What It Takes to Get Incorporation Into Guidelines and Reimbursement for Advanced Cancer Diagnostics: Lessons from Oncotype DX

What It Takes to Get Incorporation Into Guidelines and Reimbursement for Advanced Cancer Diagnostics: Lessons from Oncotype DX WSMOS Meeting Oct 2013 Steven Shak, MD Genomic Health

Disclosure: October 2013 Steven Shak, M.D. I have the following financial relationships to disclose: Employee of: Genomic Health, Inc. Stockholder in: Genomic Health, Inc.

Personalized Medicine and Diagnostics Moves to Center of Global Healthcare Solution Economy in Crisis Technology Accelerating Personalized Medicine Healthcare Reform Healthcare Spending Soaring

Trastuzumab: Humanized Anti-HER2 Antibody Targets the HER2 protein on the surface of breast cancer cells Safety and efficacy in HER2 positive breast cancer demonstrated in large randomized trials Approval of Trastuzumab For advanced disease and early adjuvant treatment Approval of HER2 tests Herceptest immunohistochemistry FISH

The Need For Diagnostics Response Rates in Major Disease

Laboratory Services Spending is a Tiny Fraction of Total Health Care Spending Total "Health Care" Spending CY2006 = $2.1 Trillion Lab Services Expenditures* $170 / Person 2.4% Other $6,856 / Person 97.6% Other Lab Services Expenditures* * Total may include clinical laboratory and anatomic services. Source: Centers for Medicare & Medicaid Services. Historical Data: National Health Expenditure Accounts CY2006.

Oncotype DX Recurrence Score Recurrence Score based on quantitative RT- PCR analysis of 21 genes Established clinical utility to aid in the selection of ER+ patients for treatment with adjuvant chemotherapy Distant recurrence (Paik et al, NEJM 2004) Breast cancer survival (Habel et al, Breast Cancer Res 2006) Chemotherapy benefit (Paik et al, JCO 2006, Albain et al, SABCS 2007) ASCO, NCCN, NICE Guidelines Standard of care Over 375,000 tests since 2004; >70 countries Reimbursed by Medicare and major payers in US and for many/all patients in Canada, Ireland, UK, Greece, Germany, Israel

Blue Cross and Blue Shield Association Technology Assessment Criteria* 1. The technology must have final approval from the appropriate governmental regulatory bodies. The indications for which the technology is approved need not be the same as those which Blue Cross and Blue Shield Association's Technology Evaluation Center is evaluating. 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes. The evidence should consist of well-designed and well-conducted investigations published in peer-reviewed journals. The quality of the body of studies and the consistency of the results are considered in evaluating the evidence. The evidence should demonstrate that the technology can measure or alter the physiological changes related to a disease, injury, illness, or condition. In addition, there should be evidence or a convincing argument based on established medical facts that such measurement or alteration affects health outcomes. Opinions and evaluations by national medical associations, consensus panels, or other technology evaluation bodies are evaluated according to the scientific quality of the supporting evidence and rationale. 3. The technology must improve the net health outcome. The technology's beneficial effects on health outcomes should outweigh any harmful effects on health outcomes. 4. The technology must be as beneficial as any established alternatives. The technology should improve the net health outcome as much as, or more than, established alternatives. 5. The improvement must be attainable outside the investigational settings. When used under the usual conditions of medical practice, the technology should be reasonably expected to satisfy TEC criteria #3 and #4. *http://www.bcbs.com/blueresources/tec/ 9

Diagnostic Development Strategy Must Address Analytical Performance, Clinical Validity, and Clinical Utility Diagnostic Tests Must Be Accurate and Clinically Meaningful Analytical performance - How reliably and reproducibly the test quantifies the analyte(s) of interest Clinical validity - How well the test relates to the clinical outcome of interest Clinical utility - Whether the results of the test provide information that can contribute to and improve upon current outcomes Cannot be considered independently Analytic performance must be evaluated in context of the clinical use Clinical validity must be assessed in context of analytic performance

Diagnostic Development and Validation Strategy Requires Multiple Studies Technical Feasibility Development Studies to Select the Final Genes Analytical Methods Finalization and Assay Validation Clinical Validation Studies Fit for Purpose Studies of Clinical Utility and Health Economics Continuing Research

Clinical Laboratory Improvement Amendments (CLIA) Regulations All assay methods and procedures defined prior to clinical validation studies, for example: Specimen eligibility Reagent qualification Instrument validation Controls and calibrators Linearity, precision, reproducibility Proficiency testing over time

Genomic Health CLIA-Certified and College of American Pathology-Accredited Reference Laboratory Oncotype DX Process Number of Standard Operating Procedures (SOPs) and Forms: Category Number of SOPs Number of Forms Equipment 33 18 Finance 1 0 Histopathology 6 6 IT 23 10 Materials Management 7 6 Pre & Post Analytical 13 3 Production & Quality Control 52 15 QA 15 36 Safety & Facilities 4 0 Total 154 94

Landmark B-20 Clinical Trial in 1990s Established Benefit of Chemotherapy In Breast Cancer Node Negative Estrogen Receptor Positive Disease Only 4 out of 100 Women Benefit 0 4 8 12 Years Fisher et al. JNCI. 1997;89:1673-82

Chemotherapy Benefit and Oncotype DX NSABP B-20 Chemotherapy Benefit Study in Node Negative, Estrogen Receptor Positive Disease Design Tam + MF Randomized Tam + CMF Tam Objective: Determine the magnitude of the chemotherapy benefit as a function of 21-gene Recurrence Score A Prospective Retrospective Study *Paik et al, J Clin Oncol. 2006;24:3726-3734.

