Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK)

POLICY NUMBER

A.2.04.45

DESCRIPTION

Over half of patients with non-small-cell lung cancer (NSCLC) present with advanced and therefore incurable disease. Treatment in this setting has been with platinum-based chemotherapy. The identification of specific, targetable oncogenic “driver mutations" in a subset of NSCLCs has resulted in a reclassification of lung tumors to include molecular subtypes that may direct targeted therapy or immunotherapy depending on the presence of specific variants.

Non-Small-Cell Lung Cancer

Treatment options for NSCLC depend on disease stage and include various combinations of surgery, radiotherapy, systemic therapy, and best supportive care. Unfortunately, in up to 85% of cases, cancer has spread locally beyond the lungs at diagnosis, precluding surgical eradication. Also, up to 40% of patients with NSCLC present with metastatic disease. When treated with standard platinum-based chemotherapy, patients with advanced NSCLC have a median survival of 8 to 11 months and a 1-year survival of 30% to 45%. The identification of specific, targetable oncogenic “driver mutations" in a subset of NSCLCs has resulted in a reclassification of lung tumors to include molecular subtypes, which are predominantly of adenocarcinoma histology.

EGFR Gene

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (TK), is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR signaling either prevent ligand binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small-molecule tyrosine kinase inhibitors [TKIs]). These targeted therapies dampen signal transduction through pathways downstream to the EGFR, such as the RAS/RAF/MAPK cascade. RAS proteins are G-proteins that cycle between active and inactive forms in response to stimulation from cell surface receptors, such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

EGFR Gene Variants

Somatic variants in the tyrosine kinase domain of the EGFR gene, notably small deletions in exon 19 and a point mutation in exon 21 (L858R, indicating substitution of leucine by arginine at codon position 858) are the most commonly found EGFR variants associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs; afatinib, erlotinib, gefitinib). These variants are referred to as sensitizing variants. Almost all patients who initially respond to an EGFR TKI experience disease progression. The most common of these secondary variants, called resistance variants, involves the substitution of methionine for threonine at position 790 (T790M) on exon 20.

EGFR Variant Frequency

Fang and colleagues reported EGFR variants (all L858R) in 3 (2%) of 146 consecutively treated Chinese patients with early-stage squamous cell carcinoma (SCC). In a separate cohort of 63 Chinese patients with SCC who received erlotinib or gefitinib as second- or third-line treatment (63% never-smokers, 21% women), EGFR variant prevalence (all exon 19 deletion or L858R) was 23.8%.

In a comprehensive analysis of 14 studies involving 2,880 patients, Mitsudomi and colleagues reported EGFR variants in 10% of men, 7% of non-Asian patients, 7% of current or former smokers, and 2% of patients with nonadenocarcinoma histologies. Eberhard and colleagues, observed EGFR variants in 6.4% of patients with SCC and Rosell and colleagues observed EGFR variants in 11.5% of patients with large cell carcinomas. Both studies had small sample sizes.

In 2 other studies, the acquired EGFR T790M variant has been estimated to be present in 50% to 60% of TKI-resistant cases in approximately 200 patients.

ALK Gene

ALK is a TK that, in NSCLC, is aberrantly activated because of a chromosomal rearrangement that leads to a fusion gene and expression of a protein with constitutive TK activity that has been demonstrated to play a role in controlling cell proliferation. The EML4-ALK fusion gene results from an inversion within the short arm of chromosome 2.

The EML4-ALK rearrangement (“ALK-positive”) is detected in 3% to 6% of NSCLC patients, with the highest prevalence in never-smokers or light ex-smokers who have adenocarcinoma.

BRAF Gene

RAF proteins are serine/threonine kinases that are downstream of RAS in the RAS-RAF-ERK-MAPK pathway. In this pathway, the BRAF gene is the most frequently mutated in NSCLC, in 1% to 3% of adenocarcinomas. Unlike melanoma, about 50% of the variants in NSCLC are non-V600E variants. Most BRAF variants occur more frequently in smokers.

