Please refer to CMS website for the most current applicable National Coverage Determination (NCD)/ Local Coverage Determination (LCD)/Local Coverage Article (LCA)/CMS Online Manual System/Transmittals.

Liquid Biopsy Page: 2 of 19

• ID Number - Jurisdiction Medicare Administrative Contractors (MACs) - Applicable States/Territories
• LCD MolDx: Inivata™, InvisionFirst®, Liquid Biopsy for Patients with Lung Cancer - L37903 L38584 L38065 - J15-CGS Administrators, LLC - KY, OH
• LCD MolIDX: Phenotypic Biomarker Detection from Circulating Tumor Cells
• LCD MolIDX: Plasma-Based Genomic Profiling in Solid Tumors
• LCD MolDx: Inivata™, InvisionFirst®, Liquid Biopsy for Patients with Lung Cancer - L37921 - J5, J8 - Wisconsin Physicians Service Insurance Corporation - IA, IN, KS, MI, MO, NE
• LCD MolIDX: Plasma-Based Genomic Profiling in Solid Tumors - L38168
• LCD MolDx: Inivata™, InvisionFirst®, Liquid Biopsy for Patients with Lung Cancer - L37987 - JE - Noridian Healthcare Solutions, LLC
• LCD MolDX: Phenotypic Biomarker Detection from Circulating Tumor Cells - L38643 - CA, HI, NV, American Samoa, Guam, Northern Mariana Islands
• LCD MolIDX: Plasma-Based Genomic Profiling in Solid Tumors - L39230
• LCD MolDx: Inivata™, InvisionFirst®, Liquid Biopsy for Patients with Lung Cancer - L37899 L38645 - JF - Noridian - AK, AZ, ID, MT, ND,

MolDx: Phenotypic Biomarker Detection from Circulating Tumor Cells

JF - Noridian Healthcare Solutions, LLC

AK, AZ, ID, MT, ND, OR, SD, UT, WA, WY

LCD

MolDX: Plasma-Based Genomic Profiling in Solid Tumors

MolDX: Inivata™, InvisionFirst®, Liquid Biopsy for Patients with Lung Cancer

L39232

L37870

Liquid Biopsy Page: 3 of 19

• LCD MolDx: Plasma-Based Genomic Profiling in Solid Tumors - 138043 - JJ, JM - Palmetto GBA - AL, GA, NC, SC, TN, VA, WV
• LCD Biomarkers for Oncology - L35396 — . JH — Novitas Solutions, Inc. — AK, LA, CO, DE, D.C., MD, MS, NJ, NM, OK, PA, TX
• LCD Molecular Pathology Procedures - L35000 - J6 - National Government Services, Inc. - IL, MN, WI

Description

Liquid biopsy is a test usually performed on blood samples but may be performed on other body fluid samples. It purportedly analyzes the presence of cancer cells released from a tumor that are circulating or fragments of deoxyribonucleic acid (DNA) from tumor cells in the fluid. It may be used to manage treatment, assist in drug selection, determine prognosis as well as therapy response and be used as a minimally invasive alternative to tumor biopsy. The test may have the potential to detect cancer at an early stage.

Liquid biopsy may identify 2 main biomarkers in an individual with cancer:

• Circulating cell-free DNA (cfDNA), also known as circulating tumor DNA (ctDNA) are DNA fragments from a tumor that circulate in the blood or body fluid of an individual who has cancer. Examples of ctDNA tests include, but may not be limited to, FoundationOne Liquid, Guardant360, Tempus xF; OR
• Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and travel through the bloodstream or lymphatic system to other parts of the body. Examples of CTC tests include, but may not be limited to, CellSearch

Liquid biopsy test may also analyze additional biomarkers such as autoantibodies, cell free ribonucleic acid (RNA) and tumor antigens.

Specifically, in an individual with previously tested cancer, who have evidence of new malignant growth despite response to a prior targeted therapy, that growth may be considered sufficiently genetically different to require additional genetic testing; AND

Individual is untreated for the cancer being tested, or the individual is not responding to treatment (eg, progression or new lesions on treatment); AND

• The individual has decided to seek further cancer treatment with the following conditions:
1. Individual is a candidate for further treatment with a drug that is either FDA approved for the individual’s cancer, or has a National Comprehensive Cancer Network (NCCN) 1 or NCCN 2A recommendation for that individual’s cancer; AND
2. The FDA approved indication or NCCN recommendation is based upon information about the presence or absence of a genetic biomarker tested for in the Guardant360 assay

Circulating Tumor Cells Testing

Liquid Biopsy Page: 5 of 19

Circulating tumor cells (CTCs) testing including, but not limited to, CellSearch (86152, 86153) will be considered medically reasonable and necessary when all the following requirements are met:

• Individual has been diagnosed with cancer; AND
• The specific cancer type has an associated biomarker that can be tested using CTCs; AND
• Tissue based testing for the specific biomarker is infeasible (quantity not sufficient or invasive biopsy is medically contraindicated) OR will not provide sufficient information for subsequent medical management (eg, in cases where human epidermal growth factor receptor 2 (HER2) overexpression is negative in a tissue biopsy but may be positive in the CTCs, due to tumor heterogeneity).

