence Outcomes research Quality improvement Moonshot applications Business Opportunities Real World Evidence Clinical Trial Optimization and Enrollment Value-based Care Biomarker Testing Surveillance, Decision Support Patient Connectivity (RWO ) 19

20 Data Matters, Context and Value in Workflow 20

21 21

Number of Markers and Cost Anatomy of a Pan-Tumor NGS MDx Test Discovery Research Nonvalidated mutations in known oncogenes Clinical Trial Inclusion and Off-Label Access Putative

22 Number of Markers and Cost Anatomy of a Pan-Tumor NGS MDx Test Discovery Research Nonvalidated mutations in known oncogenes Clinical Trial Inclusion and Off-Label Access Putative markers or genes Novel Therapeutic Inclusion/ Exclusion Markers Off-Label Approved Therapeutic Markers Indicated Cancer Markers Companion Diagnostics Clinical Evidence and Payer Coverage 22

23 Extracting Value from Tumor Data in Workflows 23

24 Decision Support and Resources 24

25 SMARCB1 RB1 TP53 ERBB4 FBXW7 BRAF KIT GNAS HRAS EGFR PDGFRA PIK3CA CDKN2A ERBB2 ABL1 JAK2 KRAS NRAS NOTCH1 ATM FGFR1 STK11 PTPN11 APC SMAD4 PTEN SMO CTNNB1 RET IDH2 SRC EZH2 VHL MPL STK11 PTPN11 APC SMAD4 PTEN SMO CTNNB1 RET IDH2 SRC Gene n=64 EZH2 VHL MPL NTRK NPM1 FLT3 FGFR3 CDH1 KDR HNF1A MLH1 ALK IDH1 GNAQ AKT1 JAK3 FGFR2 GNA11 MET CSF1R ROS-1 PIK3 AKT BRAFR DDR2 HER2 BCR/ABL TPMT c-kit PML/RAR PDGFR MYCN MS4A1 CD274 Kidney Cancer Laryngeal and Hypopharyngeal Cancer Leukemia - Acute Lymphocytic (ALL) Leukemia - Acute Myeloid (AML) Leukemia - Chronic Lymphocytic (CLL) Leukemia - Chronic Myeloid (CML) Leukemia - Chronic Myelomonocytic (CMML) Liver Cancer Lung Cancer - Non-Small Cell Lung Cancer - Small Cell Lung Carcinoid Tumor Lymphoma Lymphoma of the Skin Malignant Mesothelioma Multiple Myeloma Myelodysplastic Syndrome Nasal Cavity and Paranasal Sinus Cancer Nasopharyngeal Cancer Neuroblastoma Non-Hodgkin Lymphoma Oral Cavity and Oropharyngeal Cancer Osteosarcoma Ovarian Cancer Pancreatic Cancer Penile Cancer Pituitary Tumors Prostate Cancer Retinoblastoma Rhabdomyosarcoma Salivary Gland Cancer Sarcoma - Adult Soft Tissue Cancer Skin Cancer - Basal and Squamous Cell Skin Cancer - Melanoma Small Intestine Cancer Stomach Cancer Testicular Cancer Thymus Cancer Thyroid Cancer Uterine Sarcoma Vaginal Cancer Vulvar Cancer Indication n=58 Adrenal Cancer Anal Cancer Bile Duct Cancer Bladder Cancer Bone Cancer Brain/CNS Tumors Breast Cancer Cervical Cancer Colon/Rectum Cancer Endometrial Cancer Esophagus Cancer Eye Cancer Gallbladder Cancer Gastrointestinal Carcinoid Tumors Gastrointestinal Stromal Tumor (GIST) Hodgkin Disease Kaposi Sarcoma Kidney Cancer Laryngeal and Hypopharyngeal Cancer Leukemia - Acute Lymphocytic (ALL) Leukemia - Acute Myeloid (AML) Leukemia - Chronic Lymphocytic (CLL) Leukemia - Chronic Myeloid (CML) Leukemia - Chronic Myelomonocytic (CMML) Liver Cancer Lung Cancer - Non-Small Cell Lung Cancer - Small Cell Lung Carcinoid Tumor Lymphoma Lymphoma of the Skin Malignant Mesothelioma Multiple Myeloma Myelodysplastic Syndrome Nasal Cavity and Paranasal Sinus Cancer