Medical Policy

Policy Num:      11.003.009
Policy Name:    Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK). 
Policy ID:          [11.003.009]  [Ac / B / M+ / P+]  [2.04.45]

Last Review:      December 05, 2024 
Next Review:      December 20, 2025

Related Policies:

11.003.026- Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
11.003.140 - Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
05.001.024 - Ado-Trastuzumab Emtansine (Trastuzumab-DM1) for Treatment of HER2-Positive Malignancies


 

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

Summary

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.

Summary of Evidence

For individuals with advanced or metastatic non-small-cell lung cancer (NSCLC) who are being considered for targeted therapy with tyrosine kinase inhibitors who undergo somatic testing for EGFR variants or ALK rearrangements using tissue biopsy specimens, the evidence includes U.S. Food and Drug Administration (FDA)-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with tyrosine kinase inhibitors who undergo somatic testing for EGFR variants or ALK rearrangements using circulating tumor DNA (ctDNA) (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with BRAF or ROS1 inhibitors who undergo somatic testing for BRAF variants or ROS1 rearrangements using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with BRAF or ROS1 inhibitors who undergo somatic testing for BRAF variants or ROS1 rearrangements using ctDNA (liquid biopsy), no evidence was identified. No plasma tests have received FDA approval as companion diagnostics to select individuals with NSCLC for treatment with BRAF inhibitors and no studies were identified. FoundationOne Liquid CDx is FDA approved as a companion diagnostic to select treatment with entrectinib in individuals with ROS1 positive NSCLC. No plasma tests have received FDA approval as companion diagnostics to select patients with ROS1 rearrangements for treatment with crizotinib and no studies for this indication were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with RET or MET inhibitors who undergo somatic testing for RET rearrangements or MET alterations using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with RET inhibitors who undergo somatic testing for RET rearrangements using ctDNA (liquid biopsy), no studies were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with MET inhibitors who undergo somatic testing for MET alterations using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with a RAS inhibitor who undergo somatic testing for KRAS variants using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with a RAS inhibitor who undergo somatic testing for KRAS variants using using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with metastatic NSCLC who are being considered for targeted therapy with a TRK inhibitor who undergo somatic testing for NTRK gene fusion using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with metastatic NSCLC who are being considered for targeted therapy with a TRK inhibitor who undergo somatic testing for NTRK gene fusion using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to summarize the evidence and guidelines on testing for EGFR, BRAF, andKRAS variants ; ALK, ROS1, and RET rearrangements; or MET alterations to select targeted treatment for individuals with advanced-stage non-small-cell lung cancer.

Policy Statements

EGFR Testing

Analysis of tumor tissue for somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) gene, may be considered medically necessary to predict treatment response to a U.S. Food and Drug Administration (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 (eg, 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 anaplastic lymphoma kinase (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 may be 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 [Alcensa]), 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 ).

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.

Testing for other variants may become available between policy updates.

Policy Guidelines

This policy does not address NTRK testing. The use of tropomyosin receptor kinase (TRK) inhibitors for individuals with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive solid tumors is addressed separately in evidence review 5.01.31.

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

For expanded panel testing, see evidence review 2.04.115.

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 U.S. Food and Drug Administration (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 evidence 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.4.2023) 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 NSCLC in patients with metastatic disease with histologic subtypes adenocarcinoma, large cell carcinoma, and NSCLC 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.

HER2 is addressed separately in evidence review 5.01.22.

NTRK is addressed separately in evidence review 5.01.31.

PD-L1 testing is addressed separately in evidence review 2.04.157.

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 (Chakravarty et al, 2022; PMID 35175857).

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.4.2023) state the following: "Studies have demonstrated cell-free tumor DNA testing to generally have very high specificity, but significantly compromised sensitivity, with up to a 30% false-negative rate; however, 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.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Non-Small-Cell Lung Cancer

Treatment options for non-small-cell lung cancer (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.^1, When treated with standard platinum-based chemotherapy, patients with advanced NSCLC have a median survival of 8 to 11 months and 1-year survival of 30% to 45%.^2,3, 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

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 TK 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 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 et al (2013) reported EGFR variants (all L858R) in 3 (2%) of 146 consecutively treated Chinese patients with early-stage squamous cell carcinoma (SCC).^4, 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 2880 patients, Mitsudomi et al (2006) 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.^5, Eberhard et al (2005)^6, observed EGFR variants in 6.4% of patients with SCC and Rosell et al (2009)^7, 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.^8,9,