NSABP B-20 Results in All Unselected Patients Proportion Free of Distant Recurrence 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 All Patients Tam + Chemo Tam N Events 424 33 227 31 p = 0.02 0 2 4 6 8 10 12 Years 10 yr 92% 88%

NSABP B-20 Results by Recurrence Score Group DRFI 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Low-Risk Patients (RS < 18) Tam + Chemo Tam Years N Events 218 11 135 5 p = 0.76 0 2 4 6 8 10 12 10 yr 97% 96% RS < 18 0.4 RS 18 30 0.3 DRFI 1.0 0.9 0.8 0.7 0.6 0.5 0.2 0.1 0.0 Int Risk Patients (RS 18-30) N Events Tam + Chemo 89 9 Tam 45 8 p = 0.71 0 2 4 6 8 10 12 Years 10 yr 89% 91% 1.0 0.9 0.8 10yr 88% 0.7 DRFI 0.6 0.5 0.4 0.3 RS 31 60% 0.2 0.1 0.0 High-Risk Patients (RS 31) Tam + Chemo Tam N Events 117 13 47 18 p = 0.001 0 2 4 6 8 10 12 Years

Oncotype DX Changed Treatment Decisions in Over One- Third of Patients Women Treatment Diagnosed Plan After Prior with Oncotype to Breast Cancer DX DX Chemotherapy Over a 37% Change recommended in Treatment for 62% Decisions of patients Chemotherapy No Chemotherapy 21 * Based on meta-analysis of seven studies with 912 patients

Cost Effectiveness of Oncotype DX* SURVIVAL. Oncotype DX Recurrence Score guided therapy is associated with a gain in individual life expectancy of 2.2 years compared with tamoxifen alone, whereas it is associated with similar life expectancy to that seen with the chemotherapy and tamoxifen strategy COSTS. Oncotype DX Recurrence Score guided therapy is estimated to provide a net cost savings of $2256 compared with chemotherapy and tamoxifen with an incremental cost-effectiveness ratio of $1944 per life year saved compared with tamoxifen alone *Lyman et al, Cancer. 2007;109:1011-1018 22

All the Payors Need to be Addressed Individually Technology Evaluation Center Florida, California, Michigan, Alabama, New York, Delaware, New Jersey, Pennsylvania, South Carolina, Arkansas, Idaho, Montana, North Dakota, Minnesota, Kansas, Arizona

Continuing Research More than 6,000 Patients Studied in 15 Trials Study Type No. Pts Nodal Status Providence Exploratory 136 Neg Rush Exploratory 78 Pos NSABP B-20 Exploratory 233 Neg NSABP B-14 Prospective* 668 Neg MD Anderson Prospective* 149 Neg Kaiser Permanente Prospective* Case-Control 790 Cases/Controls Neg NSABP B-14 Prospective* Placebo vs Tam 645 Neg Milan Exploratory 89 Neg/Pos NSABP B-20 Prospective* Tam vs Tam+Chemo 651 Neg ECOG 2197 Exploratory and Prospective* 776 Neg/Pos SWOG 8814 Prospective* Tam vs Tam+Chemo 367 Pos ATAC Prospective* Tam vs AI 1231 Neg/Pos Japan Multicenter Prospective* 280 Neg/Pos NSABP B-28 Prospective* AC vs AC+Paclitaxel 1065 Pos NCCTG N9831 Prospective* CT vs CT+Trasuzumab 901 Neg/Pos *Prospective Retrospective Studies 25

Commitment to this Paradigm Driving A Revolution in Cancer Care Do I need chemotherapy? Do I have an aggressive disease? Do I need radiation? Do I need surgery? Invasive Breast Cancer Stage II/ MMR Colon Cancer DCIS Breast Cancer Prostate Cancer 26

Policies and Incentives for Integration of Genomics and Next Generation Sequencing... Delivering what patients, physicians, and payors need Tests must be Fit for Purpose ; multiple studies required to provide the evidence (actionable, beyond traditional measures) Technical innovation brought to standardized implementation Reimbursement based on value, providing the resources to do it right Continuing research as treatment evolves Leadership, collaborations, teamwork

Understanding and Treating Cancer Across the Continuum The Patient Journey Risk Assessment Screening & Prevention Early Disease Diagnosis Adjuvant Treatment Selection Advanced Disease Diagnosis Treatment Selection Treatment Monitoring Diagnostics will increasingly play a critical role All Cancer Patients in the Future Will Benefit From Personalized Medicine and Diagnostics: Molecularly-guided staging Molecularly-guided treatment Molecularly-guided prevention

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