ROS1 Gene

ROS1 codes for a receptor TK of the insulin receptor family and chromosomal rearrangements result in fusion genes. The prevalence of ROS1 fusions in NSCLC varies from 0.9% to 3.7%. Patients with ROS1 fusions are typically never-smokers with adenocarcinoma.

KRAS Gene

The KRAS gene (which encodes RAS proteins) can harbor oncogenic variants that result in a constitutively activated protein, independent of signaling from the EGFR, possibly rendering a tumor resistant to therapies that target the EGFR. Variants in the KRAS gene, mainly codons 12 and 13, have been reported in 20% to 30% of NSCLC, and occur most often in adenocarcinomas in heavy smokers.

KRAS variants can be detected by direct sequencing, polymerase chain reaction technologies, or next-generation sequencing.

EGFR, ALK, ROS1, and KRAS driver mutations are considered to be mutually exclusive.

RET Gene

RET (rearranged during transfection) is a proto-oncogene that encodes a receptor TK growth factor. Translocations that result in fusion genes with several partners have been reported. RET fusions occur in 0.6% to 2% of NSCLCs and in 1.2% to 2% of adenocarcinomas.

MET Gene

MET alteration is one of the critical events for acquired resistance in EGFR-mutated adenocarcinomas refractory to EGFR TKIs.

Neurotrophic Receptor Tyrosine Kinase (NTRK) GeneFusion Testing

The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry. Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusion transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners.

Circulating Tumor DNA (Liquid Biopsy)

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.

Targeted Treatment

U.S. FDA-approved targeted treatments for the variants described above are summarized in Table 1. (Note this information is current as of October 8, 2024. The FDA maintains a list of oncology drug approval notifications at https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications .) This policy does not evaluate any FDA-approved monoclonal antibody therapies, and they are not included in the table below.

Table 1. Targeted Treatments for Non-Small-Cell Lung Cancer

ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; FDA: U.S. Food and Drug Administration; MET: mesenchymal-epithelial transition.

Table 2 summarizes the FDA-approved targeted treatments for individuals with NSCLC along with the concurrently approved companion diagnostic tests. The information in Table 2 is current as of October 18, 2023. An up-to-date list of FDA cleared or approved companion diagnostics is available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools)

Table 2. Targeted Treatments for Advanced NSCLC and FDA Approved Companion Diagnostic Tests

Sources: U.S. Food and Drug Administration (2023); U.S. Food and Drug Administration (n.d.)ALK: anaplastic lymphoma kinase; CDx: companion diagnostic; EGFR: epidermal growth factor receptor; FDA: Food and Drug Administration; FISH: fluorescence in situ hybridization; MET: mesenchymal-epithelial transition; NCCN: National Comprehensive Cancer Network; NSCLC: non-small-cell lung cancer; PCR: polymerase chain reaction; TKI: tyrosine kinase inhibitor.

Laboratory-Developed Tests

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed under CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

POLICY

EGFR Testing

Analysis of tumor tissue for somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the EGFR gene, may be considered medically necessary to predict treatment response to an FDA-approved therapy (eg, erlotinib [Tarceva] alone or in combination with ramucirumab [Cyramza], gefitinib [Iressa], afatinib [Gilotrif], dacomitinib [Vizimpro], or osimertinib [Tagrisso]) in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous-cell non-small-cell lung cancer (NSCLC), and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of tumor tissue for somatic variants in exon 20 (eg, insertion mutations) within the EGFR gene, may be considered medically necessary to predict treatment response to an FDA-approved therapy (eg, mobocertinib [Exkivity]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

At diagnosis, analysis of plasma for somatic variants in exons 19 through 21 (eg, exon 19 deletions, L858R, T790M) within the EGFR gene, using an FDA-approved companion diagnostic plasma test to detect circulating tumor DNA (ctDNA) may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

At progression, analysis of plasma for the EGFR T790M resistance variant for targeted therapy with osimertinib using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC not otherwise specified, when tissue biopsy to obtain new tissue is not feasible (e.g., in those who do not have enough tissue for standard molecular testing using formalin-fixed paraffin-embedded tissue, do not have a biopsy-amenable lesion, or cannot undergo biopsy), and when the individual does not have any FDA-labeled contraindications to osimertinib and it is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of somatic variants in the EGFR gene in tissue or plasma, including variants within exons 22 to 24, is considered investigational in all other situations.