There is clear documentation of at least 1 of these reasons for testing in the medical record; AND

• At least 1 of the following criteria are met AND there is clear documentation of at least 1 of these in the medical record:
• Individual’s cancer has not previously been tested for the specific biomarker; OR
• Individual has newly metastatic cancer, and a metastatic lesion has not been tested for the specific biomarker; OR
• Individual demonstrates signs of clinical, radiological or pathologic disease progression; OR
• There is concern for resistance to treatment based on specific and well-established clinical indications; AND
• The CTC-based biomarker test meets the following criteria to establish the test as reasonable and necessary:
• The clinical validation has demonstrated performance that is equivalent or superior to tissue- based testing or another already accepted test for the same biomarker for the same intended use; AND
• Clinical validity (for new analytes) must be established through studies published in the peer-reviewed literature for the intended use of the test in the intended population; AND
• For a given encounter, only 1 test for assessing the biomarker may be performed UNLESS a second test, meeting all the criteria established herein, is reasonable and necessary as an adjunct to the first test

InVisionFirst Testing

InVisionFirst (0388U) will be considered medically reasonable and necessary when the following requirements are met:

• Diagnosed with advanced (Stage IIIB/IV) NSCLC; AND either of the following:
• At diagnosis:
• When results for EGFR single nucleotide variants (SNVs) and insertions and deletions (indels); rearrangements in ALK and ROS1; and SNVs for BRAF are not available; AND
• Tissue-based CGP is infeasible (quantity not sufficient for tissue-based CGP or invasive biopsy is medically contraindicated)
• At progression:
• For an individual progressing on or after chemotherapy or immunotherapy who have not been tested for EGFR SNVs and indels; rearrangements in ALK and ROS1; and SNVs for BRAFs, AND
• Tissue-based CGP is infeasible; OR
• Progression on EGFR tyrosine kinase inhibitors (TKIs)

Liquid Biopsy Page: 6 of 19

General Liquid Biopsy Testing Criteria

Liquid biopsy (eg, cfDNA, ctDNA) including, but not limited to, FoundationOne Liquid CDx (0239U), Guardant360 CDx (0242U) will be considered medically reasonable and necessary when all the following requirements are met:

• Individual diagnosed with either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; AND
• Tissue based, CGP is infeasible (quantity not sufficient for tissue based CGP or invasive biopsy is medically contraindicated); AND
• Individual has not been previously tested with the same test using next generation sequencing (NGS) for the same cancer genetic content; AND
• Decided to seek further cancer treatment (eg, therapeutic chemotherapy); AND
• The diagnostic laboratory test using NGS must have:
• FDA approval or clearance as a companion in vitro diagnostic; AND
• FDA approved or cleared indication for use in that individual’s cancer; AND
• Results provided to the treating physician for management of the individual using a report template to specify treatment options

Liquid Biopsy Page: 7 of 19

The use of the criteria in this Medicare Advantage Medical Coverage Policy provides clinical benefits highly likely to outweigh any clinical harms. Services that do not meet the criteria above are not medically necessary and thus do not provide a clinical benefit. Medically unnecessary services carry risks of adverse outcomes and may interfere with the pursuit of other treatments which have demonstrated efficacy.

Coverage Limitations

US Government Publishing Office.

Electronic code of federal regulations: part 411 – 42 CFR § 411.15 - Particular services excluded from coverage

The following tests may not be considered a benefit (statutory exclusion)73:

• Tests considered screening in the absence of clinical signs and symptoms of disease that are not specifically identified by the law; OR
• Tests that confirm a diagnosis or known information; OR
• Tests to determine risk for developing a disease or condition; OR
• Tests performed to measure the quality of a process; OR
• Tests without diagnosis specific indications; OR
• Tests identified as investigational by available literature and/or the literature supplied by the developer and are not a part of a clinical trial

These treatments and services fall within the Medicare program’s statutory exclusion that prohibits payment for items and services that have not been demonstrated to be reasonable and necessary for the diagnosis and treatment of illness or injury ( §1862(a)(1) of the Act). Other services/items fall within the Medicare program’s statutory exclusion at 1862(a)(12), which prohibits payment.

The following services/items will not be considered medically reasonable and necessary:

• Genetic tests that have not demonstrated clinical utility, analytical and clinical validity via the MolDX Program
• Liquid and solid tumor tissue testing for the same diagnosis and same genetic content
• Duplicate testing of the same biomarker (from the same sample type and for the same clinical indication) using different methodologies is not covered

A review of the current medical literature shows that the evidence is insufficient to determine that these services are standard medical treatments. There remains an absence of randomized, blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of these services in clinical management.

Screening services such as presymptomatic genetic tests and services used to detect and undiagnosed diseased or disease predisposition are not a Medicare benefit and are not covered.

Liquid Biopsy Page: 8 of 19