Nasopharyngeal Cancer Neuroblastoma Non-Hodgkin Lymphoma 25 Oral Cavity and Oropharyngeal Cancer Osteosarcoma Gene - Indication Drug Relationship Complexity cabozantinib (Cometriq ) carfilzomib (Kyprolis ) ceritinib (LDK378/Zykadia ) cetuximab (Erbitux ) cobimetinib (Cotellic ) crizotinib (Xalkori ) dabrafenib (Tafinlar ) daratumumab (Darzalex ) dasatinib (Sprycel ) Drug n=93 denileukin diftitox (Ontak ) Denosumab (Xgeva ) abiraterone acetate (Zytiga ) dinutuximab (Unituxin ) ado-trastuzumab emtansine (Kadcyldurvalumab (Imfinzi ) afatinib dimaleate (Gilotrif ) elotuzumab (Empliciti ) alectinib (Alecensa ) enzalutamide (Xtandi ) alemtuzumab (Campath ) erlotinib (Tarceva ) alitretinoin (Panretin ) everolimus (Afinitor ) anastrozole (Arimidex ) exemestane (Aromasin ) atezolizumab (Tecentriq ) fulvestrant (Faslodex ) avelumab (Bavencio ) gefitinib (Iressa ) axitinib (Inlyta ) Ibritumomab tiuxetan (Zevalin ) belinostat (Beleodaq ) ibrutinib (Imbruvica ) bevacizumab (Avastin ) idelalisib (Zydelig ) bexarotene (Targretin ) Imatinib mesylate (Gleevec ) blinatumomab (Blincyto ) ipilimumab (Yervoy ) bortezomib (Velcade ) ixazomib citrate (Ninlaro ) bosutinib (Bosulif ) Lanreotide acetate (Somatuline De brentuximab vedotin (Adcetris ) lapatinib (Tykerb ) brigatinib (Alunbrig ) lenvatinib mesylate (Lenvima ) cabazitaxel (Jevtana ) letrozole (Femara ) cabozantinib (Cabometyx ) midostaurin (Rydapt ) cabozantinib (Cometriq ) necitumumab (Portrazza ) carfilzomib (Kyprolis ) neratinib maleate (Nerlynx ) ceritinib (LDK378/Zykadia ) nilotinib (Tasigna ) cetuximab (Erbitux ) niraparib tosylate monohydrate (Ze cobimetinib (Cotellic ) nivolumab (Opdivo ) crizotinib (Xalkori ) obinutuzumab (Gazyva ) dabrafenib (Tafinlar ) ofatumumab (Arzerra ) daratumumab (Darzalex ) olaparib (Lynparza ) dasatinib (Sprycel ) olaratumab (Lartruvo ) denileukin diftitox (Ontak ) osimertinib (Tagrisso ) Denosumab (Xgeva ) palbociclib (Ibrance ) dinutuximab (Unituxin ) panitumumab (Vectibix ) durvalumab (Imfinzi ) panobinostat (Farydak ) elotuzumab (Empliciti ) pazopanib (Votrient ) enzalutamide (Xtandi ) neratinib maleate (Nerlynx ) nilotinib (Tasigna ) niraparib tosylate monohydrate (Ze nivolumab (Opdivo ) obinutuzumab (Gazyva ) ofatumumab (Arzerra ) olaparib (Lynparza ) olaratumab (Lartruvo ) osimertinib (Tagrisso ) palbociclib (Ibrance ) panitumumab (Vectibix ) panobinostat (Farydak ) pazopanib (Votrient ) pembrolizumab (Keytruda ) pertuzumab (Perjeta ) ponatinib hydrochloride (Iclusig ) pralatrexate (Folotyn ) radium 223 dichloride (Xofigo ) ramucirumab (Cyramza ) regorafenib (Stivarga ) ribociclib (Kisqali ) rituximab (Rituxan ) romidepsin (Istodax ) rucaparib camsylate (Rubraca ) ruxolitinib phosphate (Jakafi ) siltuximab (Sylvant ) sonidegib (Odomzo ) sorafenib (Nexavar ) sunitinib (Sutent ) tamoxifen (Nolvadex) temsirolimus (Torisel ) toremifene (Fareston ) trametinib (Mekinist ) trastuzumab (Herceptin ) Tretinoin (Vesanoid ) vandetanib (Caprelsa ) vemurafenib (Zelboraf ) venetoclax (Venclexta ) vismodegib (Erivedge ) vorinostat (Zolinza ) aflibercept (Zaltrap )