ALK Testing

Analysis of tumor tissue for somatic rearrangement variants of the ALK gene in tissue may be considered medically necessary to predict treatment response to an FDA-approved ALK inhibitor therapy (eg, crizotinib [Xalkori], ceritinib [Zykadia], alectinib [Alecensa], brigatinib [Alunbrig], or lorlatinib [Lorbrena]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of plasma for somatic rearrangement variants of the ALK gene using an FDA-approved companion diagnostic plasma test to detect ctDNA is considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved ALK inhibitor therapy in individuals with NSCLC (eg, alectinib [Alecensa]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels (see Policy Guidelines).

Analysis of somatic rearrangement variants of the ALK gene in tissue or plasma is considered investigational in all other situations.

BRAF V600E Testing

Analysis of tumor tissue for the somatic BRAF V600E variant may be considered medically necessary to predict treatment response to an FDA-approved BRAF and/or MEK inhibitor therapy (eg, dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines section).

Analysis of tumor tissue for the somatic BRAF V600E variant is considered investigational in all other situations.

Analysis of plasma for the somatic BRAF V600E variant to detect ctDNA is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to BRAF and/or MEK inhibitor therapy (eg, dabrafenib [Tafinlar], trametinib [Mekinist]) in individuals with NSCLC.

ROS1 Testing

Analysis of tumor tissue for somatic rearrangement variants of the ROS1 gene may be considered medically necessary to predict treatment response to an FDA-approved ROS1 inhibitor therapy (eg, crizotinib [Xalkori]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of tumor tissue for somatic rearrangement variants of the ROS1 gene is considered investigational in all other situations.

Analysis of plasma for somatic rearrangement variants of the ROS1 gene to detect ctDNA is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to ROS1 inhibitor therapy (eg, crizotinib [Xalkori] or entrectinib) in individuals with NSCLC.

KRAS Testing

Analysis of tumor tissue for somatic variants of the KRAS gene (eg, G12C) may be considered medically necessary to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of plasma for somatic variants of the KRAS gene (eg, G12C) using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels (see Policy Guidelines).

All other uses of analysis of somatic variants of the KRAS gene in tissue or plasma are considered investigational.

RET Rearrangement Testing

Analysis of tumor tissue for somatic alterations in the RET gene may be considered medically necessary to predict treatment response to RET inhibitor therapy (e.g., pralsetinib [Gavreto] or selpercatinib [Retevmo]) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of tumor tissue for somatic alterations in the RET gene is considered investigational in all other situations.

Analysis of plasma for somatic alterations of the RET gene using plasma specimens to detect ctDNA is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to RET inhibitor therapy (eg, selpercatinib [Retevmo], pralsetinib [Gavreto]) in individuals with NSCLC.

MET Exon 14 Skipping Alteration

Analysis of tumor tissue for somatic alterations in tissue that leads to MET exon 14 skipping may be considered medically necessary to predict treatment response to capmatinib (Tabrecta) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of plasma for somatic alteration that leads to MET exon 14 skipping using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to MET inhibitor therapy (eg, capmatinib [Tabrecta]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels (see Policy Guidelines).

All other uses of analysis of somatic variants of the MET gene in tissue or plasma are considered investigational.

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing

Analysis of tumor tissue for NTRK gene fusions may be considered medically necessary to predict treatment response to TRK inhibitor therapy (e.g., larotrectinib [Vitrakvi] or entrectinib [Rozlytrek]) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

Analysis of plasma for NTRK gene fusions using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to TRK inhibitor therapy (e.g., larotrectinib [Vitrakvi] or entrectinib [Rozlytrek]) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels (see Policy Guidelines).

All other uses of analysis of NTRK fusions in tissue or plasma are considered investigational.

Plasma Testing When Tissue is Insufficient

Plasma tests for oncogenic driver variants deemed medically necessary on tissue biopsy may be considered medically necessary to predict treatment response to targeted therapy for individuals meeting the following criteria:

• Individual does not have sufficient tissue for standard molecular testing using formalin-fixed paraffin-embedded tissue; AND

• Follow-up tissue-based analysis is planned should no driver variant be identified via plasma testing.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

This policy does not address germline testing for inherited risk of developing cancer.

