LCD L35396: Biomarkers for Oncology

Compliance with the provisions in this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

The emergence of personalized laboratory medicine has been characterized by a multitude of testing options which can more precisely pinpoint management needs of individual patients. As a result, the growing compendium of products described as biomarkers requires careful evaluation by both clinicians and laboratorians as to what testing configurations are reasonable and necessary under the Medicare Act. There are a plethora of burgeoning tools, including both gene-based (genomic) and protein-based (proteomic) assay formats, in tandem with more conventional (longstanding) flow cytometric, cytogenetic, etc. biomarkers. Classified somewhat differently, there are highly diverse approaches ranging from single mutation biomarkers to multiple biomarker platforms, the latter of which often depend upon sophisticated biomathematical interpretative algorithms.

The term “biomarker” refers to a broad subcategory of medical signs (i.e., objective indications of medical state observed from outside the patient) which can be measured accurately and reproducibly. Medical signs stand in contrast to medical symptoms, which are limited to indications of health or illness perceived by the patient. In 1998, the National Institute of Health (NIH) defined a biomarker as: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes pathogenic processes, or pharmacologic response to a therapeutic intervention." 1

This current LCD focuses upon selected testing in oncology, with some emphasis upon applying the revised 2016 CPT molecular coding format. The LCD primarily applies to molecular biomarker testing but does involve some other types of related biomarker testing, such as proteomics.

There are separate Local Coverage Determinations (LCDs) that address other biomarkers, which include a multitude of assays which are not specifically discussed below. (Please refer to the Novitas website for a complete listing of LCDs.)

Local Medicare coverage of such biomarkers must be predicated upon four fundamental principles:

• First, the biomarkers must have proven clinical validity/utility (CVU).

• Second, to support the medical necessity of the service, there must be acceptance/uptake of specific testing into patient management. It is essential that physicians be familiar enough with all specific biomarkers, of which they order, such that all test results may become clinically actionable.

• Providers managing oncological conditions must demonstrate that the use of biomarkers will be used to assist in the management/treatment of the beneficiary.

• Peer-reviewed full manuscript evidence is required to support combination panels for multiple biomarkers, particularly regarding their alleged composite clinical validity/utility. For example, such potential billing for multiple, diverse biomarkers (e.g., diagnostic/monitoring/prognostic/predictive) can only achieve medical necessity when it is evident how each requested biomarker can be individually contributory.

It is useful to categorize oncology biomarkers into functional clusters which reflect both (1) The predominant intent of testing (with the caveat that individual assays may cross over into more than one category) and (2) the relative evidentiary expectations:

• Oncology Biomarkers Used for Diagnosis/Classification/Monitoring/Surveillance: These types of assays are supportable by case-control sensitivity/specificity studies, with appropriate designs in place to minimize the extent of bias and confounding.

• Oncology Biomarkers Used for Prognosis/Prediction: Oncology biomarkers used for prognosis/prediction (i.e., a predictive biomarker is associated with response [benefit] or lack of response to a particular therapy, relative to other available therapy, whereas a prognostic biomarker provides information on the likely outcome of the disease in an untreated individual).

There is a complex and diverse set of study methods which can drive the robust formulation of evidence for such esoteric testing. This is well-summarized by Deverka et al 2 at the Center for Medical Technology Policy, but there are currently NO standardized thresholds or benchmarks for evaluating the CVU/medical necessity of emerging biomarkers. However, the following sources (although not exhaustive and complete) may help support CVU when requesting reconsideration for coverage of biomarkers that are not included in this LCD:

• FDA labeling documentation.

• National Comprehensive Cancer Network (NCCN) Biomarkers Compendium recommendations, particularly where Category 1 evidence is noted.

• Findings from well-established, independent technology assessments (e.g., Evaluation of Genomic Applications in Practice and Prevention [EGAPP], Agency for Healthcare Research and Quality [AHRQ], Blue Cross and Blue Shield Association Technology Evaluation Center [BCBSA TEC] and the Cochrane Collaboration).

• Other independent, objective evaluations or systematic literature reviews, which can substantively contribute to the evidence base, including, but not restricted to, emerging National Institutes of Health (National Cancer Institute) guidelines for the accrual of genomics/proteomics clinical validity/utility evidence. Although there is not a prescriptive format for such systematic reviews, the documentation submitted for reconsideration purposes should include the following three elements:

• Some type of recurring/periodic Committee structure, which is comprised of at least qualified biomathematicians/methodologists, molecular pathology laboratory specialists and relevant clinicians (e.g., oncologists).

• Evidence of active sharing of the critical evaluations in a manner that enables sufficiently broad input into this process, and a feasibly wide acceptance of this process by representative molecular pathology stakeholders. There is no preference between such a Committee being based at a single site, or even rotating among several sites.

• Transparency of the biomarker evaluations via minutes (or a summary of minutes).

Covered Indications

MOLECULAR TESTS

Covered clinical types of application(s) are identified below as diagnostic (DX), prognostic (PROG), or predictive (PRED).