26 SMARCB1 RB1 TP53 ERBB4 FBXW7 BRAF KIT GNAS HRAS EGFR PDGFRA PIK3CA CDKN2A ERBB2 ABL1 JAK2 KRAS NRAS NOTCH1 ATM FGFR1 STK11 PTPN11 APC SMAD4 PTEN SMO CTNNB1 RET IDH2 SRC EZH2 VHL MPL NPM1 NTRK FLT3 FGFR3 CDH1 KDR HNF1A MLH1 ALK IDH1 GNAQ AKT1 JAK3 FGFR2 GNA11 MET CSF1R ROS-1 PIK3 AKT BRAFR DDR2 HER2 BCR/ABL TPMT c-kit PML/RAR PDGFR MYCN MS4A1 CD274 Adrenal Cancer Anal Cancer Bile Duct Cancer Bladder Cancer Bone Cancer Brain/CNS Tumors Breast Cancer Cervical Cancer Colon/Rectum Cancer Endometrial Cancer Esophagus Cancer Eye Cancer Gallbladder Cancer Gastrointestinal Carcinoid Tumors Gastrointestinal Stromal Tumor (GIST) Hodgkin Disease Kaposi Sarcoma Kidney Cancer Laryngeal and Hypopharyngeal Cancer Leukemia - Acute Lymphocytic (ALL) Leukemia - Acute Myeloid (AML) Leukemia - Chronic Lymphocytic (CLL) Leukemia - Chronic Myeloid (CML) Leukemia - Chronic Myelomonocytic (CMML) Liver Cancer Lung Cancer - Non-Small Cell Lung Cancer - Small Cell Lung Carcinoid Tumor Lymphoma Lymphoma of the Skin Malignant Mesothelioma Multiple Myeloma Myelodysplastic Syndrome Nasopharyngeal Cancer Neuroblastoma Non-Hodgkin Lymphoma Oral Cavity and Oropharyngeal Cancer Osteosarcoma Ovarian Cancer Pancreatic Cancer Penile Cancer Pituitary Tumors Prostate Cancer Gene Indication Retinoblastoma Rhabdomyosarcoma Salivary Gland Cancer Sarcoma - Adult Soft Tissue Cancer Skin Cancer - Basal and Squamous Cell Skin Cancer - Melanoma Small Intestine Cancer Stomach Cancer Testicular Cancer Thymus Cancer Thyroid Cancer Uterine Sarcoma Vaginal Cancer Vulvar Cancer 26

n=345,216 abiraterone acetate (Zytiga ) ado-trastuzumab emtansine (Kadcyl afatinib dimaleate (Gilotrif ) alectinib (Alecensa ) alemtuzumab (Campath ) alitretinoin (Panretin ) anastrozole (Arimidex )

(Bosulif ) brentuximab vedotin (Adcetris ) brigatinib (Alunbrig ) cabazitaxel (Jevtana ) cabozantinib (Cabometyx ) cabozantinib (Cometriq ) carfilzomib (Kyprolis ) ceritinib (LDK378/Zykadia )

(Unituxin ) durvalumab (Imfinzi ) elotuzumab (Empliciti ) enzalutamide (Xtandi ) erlotinib (Tarceva ) everolimus (Afinitor ) exemestane (Aromasin ) fulvestrant (Faslodex ) gefitinib (Iressa )

27 n=345,216 abiraterone acetate (Zytiga ) ado-trastuzumab emtansine (Kadcyl afatinib dimaleate (Gilotrif ) alectinib (Alecensa ) alemtuzumab (Campath ) alitretinoin (Panretin ) anastrozole (Arimidex ) atezolizumab (Tecentriq ) avelumab (Bavencio ) axitinib (Inlyta ) belinostat (Beleodaq ) bevacizumab (Avastin ) bexarotene (Targretin ) blinatumomab (Blincyto ) bortezomib (Velcade ) bosutinib (Bosulif ) brentuximab vedotin (Adcetris ) brigatinib (Alunbrig ) cabazitaxel (Jevtana ) cabozantinib (Cabometyx ) cabozantinib (Cometriq ) carfilzomib (Kyprolis ) ceritinib (LDK378/Zykadia ) cetuximab (Erbitux ) cobimetinib (Cotellic ) crizotinib (Xalkori ) dabrafenib (Tafinlar ) daratumumab (Darzalex ) dasatinib (Sprycel ) denileukin diftitox (Ontak ) Denosumab (Xgeva ) dinutuximab (Unituxin ) durvalumab (Imfinzi ) elotuzumab (Empliciti ) enzalutamide (Xtandi ) erlotinib (Tarceva ) everolimus (Afinitor ) exemestane (Aromasin ) fulvestrant (Faslodex ) gefitinib (Iressa ) Ibritumomab tiuxetan (Zevalin ) ibrutinib (Imbruvica ) idelalisib (Zydelig ) Imatinib mesylate (Gleevec ) ipilimumab (Yervoy ) ixazomib citrate (Ninlaro ) Lanreotide acetate (Somatuline De lapatinib (Tykerb ) lenvatinib mesylate (Lenvima ) letrozole (Femara ) midostaurin (Rydapt ) necitumumab (Portrazza ) neratinib maleate (Nerlynx ) nilotinib (Tasigna ) niraparib tosylate monohydrate (Ze nivolumab (Opdivo ) obinutuzumab (Gazyva ) ofatumumab (Arzerra ) olaparib (Lynparza ) olaratumab (Lartruvo ) osimertinib (Tagrisso ) palbociclib (Ibrance ) panitumumab (Vectibix ) panobinostat (Farydak ) pazopanib (Votrient ) pembrolizumab (Keytruda ) pertuzumab (Perjeta ) ponatinib hydrochloride (Iclusig ) pralatrexate (Folotyn ) radium 223 dichloride (Xofigo ) ramucirumab (Cyramza ) regorafenib (Stivarga ) ribociclib (Kisqali ) rituximab (Rituxan ) romidepsin (Istodax ) rucaparib camsylate (Rubraca ) ruxolitinib phosphate (Jakafi ) siltuximab (Sylvant ) sonidegib (Odomzo ) sorafenib (Nexavar ) sunitinib (Sutent ) tamoxifen (Nolvadex) temsirolimus (Torisel ) toremifene (Fareston ) trametinib (Mekinist ) trastuzumab (Herceptin ) Tretinoin (Vesanoid ) vandetanib (Caprelsa ) vemurafenib (Zelboraf ) venetoclax (Venclexta ) vismodegib (Erivedge ) vorinostat (Zolinza ) aflibercept (Zaltrap ) 27