This policy does not address monoclonal antibody therapies such as amivantamab-vmjw (Rybrevant).

For expanded panel testing, see the Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies medical policy.

This policy does not address HER2 testing. Agents targeted against HER2 in non-small-cell lung cancer (NSCLC) with approved companion diagnostic tests include the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu), which is not a true targeted therapy.

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics (i.e., as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive policy review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

For guidance on testing criteria between policy updates, refer to the FDA's List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) ( https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools ) for an updated list of FDA-approved tumor markers and consult the most current version of NCCN management algorithms. The most recent guidelines (v.10.2024) recommend that EGFR variants (category 1), ALK rearrangements (category 1), and PD-L1 testing (category 1) as well as KRAS, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping alteration, RET, and HER2 testing (all category 2A) be performed in the workup of non-small-cell lung cancer in patients with metastatic disease with histologic subtypes adenocarcinoma, large cell carcinoma, and non-small-cell lung cancer not otherwise specified. The guidelines add that testing should be conducted as part of broad molecular profiling, defined as a single assay or a combination of a limited number of assays and that it is acceptable to have a tiered approach based on low-prevalence, co-occurring biomarkers. The guidelines additionally recommend identifying the emerging biomarker, high-level MET amplification, while noting that the definition of this biomarker is evolving and may differ according to the assay used.

PD-L1 testing is addressed separately in the Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB) medical policy.

The 2018 guidelines issued jointly by the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology have recommended the following:

"One set of genes must be offered by all laboratories that test lung cancers, as an absolute minimum: EGFR, ALK, and ROS1. A second group of genes should be included in any expanded panel that is offered for lung cancer patients: BRAF, MET, RET, ERBB2 (HER2), and KRAS, if adequate material is available. KRAS testing may also be offered as a single-gene test to exclude patients from expanded panel testing. All other genes are considered investigational at the time of publication."

Repeat Genomic Testing

There may be utility in repeated testing of gene variants for determining targeted therapy or immunotherapy in individuals with NSCLC, as tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for treatment decision-making. For example, repeat testing (tissue or liquid based) of EGFR for T790M at progression on or after EGFR tyrosine kinase inhibitor therapy may be considered to select patients for treatment with osimertinib. T790M is an acquired resistance mutation that is rarely seen at initial diagnosis. The American Society of Clinical Oncology (ASCO) currently suggests repeat genomic testing for individuals on targeted therapy with suspected acquired resistance, especially if choice of next-line therapy would be guided. The ASCO guidance is not tumor specific, and it cautions to consider clinical utility.

Concurrent Somatic Liquid-Based and Tissue-Based Genomic Testing

Liquid biopsy testing uses blood samples and assesses cancer DNA and non-cancer DNA in the same blood sample. The goal is to identify options for genome-informed treatment. Some providers will order a liquid biopsy test and a tissue biopsy test at the same time to hasten time to treatment. If the intent of concurrent testing is to follow an individual over time to monitor for resistance variant T790M, then consideration could be given to doing liquid biopsy at diagnosis with the tissue biopsy to make sure that mutations that are going to be followed longitudinally can be detected by the liquid biopsy. Current NCCN guidelines for NSCLC (v.10.2024) state the following: "Studies have demonstrated ctDNA and tissue testing to have very high specificity. Both ctDNA and tissue testing have appreciable false-negative rates, supporting the complementarity of these approaches, and data support complementary testing to reduce turnaround time and increase yield of targetable alteration detection."

Recommended Testing Strategies

Individuals who meet criteria for genetic testing as outlined in the policy statements above should be tested for the variants specified.

• When tumor tissue is available, use of tissue for testing of any/all variants and biomarkers outlined in this policy is recommended, but is not required in all situations. In certain situations, circulating tumor DNA testing (liquid biopsy) may be an option.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

7/27/2006: Approved by Medical Policy Advisory Committee (MPAC)

8/16/2007: Policy reviewed, no changes

1/06/2009: Policy reviewed. No changes.

