CONFIDENTIAL Evidence Dossier PUBLISH DATE January 22, 2021 National Comprehensive Cancer Network® (NCCN) makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. US-FLDX-2000011 Jump to Table of Contents Last update: January 22, 2021 1 EXECUTIVE SUMMARY In August 2020, FoundationOne® Liquid CDx became the broadest United States (US) Food and Drug Administration (FDA)-approved circulating tumor deoxyribonucleic acid (ctDNA)-based comprehensive genomic profiling (CGP) assay (liquid biopsy) for use as a companion diagnostic to identify patients who may benefit from treatment with certain targeted therapies in accordance with the approved therapeutic product labeling. FoundationOne Liquid CDx is currently an FDA-approved companion diagnostic for 7 drug therapies in 4 cancer types.1 Additionally, FoundationOne Liquid CDx is intended to provide tumor mutation profiling to be used by qualified healthcare professionals in accordance with professional guidelines in oncology for patients with malignant neoplasms (FoundationOne Liquid CDx Test Description). FoundationOne Liquid CDx is the new liquid biopsy test that replaces the previously available liquid biopsy laboratory developed test (LDT), FoundationOne Liquid (Table 6-4). FoundationOne Liquid CDx is part of a portfolio of CGP assays that provides a CGP testing option for any advanced cancer patient (Figure 1-1). Figure 1-1. Foundation Medicine Portfolio Abbreviations: DNA, deoxyribonucleic acid; NY, New York; FDA, Food and Drug Administration; RNA, ribonucleic acid. Source: Foundation Medicine, Inc. Identifying Appropriate Treatment Options in Advanced Cancer Represents Significant Unmet Need Approximately 540,000 people are diagnosed with advanced cancer annually in the US (Figure 1-2) (Epidemiology of Advanced Cancer).2,3,4 Prognosis remains poor for most types of metastatic solid CONFIDENTIAL PAGE 2 Jump to Table of Contents Last update: January 22, 2021 tumors, with relatively low 5-year survival, ranging from 5% in patients with non-small cell lung cancer (NSCLC) to 39% in patients with head and neck cancer (Historical Treatment of Advanced Cancer).5,6 Figure 1-2. Estimated 2020 Distribution of Stage of Disease Within the Select Solid Tumor Cancers 350,000 300,000 250,000 200,000 150,000 100,000 50,000 0 Breast Melanoma Prostate NSCLC Pancreas Hepatobiliarya Ovarian Stage III or IV All stages a Hepatobiliary only includes HCC for this calculation. Abbreviations: HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer. Source: Kantar Health 2020.4 Avoidance of therapies that are unlikely to benefit patients and potentially have serious side effects will maximize patient outcomes and reduce costs (Historical Treatment of Advanced Cancer).7-9 . Response rates (RRs) to chemotherapy, the historical standard of care, are typically poor among patients with advanced cancer, with complete responses (CRs) observed in 10% or fewer patients.10 . Further, chemotherapy-related adverse events result in hospitalization in up to 20% of advanced cancer patients.7-9 . The goal is to provide patients with therapies that have a potential to provide benefit, and although all therapies have toxicities, the benefit:risk ratio, is of utmost importance when making therapeutic decisions for patients.8 A precision medicine approach can have advantages over cytotoxic regimens. The use of biomarker-based targeted therapy has been shown to improve treatment response and survival outcomes in patients with actionable alterations for which there is targeted therapy available (either FDA approved or in clinical trials) as compared with standard of care chemotherapy or best supportive care (BSC) (Figure 1-3) (Molecularly Matched Therapies Improve Clinical Outcomes).11-13 CONFIDENTIAL PAGE 3 Jump to Table of Contents Last update: January 22, 2021 Figure 1-3. Response Rates (A) and Survival (B) With Genomically Matched Therapy vs Nonmatched Therapy Across Tumor Types 35 A 31 B 30 25 20 15 10 5 Overall Respone% Rate, 5 0 Matched therapy Nonmatched therapy a Meta-analysis comparing patient outcomes from phase 1 studies that used a biomarker-based selection strategy vs those that did not. Source: Schwaederle 2016.13 b Prospective study comparing patients who received genomically matched therapy vs those who received unmatched therapy. Source: Kopetz 2019.14 Abbreviations: CI, confidence interval; HR, hazard ratio. However, the growing complexity of advanced cancer treatment is associated with significant drug spend. Costs to treat advanced cancer are generally at least 2-fold higher than for earlier-stage disease.15-18 . The recent surge in new treatment options (and the resulting increasing numbers of cancer