LCD L37810: Genomic Sequence Analysis Panels in the Treatment of Solid Organ Neoplasms

Non-Small Cell Lung Cancer (NSCLC)

Indications and Limitations of Coverage

Genomic Sequential Analysis Panel will be considered reasonable and necessary in the evaluation of tumor tissue in the following clinical circumstances:

• Newly diagnosed patients with advanced (stage IIIB or IV) NSCLC, who are not treatable by resection or radiation with curative intent, and who are suitable candidates for therapy at the time of testing.

• Previously diagnosed patients with advanced (stage IIIB or IV) NSCLC, who have not responded to at least one systemic therapy, or who have progressed following resection. The patient must be a candidate for treatment at the time of the testing.

• Previously diagnosed patients with advanced (stage IIIB or IV) NSCLC, who have been resistant to at least one targeted therapy, are able to undergo tumor tissue biopsy for testing, and who are suitable candidates for additional treatment at the time of testing.

Metastatic Colorectal Cancer (mCRC)

Indications and Limitations of Coverage

Genomic Sequential Analysis Panel will be considered reasonable and necessary when the test is performed in a CLIA-certified laboratory qualified to perform high complexity testing, ordered by a treating physician, and the patient has:

• metastatic CRC; and

• is a candidate for intensive chemotherapy with an anti-EGFR biologic agent; and

• has not had prior RAS/BRAF testing (except after initiation of anti-EGFR therapy with evidence of acquired resistance).

Next-Generation Sequence (NGS) Comprehensive Genomic Profile (CGP) Testing

Indications and Limitations of Coverage

This policy section describes coverage of NGS CGP diagnostic testing for patients with advanced cancer as allowable by a Medicare Administrative Contractor (MAC) under the National Coverage Determination (NCD) 90.2 (1). The policy scope is specific to solid tumors and exclusive of hematologic malignancies (the subject of separate LCD L37606), circulating tumor DNA testing (ctDNA), and other cancer-related uses of NGS, such as germline testing.

CGP is a NGS approach that uses a single assay to assess hundreds of genes including relevant cancer biomarkers, with solid evidentiary support for clinical utility in guidelines and clinical trials. CGP assays include not only individual genetic variants (single nucleotide variants (SNVs), insertions/deletions (INDELs), copy number alterations (CNAs), structural variants (SVs), and splice-site variants), but also patterns of mutations such as DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and total mutational burden (TMB). CGP testing may also include RNA sequencing to detect structural rearrangements, such as fusions/translocations and functional splicing mutations.

CGP NGS testing for patients with advanced cancer is reasonable and necessary only when performed in a CLIA-certified laboratory, when ordered by a treating physician, and when the patient has:

• either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and

• not been previously tested with a CGP for the same cancer genetic content; and

• decided to seek further cancer treatment (e.g., therapeutic chemotherapy)

Additionally, the test performed must be able to detect at least the minimum genes and genomic positions required for the identification of clinically supported, FDA-approved therapies. The genes and genomic positions required are listed in Category 1 or 2A of the most current version of the National Comprehensive Cancer Network (NCCN) Biomarkers Compendium (2). Testing assays must be FDA approved/cleared, or if a laboratory developed test (LDT), have a published, peer-reviewed study supporting analytic validity, or certification by a third-party consistent with the New York State Department of Health’s Clinical Laboratory Evaluation Program (CLEP) review standards.

Non-Small Cell Lung Cancer (NSCLC)

The American Cancer Society estimates that over 220,000 new cases of lung cancer will be diagnosed in 2015, with over 85% of those cancers being classified as non-small cell lung cancer. Lung cancer represents approximately 13% of all new cancer diagnoses, and approximately 27% of cancer deaths. The estimated 5yr survival rate for all lung cancer patients is 17% and is only 4% for patients with metastatic disease.

Most lung cancers are epithelial in origin, with squamous cell carcinomas, adenocarcinomas, and small cell carcinomas being the predominant histologic types. The first two, squamous and adenocarcinomas, have been traditionally grouped as non-small cell lung cancer (NSCLC). Surgery remains the cornerstone of treatment for early stage NSCLC of either type, however treatment of advanced stage disease is based primarily on drugs. Distinctive response patterns to specific therapeutic drugs have been demonstrated over the past 12 years, necessitating the distinction between squamous cell and adenocarcinoma morphology. Consequently, the most recent WHO guidelines advocate sub-classification of all NSCLC in to a more specific subtype whenever possible. This is typically accomplished by histologic evaluation with support from specific immunohistochemical studies, which are particularly useful in the evaluation of small biopsies.

Adenocarcinomas account for approximately 40% of all lung cancers, and are the most common lung cancer in never- or light smokers. Adenocarcinomas are characterized by glandular differentiation, mucin production, or pneumocyte marker expression. Certain genomic alterations are more commonly found in lung adenocarcinomas (when compared to squamous or small cell carcinomas) and clinical laboratory testing to identify these alterations is important in two respects: First, some mutations are now recognized as “driver mutations,” which are essential for tumor cell survival. Inhibition of these mutated proteins results in tumor cell death, making them attractive therapeutic targets. While not all driver mutations have specific therapies at this time, an important corollary of this concept is that with rare exception, such driver mutations are mutually exclusive, i.e. the identification of one driver mutation in a tumor effectively makes the likelihood that another driver mutation is present extremely unlikely.