04/25/2011: Policy description updated. Policy statement revised to state that analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to erlotinib in patients with advanced NSCLC. Other applications related to NSCLC remain investigational. Code Reference section changed from non-covered to covered.

02/24/2012: Policy reviewed; no changes.

01/10/2013: Added the following new 2013 CPT code to the Code Reference section: 81235. Added ICD-9 codes 162.3 - 162.9 to the Code Reference section.

09/16/2014: Policy title changed from "Epidermal Growth Factor Receptor for Patients with Non-Small Cell Lung Cancer (NSCLC)" to "Epidermal Growth Factor Receptor Mutation Analysis for Patients with Non-Small-Cell Lung Cancer." Policy description revised. Medically necessary policy statement revised to state: Except as noted below, analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to erlotinib or afatinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded. Policy guidelines updated regarding EGFR mutation testing.

08/26/2015: Medical policy revised to add ICD-10 codes.

02/15/2016: Policy title changed from "Epidermal Growth Factor Receptor Mutation Analysis for Patients with Non-Small-Cell Lung Cancer" to "Molecular Analysis for Targeted Therapy of Non-Small-Cell Lung Cancer." Policy description updated regarding EGFR, ALK, ROS, RET, MET, BRAF, and HER2 genes. Added the following policy statements: 1) Analysis of somatic rearrangement mutations of the ALK gene may be considered medically necessary to predict treatment response to crizotinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded. 2) Analysis of somatic rearrangement mutations of the ALK gene is considered investigational in all other situations. Added policy statement that testing for ROS, RET, MET, BRAF, and HER2 mutations is considered investigational. Policy guidelines updated to add current information regarding EGFR mutation and ALK rearrangement testing. Medically necessary and investigative definitions added. Code Reference section updated to add CPT code 81401.

06/06/2016: Policy number A.2.04.45 added.

06/27/2017: Code Reference section updated to revise code description for CPT code 81401, effective 07/01/2017.

03/27/2018: Code Reference section updated to change ICD-10 diagnosis code range C34.10 - C34.92 to C34.00 - C34.92.

04/16/2018: Policy description updated regarding the KRAS gene and targeted therapies. Medically necessary statement for EGFR testing updated to include gefitinib (Iressa®). Added medically necessary statement for analysis of the T790M variants in the EGFR gene. Medically necessary statement for ALK testing updated to include ceritinib (Zykadia™), alectinib (Alecensa®), and brigatinib (Alunbrig™). Added policy statements that analysis of the BRAF V600E variant and somatic rearrangement variants of the ROS1 gene may be medically necessary in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded. Added investigational statement regarding KRAS testing. Policy Guidelines updated with the 2017 guidelines from the NCCN. Code Reference section updated to add CPT code 81406 to the Covered Codes table. Added CPT codes 81275, 81276, 81404, 81405, and 81479 to the Investigational Codes table.

11/08/2018: Policy description updated regarding targeted therapies, indications for treatment, and diagnostic tests. Policy statement for EGFR testing updated to state that analysis of somatic variants in exons 18 through 21 within the EGFR may be considered medically necessary to predict treatment to an EGFR TKI therapy in patients with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC not otherwise specified. Investigational statement updated to change "exons 18 to 24" to "exons 22 to 24." Policy Guidelines updated with 2018 guidelines for gene testing.

07/07/2020: Policy description updated regarding NTRK gene fusions, tumor mutational burden, and targeted therapies. Added medically necessary statement for NTRK gene fusion testing and an investigational statement for tumor mutational burden testing. Policy Guidelines updated regarding the 2019 guidelines from the NCCN. Code Reference section updated to move CPT code 81479 from investigational to covered.

09/01/2021: Policy title changed from "Molecular Analysis for Targeted Therapy of Non-Small-Cell Lung Cancer" to "Molecular Analysis for Targeted Therapy or Immunotherapy of Non-Small-Cell Lung Cancer." Policy description updated regarding the KRAS gene, HER2 gene, MET gene, PD-1/PD-L1, and targeted treatment and immunotherapy. Added medically necessary statements for RET rearrangement testing, MET exon 14 skipping alteration, and PD-L1 testing. Policy Guidelines updated regarding recommended testing strategies. Code Reference section updated to move CPT code 81404 from investigational to covered. Added CPT codes 81191, 81192, 81193, and 81194 as covered.