being treated with available medicines and for longer) is a key driver in spending and growth rates.19-21 It is essential to appropriately select patients for treatment with targeted and immunotherapies. The majority of cancer types have ≥1 targetable biomarker; despite this, generally fewer than 50% of patients receive molecular testing (Real-World Molecular Testing Patterns).22-27 . The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC recommend molecular testing and state that broad molecular profiling is a key component in improving the care of patients with metastatic NSCLC.28 Further, the NCCN Guidelines® for NSCLC, Prostate Cancer, Breast Cancer, Melanoma: Cutaneous, and Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer include molecular testing recommendations for all eligible patients with metastatic disease (Guideline Recommendations for Molecular Testing).29-33 . In addition to the many targeted therapies and immunotherapy agents now available, the NCCN Guidelines state that the best management of any patient with cancer is in a clinical trial;29-35 approximately 40% of clinical trials utilize the presence of tumor genomic alterations or biomarkers for eligibility and/or stratification (Guideline Recommendations for Molecular Testing).21 CONFIDENTIAL PAGE 4 Jump to Table of Contents Last update: January 22, 2021 A CGP Approach to Testing Optimizes Treatment Selection As the field of molecular profiling is rapidly evolving, there is a shift in focus from a few small, predictive, disease-specific tests to a broader panel testing that can analyze changes in a myriad of genes or gene products (Evidence of Improved Detection of Genomic Alterations With CGP).34 Overall, CGP testing provides valuable information on the presence of actionable biomarkers, which enables healthcare providers to make evidence-based treatment decisions regarding treatments that result in improved outcomes for patients with advanced cancer (Decision Impact of CGP in Clinical Practice).13,31,32 . CGP utilizes next-generation sequencing (NGS) technology to examine entire regions of cancer- relevant genes (in contrast to limited “hotspot” tests) and genes in established cancer pathways for all tumor types, identifying the 4 main classes of genomic alterations (base substitutions, insertions or deletions, copy number alterations [CNAs], gene rearrangements) and reporting complex biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI), to inform cancer treatment decisions via a single assay.30,34,36-38 . Results from CGP can provide information about genomic alteration to guide uses of FDA- approved targeted therapies, and potential eligibility for oncology clinical trials, and information that enables physicians to use chemotherapy more effectively (Decision Impact of CGP in Clinical Practice).14,21,39,40 CGP Allows for Improved Detection of Genomic Alterations . Of patients with advanced cancer who undergo CGP, 51.7% to 99% will have an actionable alteration that can be matched to either a targeted therapy or to a genomically matched clinical trial.11,14,29,39,41-52 . In patients who previously underwent conventional testing methods (ie, fluorescence in situ hybridization [FISH], polymerase chain reaction [PCR], single-gene tests, and hotspot testing), CGP identified at least 1 actionable genomic alteration not previously identified in up to 84% across multiple tumor types (Evidence of Improved Detection of Genomic Alterations With CGP).14,47 . Further, CGP has been shown to improve detection of genomic alterations within specific tumor types (Table 1-1).53-56 Table 1-1. Detection of More Patients With Actionable Genomic Alterations With CGP in Specific Tumor Types Melanoma CGP can identify up to 37% more patients with BRAF alterations compared (Boussemart 2019)53 with traditional PCR-based methods53 Colorectal cancer (CRC) Of the 6.4% of patients who harbor potentially resistant KRAS mutations outside (Rankin 2016)54 of codons 12 and 13, CGP may be able to identify 88% of those resistance alterations not assessed by focused PCR-based testing54 Breast cancer CGP can identify patients who harbor multiple PIK3CA mutations that are 55 55 (Vasan 2019) traditionally missed by hotspot testing CONFIDENTIAL PAGE 5 Jump to Table of Contents Last update: January 22, 2021 NSCLC CGP has been shown to identify up to 35% more patients with ALK fusions (Rozenblum 2017)56 and 21% more patients with EGFR alterationsa compared with traditional methods in NSCLC56 a 41% of these EGFR mutations are common alterations targetable by an FDA-approved therapy in the patient’s tumor type. Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, v-raf murine sarcoma