28 Oncology Precision Medicine Dataset Snapshot (2016) 28

29 State of Reimbursement 29

A Revolution in Health Care 2014-2024 Forecasted Patient Volumes Shifting incentives Payment pressures/innovations New competitors Technology

30 A Revolution in Health Care Forecasted Patient Volumes Shifting incentives Payment pressures/innovations New competitors Technology advancements Consumer expectations Cost shifting- risk bearing models Sources: Sg2 Impact of Change v14.0; NIS; PharMetrics; CMS; Sg2 Analysis 30

31 Pan-gene MDx Testing 31

32 Medicare FFS Payment Cuts Source: The Advisory Board

33 33

34 The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) is a bipartisan legislation signed into law on April 16, 2015 Repeals the Sustainable Growth Rate formula for physician payments Adapted from Deloitte Advisory Regulatory Services for Life Sciences and Health Care Establishes a path toward a new payment system more closely aligned to quality and outcomes 34 Offers significant financial incentives for health care professionals to participate in riskbearing, coordinated care models

35 Merit-based Incentive Payment Systems (MIPS) Components of MIPS Composite Score ( ) 50% 45% 10% 15% 30% 30% 25% 25% 25% 15% 15% 15% Source: Public Law (April 16, 2015;) Adapted from Deloitte Advisory Regulatory Services for Life Sciences and Health Care 35 Quality: PQRS Resource Use: Value-based Payment Modifier measures Meaningful Use of EHRs: EHR Incentive Payment measure Clinical Improvement Activities: Expanded access, population management, care coordination, beneficiary engagement, patient safety, and alternative payment models Existing incentive programs end 2018, and performance consolidated into a new composite score MIPS payment starting 2019

36 36

37 Providing Opportunities for Scalable Impact: An approximate trajectory of value 37

38 Closing Thoughts Central vs. local program management strategy Testing strategy Dx business? Compete with artificial economies and secondary usage markets subsidizing testing? Research strategy? Data readiness (also governance, ownership, operations, policy) Are other capabilities built and prepared to derive value? Is the program an investment or operational upgrade? Can the team be a service company? Is your organization ready for a challenge? Can you stay focused? Avoid envy? 38

39 Need for Good Data (Evidence) 39

40 Respect the Complexity of Biology= Fight the urge to be reductionist, but go forward 40

41 Questions? Damon Hostin, CEO Precision Medicine Alliance, LLC Dignity Health/Catholic Health Initiatives Please complete session evaluation! Presentation thanks to: Anne Lincoln, MS, Oncology Program Manager, PMA Kristen Collins, MPH, Program Coordinator, PMA 41

Genetics in Cancer Therapy. Raju Kucherlapati, Ph.D. Harvard Medical School

Genetics in Cancer Therapy. Raju Kucherlapati, Ph.D. Harvard Medical School Genetics in Cancer Therapy Raju Kucherlapati, Ph.D. Harvard Medical School RK Financial interests I do not intend to discuss an off-label use of a product during this activity AVEO Pharmaceuticals KEW