1. Colorectal Cancer

• KRAS (12/13) - PRED of resistance to an anti-EGFR agent

• KRAS codon 61 - PRED of resistance to an anti-EGFR agent

• KRAS codon 146 - PRED of resistance to an anti-EGFR agent

• NRAS - PRED of resistance to an anti-EGFR agent

• BRAF - PRED of resistance to an anti-EGFR agent + DX (sporadic vs. Lynch syndrome)

• PIK3CA - PRED of resistance to an anti-EGFR agent + PROG for local recurrence

• MSI by PCR - PRED of 5-FU resistance + DX

• MLH1 promoter hypermethylation - PRED of 5-FU resistance + DX

• mRNA (oncotype-Colon) – PRED for the recurrence risk for patients with Stage II colon cancer

• Hereditary colon cancer disorders

• Sept9

ColonSeq

This testing provides information to the patient and provider regarding potential treatment options and implications for RAS and BRAF mutations.

Please refer to DA52986-Billing and Coding: Biomarkers for Oncology regarding coding and billing information.

2. Non-Small Cell Lung Cancer (NSCLC)

• EGFR- PRED of anti-EGFR response

• KRAS (12/13) - PRED of anti-EGFR resistance

• KRAS codon 61 - PRED of anti-EGFR resistance

• KRAS codon 146 - PRED of anti-EGFR resistance

• BRAF - PROG + PRED for anti-RAF inhibitor

ThermoFisher Oncomine DX Target Test for Non-Small Cell Lung Cancer (NSCLC) is a 23 gene panel including a 3 gene target test (companion test) approved by the FDA in June 2017 for NSCLC from tissue specimens. It can simultaneously identify the three gene variants that are a key to targeted therapy selection: BRAF and ROS1, and EGFR. The targeted therapies are dabrafenib (Tafinlar) in combination with trametinib (Mekinist), crizotinib (Xalkori), and gefitinib (Iressa), respectively. These three drugs are approved therapies for NSCLC patients with the above gene variants. Oncomine DX Target Test is the only FDA approved companion test that detects ROS1 fusions and that detects BRAF V600E, but it does not detect ALK fusions. Coverage is limited as specified in NCD 90.2, Next Generation Sequencing (NGS) for Patients with Advanced Cancer. Please refer to the NCD for full coverage details.

LungSeq

Testing for genetic alteration in these genes can determine targeted therapy options that have the potential to decrease tumor burden, decrease symptoms, increase survival, and dramatically improve the quality of life for patients with specific genetic alterations.

Please refer to A52986, Billing and Coding: Biomarkers for Oncology regarding coding and billing information.

3. Melanoma

• BRAF - PRED of response to Vemurafenib

• KIT - PRED of response to Imatinib (TKI)

• NRAS - PROG + PRED for anti-MEK inhibitor

4. Uveal Melanoma

• GNAQ – PROG

• GNA11 - PROG

5. Brain

• BRAF - PRED

• EGFR - PRED

• MGMT - PRED

• IDH1 - DX + PROG

• IDH2 - DX + PROG

• PIK3CA - PRED

• PTEN - PRED

• CIMP - PRED

• TERT - DX

6. Thyroid

• BRAF - DX + PRED

• KRAS - PRED for Selumetinib

• HRAS - PRED for Selumetinib

• NRAS - PRED for Selumetinib

• PIK3CA - PRED

• RET - DX

• PAX8/PPARG- DX

ThyraMIR Thyroid miRNA classifier (aPCR based microRNA gene expression classifier) (PRED) evaluates the expression levels of 10miRNA genes within an FNA biopsy: miR-29b-1-5p, miR-31-5p, miR-138-1-3p, miR-139-5p, miR-146b-5p, miR-155, miR-204-5p, miR-222-3p, miR-375, and miR-551b-3p.

Oncology Thyroid, provides gene expression analysis of 142 genes utilizing fine needle aspirate, algorithm reported as a categorical result (Afirma - PRED).

ThyraMIR is used as a companion test to ThyGeNEXT when ThyGeNEXT results are inconclusive.

• ThyraMIR, ThyGeNEXT and Afirma services will be considered reasonable and necessary for patients with any of the following conditions:

• An indeterminate pathology on fine needle aspiration

• Patients with one or more thyroid nodules with a history or characteristics suggesting malignancy such as:

• Nodule growth over time

• Family history of thyroid cancer

• Hoarseness, difficulty swallowing or breathing

• History of exposure to ionizing radiation

• Hard nodule compared with rest of gland consistency

• Presence of cervical adenopathy

• RosettaGX Reveal thyroid MicroRNA test, an assay used for the classification of indeterminate thyroid nodules, will be considered reasonable and necessary when the conditions outlined above for ThyraMIR, ThyGeNEXT and Afirma are met.

• ThyroSeq is a test utilized to better define the need for thyroid surgery and the type of such surgery. ThyroSeq will be considered reasonable and necessary when the conditions outlined above for ThyraMir, ThyGeNEXT, and Afirma are met.

7. Ovary/Fallopian Tube/Peritoneum

Please refer to the “History/Background and/or General Information” section for general information on biomarkers.

Multiple sources of literature were submitted for consideration. The literature consisted of various investigational, observational, and experimental studies, as well as some letters to the editor in support of the leukemia biomarkers expansion, and ThyGeNEXT panel. The literature was reviewed and the following is a summary of the evidence submitted:

Numerous articles were submitted in support of the Leukemia biomarker expansion request. Taking into consideration the independent, objective evaluation and systematic literature review, which substantively contributed to the evidence base of the requested leukemia biomarkers and subsequently approved by the Molecular Testing Evaluation Committee (MTEC), all the requested biomarkers are considered reasonable and necessary for the listed disease states below:

• Acute Lymphoblastic Leukemia