Medical Policy

Policy Num:       11.003.011
Policy Name:     Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)
Policy ID:           [11.003.011]  [Ac / B / M+ / P+]  [2.04.77]

Last Review:      July 19. 2024
Next Review:     July 20, 2025

 

Related Policies:

11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
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)
11.003.009 - 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)
05.001.034 - Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)

Population Reference No.

Populations

Interventions

Comparators

Outcomes

1

Individuals:

·       With melanoma

Interventions of interest are:

·       BRAF gene variant testing to select treatment with FDA-approved targeted therapy

Comparators of interest are:

·       Standard treatment without genetic testing

Relevant outcomes include:

·       Overall survival

·       Disease-specific survival

·       Test accuracy

2

Individuals:

·       With glioma

Interventions of interest are:

·       BRAF gene variant testing to select treatment with FDA-approved targeted therapy

Comparators of interest are:

·       Standard treatment without genetic testing

Relevant outcomes include:

·       Overall survival

·       Disease-specific survival

·       Test accuracy

3

Individuals:

·       With unresectable or metastatic melanoma

Interventions of interest are:

·       NTRK gene fusion testing to select treatment with FDA-approved targeted therapy

Comparators of interest are:

·       Standard treatment without genetic testing

 

Relevant outcomes include:

·       Overall survival

·      Disease-specific survival

·      Test accuracy

4

Individuals:

·       With glioma

Interventions of interest are:

·       NTRK gene fusion testing to select treatment with FDA-approved targeted therapy

Comparators of interest are:

·       Standard treatment without genetic testing

Relevant outcomes include:

·       Overall survival

·       Disease-specific survival

·       Test accuracy

Summary

Description

The identification of specific, targetable oncogenic “driver mutations” in a subset of melanomas and gliomas has resulted in a reclassification of solid tumors to include molecular subtypes that may direct targeted therapy depending on the presence of specific variants. B-raf proto-oncogene, serine/threonine kinase (BRAF) and mitogen-activated protein kinase (MEK) inhibitors are drugs designed to target a somatic variant in the BRAF gene. BRAF and MEK inhibitors were originally developed for patients with advanced melanoma. BRAF encodes a kinase component in the rapidly accelerated fibrosarcoma (RAF)-MEK-extracellular signal-regulated kinase (ERK) signal transduction phosphorylation cascade. Variants in BRAF cause constitutive kinase activity, which is believed to promote oncogenic proliferation. Direct and specific inhibition of the mutated kinase has been shown to retard tumor growth significantly and may improve patient survival.

Summary of Evidence

For individuals with melanoma who receive BRAF gene variant testing to select treatment with Food and Drug Administration (FDA)-approved targeted therapy, the evidence includes 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 glioma who receive BRAF gene variant testing to select treatment with FDA-approved targeted therapy, 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 melanoma who receive NTRK gene fusion testing to select treatment with Food and Drug Administration (FDA)-approved targeted therapy, the evidence includes 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 glioma who receive NTRK gene fusion testing to select treatment with Food and Drug Administration (FDA)-approved targeted therapy, the evidence includes 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.

Additional Information

Not applicable.

OBJECTIVE

The objective of this review is to summarize the evidence and guidelines on testing for BRAF variants and NTRK fusions to select treatment with FDA-approved targeted therapy for individuals with melanoma or glioma.

POLICY Statements

Testing for BRAF V600 variants in individuals with unresectable or metastatic melanoma, or with resected stage III melanoma may be considered medically necessary to select individuals for treatment with FDA-approved BRAF inhibitors or MEK inhibitors (see Policy Guidelines).

Testing for BRAF V600 variants for all other individuals with melanoma is considered investigational.

Testing for BRAF V600E variants in individuals with glioma may be considered medically necessary to select individuals for targeted treatment with dabrafenib in combination with trametinib.

Testing for BRAF V600 variants for all other individuals with glioma to select targeted treatment is considered investigational.

Testing for NTRK gene fusions in individuals with unresectable or metastatic melanoma may be considered medically necessary to select individuals for treatment with FDA-approved kinase inhibitors (see Policy Guidelines).

Testing for NTRK gene fusions in individuals with glioma may be considered medically necessary to select individuals for treatment with FDA-approved kinase inhibitors.

Testing for NTRK gene fusions for all other individuals with melanoma or glioma to select targeted treatment other than FDA-approved kinase inhibitors is considered investigational.

POLICY GUIDELINES

This policy does not address use of BRAF testing for the purpose of Central Nervous System (CNS) tumor diagnosis. As molecular diagnostic tests including BRAF might be performed for CNS tumor classification, Plans might need to consult the WHO Classification of Tumors of the CNS or other sources.

This policy on BRAF testing varies from National Comprehensive Cancer Network (NCCN)-Pediatric CNS guidelines for pediatric gliomas. Plans might locally consider coverage of BRAF V600E testing to inform coverage of vemurafenib.

NCCN Guidelines on Cutaneous Melanoma (v.2.2024) note, "Molecular testing may be performed on tumor tissue, or if not available, on peripheral blood (liquid biopsy). Given the possibility of a false negative, a negative liquid biopsy should prompt tissue testing."