03/15/2023: Policy title changed from "Molecular Analysis for Targeted Therapy or Immunotherapy of Non-Small-Cell Lung Cancer" to "Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)." The Circulating Tumor DNA for Management of Non-Small-Cell Lung Cancer (Liquid Biopsy) medical policy was merged with this policy. Policy description updated regarding EGFR gene variants, EGFR variant frequency, and targeted treatments and immunotherapy for NSCLC. Added new indications and medically necessary policy statements for EGFR testing, ALK testing, MET Exon 14 skipping alteration, and plasma testing when tissue is insufficient. Added new indications and investigational policy statements for BRAF V600E testing, ROS1 testing, and RET rearrangement testing. KRAS and HER2 testing changed from investigational to medically necessary when meeting the specified criteria. Revised policy statements for PD-L1 testing and tumor mutational burden testing. Policy Guidelines updated regarding testing for individual genes associated with FDA-approved therapeutics, repeat genomic testing, and concurrent somatic liquid-based and tissue-based genomic testing. Code Reference section updated to add CPT codes 81210, 81275, 81276, 81405, 86152, and 86153 as covered codes.

04/03/2023: Policy description updated to correct spelling of Rybrevant.

05/17/2023: Policy description tables updated to add adagrasib (Krazati) to the list of targeted treatments for non-small-cell lung cancer (NSCLC). Policy statements for KRAS testing updated to include adagrasib (Krazati). Sources updated.

07/01/2023: Code Reference section updated to add new CPT codes 0388U and 0397U as investigational.

09/25/2023: Code Reference section updated to add new CPT code 0414U, effective 10/01/2023.

12/21/2023: Code Reference section updated to add new 2024 CPT code 0436U, effective 01/01/2024.

04/01/2024: Policy title changed from "Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)" to "Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS)." Policy description updated to remove information regarding HER2 gene, PD-1/PD-L1, tumor mutational burden, and targeted treatments of NSCLC. Added information regarding circulating tumor DNA (liquid biopsy), FDA-approved targeted treatments for NSCLC and companion diagnostic tests, and laboratory-developed tests. Second medically necessary policy statement for EGFR testing updated to remove "amivantamab (Rybrevant)." Policy statements for EGFR testing at diagnosis and progression updated to replace the names of the individual tests with the use of an "FDA-approved companion diagnostic plasma test." Removed medically necessary statement regarding analysis of plasma for somatic variants in exon 20 within the EGFR gene. Policy statements regarding ROS1 testing updated to remove Rozlytrek. Removed policy statements regarding HER2 testing, PD-L1 testing, and tumor mutational burden testing. Medically necessary statement regarding RET testing updated to add "RET inhibitor therapy." Policy Guidelines updated regarding testing.

06/06/2024: Policy reviewed; no changes.

10/01/2024: Code Reference section updated to add new CPT code 0478U. Removed deleted CPT code 0397U.

02/04/2025: Policy title updated to include NTRK testing. Policy description updated regarding NTRK gene fusion testing and targeted treatments for NSCLC. Medically necessary statements for KRAS testing updated to remove adagrasib (Krazati). Revised medically necessary statement for NTRK testing to add new indications. Added medically necessary statement for NTRK gene fusions using an FDA-approved companion diagnostic plasma test to detect ctDNA. Added statement that all other uses of analysis of NTRK fusions in tissue or plasma are considered investigational. Policy Guidelines updated to state that this policy does not address monoclonal antibody therapies such as amivantamab-vmjw (Rybrevant). Updated information regarding liquid- and tissue-based testing.

SOURCE(S)

1. Blue Cross Blue Shield Association Policy # 2.04.45

2. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools . P210040 Letter. December 2022. Accessed April 2023.

3. Krazati prescribing information. Mirati Therapeutics, Inc. December 2021. Last accessed April 2023.

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.   

Covered Codes

Investigational Codes

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