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.^10, 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%.^10, 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.^10,RET fusions occur in 0.6% to 2% of NSCLCs and 1.2% to 2% of adenocarcinomas.^10,

MET Gene

MET alteration is one of the critical events for acquired resistance in EGFR-mutated adenocarcinomas refractory to EGFR TKIs.^10,

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion 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.^11, 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. Food and Drug Administration (FDA) -approved targeted treatments for the variants described above are summarized in Table 1. (Note this information is current as of October 18, 2023. 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.)

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

    Source: FDA (2023)12, ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; FDA: U.S. Food and Drug Administration; MET: mesenchymal-epithelial transition.

Regulatory Status

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 or Metastatic Colorectal Cancer and FDA Approved Companion Diagnostic Tests

    Sources: U.S. Food and Drug Administration ( 2023 )43,; U.S. Food and Drug Administration (n.d.)11, ALK: anaplastic lymphoma kinase; CDx: companion diagnostic;EGFR: epidermal growth factor receptor; FDA: U.S. 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.

Rationale

This evidence review was created in April 2006 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through September 30, 2024.

Testing for individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. The pivotal evidence is included in Table 2 for informational purposes. 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Somatic Biomarker Testing Using Tissue Biopsy to Select Targeted Therapy for Advanced-Stage Non-Small-Cell Lung Cancer

Review of Evidence

Testing for EGFR Variants or ALK Rearrangements with Tissue Biopsy

For individuals with advanced or metastatic non-small-cell lung cancer (NSCLC) who are being considered for targeted therapy with tyrosine kinase inhibitors (TKIs) who undergo somatic testing for epidermal growth factor receptor (EGFR) variants or anaplastic lymphoma kinase (ALK) rearrangements using tissue biopsy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

Testing for BRAF Variants or ROS1 Rearrangements with Tissue Biopsy

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with BRAF or ROS1 inhibitors who undergo somatic testing for BRAF variants or ROS1 rearrangements using tissue biopsy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

Testing for RET Rearrangementsor MET alterations with Tissue Biopsy

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with RET or mesenchymal-epithelial transition (MET) inhibitors who undergo somatic testing for RET rearrangements or MET alterations using tissue biopsy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

Testing for KRAS Variants with Tissue Biopsy

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with a RAS inhibitor who undergo somatic testing for KRAS variants using tissue biopsy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Testing for NTRK Gene Fusion with Tissue Biopsy

For individuals with metastatic NSCLC who are being considered for targeted therapy with a TRK inhibitor who undergo somatic testing for NTRK gene fusion using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Biomarker Testing Using Circulating Tumor DNA (Liquid Biopsy) to Select Targeted Therapy for Advanced-Stage Non-Small-Cell Lung Cancer

Testing for EGFR Variants or ALK Rearrangements with Circulating Tumor DNA (Liquid Biopsy)

For individuals with advanced-stage NSCLC who receive somatic testing for EGFR variants or ALK rearrangements using circulating tumor DNA (ctDNA) (liquid biopsy) to guide targeted treatment with TKIs, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

Testing BRAF Variants or ROS1 Rearrangements with Circulating Tumor DNA (Liquid Biopsy)

No plasma tests have received FDA approval as companion diagnostics to select individuals with NSCLC for treatment with BRAF inhibitors and no studies were identified.

In December 2022, FoundationOne Liquid CDx was FDA approved as a companion diagnostic to select treatment with entrectinib in individuals with NSCLC. No plasma tests have received FDA approval as companion diagnostics to select patients with ROS1 rearrangements for treatment with crizotinib and no studies for this indication were identified.

Testing for MET Exon 14 Skipping Alterations with Circulating Tumor DNA (Liquid Biopsy)

For individuals with advanced-stage NSCLC who receive somatic testing for MET Exon 14 skipping alterations using ctDNA (liquid biopsy) to guide targeted treatment with MET inhibitors, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

Testing for RET Rearrangements with Circulating Tumor DNA (Liquid Biopsy)

No plasma tests have received FDA approval as companion diagnostics to select individuals with NSCLC for treatment with RET inhibitors and no studies were identified.

Testing for KRAS Variants with Circulating Tumor DNA (Liquid Biopsy)

For individuals with advanced-stage NSCLC who receive somatic testing for KRAS variants using ctDNA (liquid biopsy) to guide targeted treatment with RAS inhibitors, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

Testing for NTRK Gene Fusion with Circulating Tumor DNA (Liquid Biopsy)

For individuals with metastatic NSCLC who are being considered for targeted therapy with a TRK inhibitor who undergo somatic testing for NTRK gene fusion using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 1

For individuals with advanced or metastatic non-small-cell lung cancer (NSCLC) who are being considered for targeted therapy with tyrosine kinase inhibitors who undergo somatic testing for EGFR variants or ALK rearrangements using tissue biopsy specimens, the evidence includes U.S. Food and Drug Administration (FDA)-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 2

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with tyrosine kinase inhibitors who undergo somatic testing for EGFR variants or ALK rearrangements using circulating tumor DNA (ctDNA) (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 3

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with BRAF or ROS1 inhibitors who undergo somatic testing for BRAF variants or ROS1 rearrangements using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 4

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with BRAF or ROS1 inhibitors who undergo somatic testing for BRAF variants or ROS1 rearrangements using ctDNA (liquid biopsy), no evidence was identified. No plasma tests have received FDA approval as companion diagnostics to select individuals with NSCLC for treatment with BRAF inhibitors and no studies were identified. FoundationOne Liquid CDx is FDA approved as a companion diagnostic to select treatment with entrectinib in individuals with ROS1 positive NSCLC. No plasma tests have received FDA approval as companion diagnostics to select patients with ROS1 rearrangements for treatment with crizotinib and no studies for this indication were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with RET or MET inhibitors who undergo somatic testing for RET rearrangements or MET alterations using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 6

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with RET inhibitors who undergo somatic testing for RET rearrangements using ctDNA (liquid biopsy), no studies were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 7

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with MET inhibitors who undergo somatic testing for MET alterations using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 8

For individuals with advanced or metastatic NSCLC who are being consi

dered for targeted therapy with a RAS inhibitor who undergo somatic testing for KRAS variants using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 9

For individuals with advanced or metastatic NSCLC who are being considered for targeted therapy with a RAS inhibitor who undergo somatic testing for KRAS variants using using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 10

For individuals with metastatic NSCLC who are being considered for targeted therapy with a TRK inhibitor who undergo somatic testing for NTRK gene fusion using tissue biopsy specimens, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Population Reference No. 11

For individuals with metastatic NSCLC who are being considered for targeted therapy with a TRK inhibitor who undergo somatic testing for NTRK gene fusion using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Chest Physicians Guidelines

In 2013, the American College of Chest Physicians updated its evidence-based practice guidelines on the treatment of stage IV non-small-cell lung cancer (NSCLC).^44, Based on a review of the literature, the College reported improved response rates, progression-free survival, and toxicity profiles with first-line erlotinib or gefitinib compared with first-line platinum-based therapy in patients with EGFR variants, especially exon 19 deletion and L858R. The College recommended, “testing patients with NSCLC for EGFR mutations at the time of diagnosis whenever feasible, and treating with first-line EGFR TKIs [tyrosine kinase inhibitors] if mutation-positive.”

American Society of Clinical Oncology

In 2021, the American Society of Clinical Oncology (ASCO) and Ontario Health published updated guidelines on therapy for stage IV NSCLC with driver alterations. ^52, The updated recommendations were based on a systematic review of randomized controlled trials from December 2015 to January 2020 and meeting abstracts from ASCO 2020. The recommendations include the following:

• All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status, when possible.

• Targeted therapies against ROS1 fusions, BRAF V600E mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting.

• Chemotherapy is still an option at most stages.

The above guidelines were updated in 2023 to add amivantamab monotherapy and mobocertinib monotherapy for second-line treatment in advanced NSCLC with an EGFR exon 20 insertion, and sotorasib monotherapy for second-line treatment in advanced NSCLC with a KRAS-G12C mutation.^53,

In 2022, the ASCO published a guideline on the management of stage III NSCLC.^54, The recommendations were based on a literature search of systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Relevant recommendations include the following:

• Presence of oncogenic driver alterations, available therapies, and patient characteristics should be taken into account.

• Patients with resected stage III NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation may be offered adjuvant osimertinib after platinum-based chemotherapy.

College of American Pathologists et al

In 2013, the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology published evidence-based guidelines for molecular testing to select patients with lung cancer for treatment with EGFR and ALK TKI therapy.^55, Based on excellent quality evidence (category A), the guidelines recommended EGFR variant and ALK rearrangement testing in patients with lung adenocarcinoma regardless of clinical characteristics (eg, smoking history).

In 2018, updated guidelines were published and added new EGFR and ALK recommendations.^56,ROS1 testing is recommended for all patients with lung adenocarcinoma irrespective of clinical characteristics (strong recommendation). BRAF, RET, HER2, KRAS, and MET testing are not recommended as routine stand-alone tests, but may be considered as part of a larger testing panel or if EGFR, ALK, and ROS1 are negative (expert consensus opinion).

National Comprehensive Cancer Network Guidelines

Testing for Molecular Biomarkers

National Comprehensive Cancer Network (NCCN) guidelines on NSCLC provide recommendations for individual biomarkers that should be tested, and recommend testing techniques. Guidelines are updated frequently; refer to the source document for current recommendations. The most recent guidelines ( v.10.2024) include the following recommendations and statements related to testing for molecular biomarkers:^14,

• Broad molecular profiling systems may be used to simultaneously test for multiple biomarkers.

• To minimize tissue use and potential wastage, the NCCN NSCLC Panel recommends that broad molecular profiling be done as part of biomarker testing using a validated test(s) that assesses potential genetic variants:

  • ALK rearrangements;

  • EGFR mutations;

  • BRAF mutations;

  • MET exon 14 skipping mutations;

  • RET rearrangements;

  • ERBB2 (HER2) mutations;

  • KRAS mutations;

  • NTRK 1/2/3 gene fusions;

  • ROS1 rearrangements.

• Both U.S. Food and Drug Administration (FDA) and laboratory-developed test platforms are available that address the need to evaluate these and other analytes.

• Broad molecular profiling is also recommended to identify emerging biomarkers for which effective therapy may be available, such as high-level MET amplifications.

• Clinicopathologic features should not be used to select patients for testing.

• The guidelines do not endorse any specific commercially available biomarker assays or commercial laboratories.

Plasma Cell-Free/Circulating Tumor DNA Testing:

The NCCN guidelines on NSCLC ( v.10.2024) include the following recommendations related to plasma cell-free/circulating tumor DNA testing.^14,

• Plasma cell free/circulating tumor DNA testing should not be used in lieu of a histologic tissue diagnosis.

• ctDNA is not routinely recommended in settings other than advanced/metastatic disease. For stages I–III, tissue-based testing is preferred. Metastatic disease confined to the thorax may have a higher yield with tissue-based testing.

• Some laboratories offer testing for molecular alterations examining nucleic acids in peripheral circulation, most commonly in processed plasma.

•  

• 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.

  • Limitations of ctDNA testing that can impact interpretation include:

    • Low tumor fraction/ctDNA; some assays include a measure of ctDNA fraction, which can aid in identification of situations in which low ctDNA fraction might suggest compromised sensitivity

    • The presence of mutations from sites other than the target lesion, most commonly clonal hematopoiesis of indeterminate potential (CHIP) or postchemotherapy marrow clones. KRAS and TP53 can be seen in either of these circumstances

    • The inherent ability of the assay to detect fusions or other genomic variation of relevance

  • Limitations of tissue testing that can impact interpretation include:

    • Low tumor percent in a sample not sufficiently mitigated by tumor enrichment or high analytic sensitivity methods

    • The inherent ability of the assay to detect fusions or other genomic variation of relevance

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

The Centers for Medicare and Medicaid Services will cover diagnostic testing with next-generation sequencing for beneficiaries with recurrent, relapsed, refractory, metastatic cancer, or advanced stages III or IV cancer if the beneficiary has not been previously tested using the same next-generation sequencing test, unless a new primary cancer diagnosis is made by the treating physician, and if the patient has decided to seek further cancer treatment. The test must have an FDA- approved or cleared indication as an in vitro diagnostic, with results and treatment options provided to the treating physician for patient management. ^57,

Ongoing and Unpublished Clinical Trials

Some currently ongoing trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

   NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial. 

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Codes

Applicable Modifiers

As per correct coding guidelines.

Policy History