NCCN Guidelines on CNS tumors (v.1.2023) do not discuss use of tissue biopsy vs. liquid biopsy.

Testing for other variants may become available between policy updates.

Testing for individual genes (not gene panels) associated with Food and Drug Administration (FDA)-approved therapeutics for therapies with 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 expanded panel testing, see evidence review 11.003.026.

For somatic biomarker testing related to use of immune checkpoint inhibitor therapy (BRAF, microsatellite instability/mismatch repair [MSI/MMR], PD-L1, tumor mutational burden [TMB]), see evidence review 11.003.140.

Note that TMB is often included in panel tests and might not have separate coding; Plans with coverage for panels might consider local decision for TMB.

FDA approves tests in between policy review cycles. As such, newly approved tests might need to be considered per local Plan discretion. 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.

Note: Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with FDA-approved therapies with NCCN recommendations of 2A or higher. The pivotal evidence is included in Table 1 for informational purposes. Additionally, no evidence review is provided for somatic tests of individual genes that do not have associated FDA-approved therapies regardless of NCCN recommendations, as these off-label therapies are deemed investigational per the Blue Cross and Blue Shield Association Medical Policy Program Policies and Procedures.

Coding

See the Codes table for details.

BENEFIT APPLICATION

Blue Card/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

Melanoma

Overall incidence rates for melanoma have been increasing for at least 30 years. In advanced (stage IV) melanoma, the disease has spread beyond the original area of skin and nearby lymph nodes. Although only a small proportion of cases are stage IV at diagnosis, the prognosis is extremely poor; 5-year survival is 15% to 20%.

Variants in the b-raf proto-oncogene, serine/threonine kinase (BRAF) kinase gene are common in tumors of patients with advanced melanoma and result in constitutive activation of a key signaling pathway (rapidly accelerated fibrosarcoma [RAF]-MEK-extracellular signal-regulated kinase [ERK] pathway) that is associated with oncogenic proliferation. In general, 50% to 70% of melanoma tumors harbor a BRAF variant; of these, 80% are positive for the BRAF V600E variant, and 16% are positive for BRAF V600K.3, Thus, 45% to 60% of advanced melanoma patients may respond to a BRAF inhibitor targeted to this mutated kinase.

BRAF inhibitors (e.g., vemurafenib, dabrafenib) and mitogen-activated protein kinase (MEK) inhibitors (e.g., trametinib, cobimetinib) have been developed for use in patients with advanced melanoma. Vemurafenib (also known as PLX4032 and RO5185426) was developed using a fragment-based, structure-guided approach that allowed the synthesis of a compound with high potency to inhibit the BRAF V600E mutated kinase and with significantly lower potency to inhibit most of many other kinases tested.4, Preclinical studies have demonstrated that vemurafenib selectively blocked the RAF-MEK-ERK pathway in BRAF mutant cells5,6,7, and caused regression of BRAF mutant human melanoma xenografts in murine models.4, Paradoxically, preclinical studies also showed that melanoma tumors with the BRAF wild-type gene sequence could respond to mutant BRAF-specific inhibitors with accelerated growth,5,6,7, suggesting that it may be harmful to administer BRAF inhibitors to patients with BRAF wild-type melanoma tumors. Potentiated growth in BRAF wild-type tumors has not yet been confirmed in melanoma patients, because the supportive clinical trials were enrichment trials, enrolling only patients with tumors positive for the BRAF V600E variant.

Glioma

Gliomas encompass a heterogeneous group of tumors and the classification of gliomas has changed over time. In 2021, the World Health Organization (WHO) updated its classification of gliomas, glioneuronal tumors, and neuronal tumors to divide them into distinct families: 1) adult-type diffuse gliomas (the majority of primary brain tumors in adults), 2) pediatric-type diffuse low-grade gliomas (expected to have good prognoses), 3) pediatric-type diffuse high-grade gliomas (expected to behave aggressively, 4) circumscribed astrocytic gliomas (referring to their more solid growth pattern as opposed to diffuse tumors), 5) glioneuronal and neuronal tumors (a diverse group of tumors, featuring neuronal differentiation), and 6) ependymal tumors (classified by site as well as histological and molecular features).8,

There is considerable interest in targeted therapies that inhibit the RAF-MEK-ERK pathway, particularly in patients with high-grade and low-grade gliomas whose tumors are in locations that prevent full resection. Evidence from early-phase trials in patients with BRAF variant-positive melanoma with brain metastases have suggested some efficacy for brain tumor response with vemurafenib and dabrafenib.9,10, indicating that these agents might be potential therapies for primary brain tumors.

Regulatory Status

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. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of these tests.

Table 1 summarizes the targeted treatments approved by the FDA for patients with melanoma along with the concurrently approved diagnostic tests as of the most recent policy update (April 30, 2024 ).

The FDA maintains a regularly updated list of 'Cleared or Approved Companion Diagnostic Devices'. New tests may become available between policy updates.11,

Table 1. FDA-Approved Targeted Treatments for Melanoma and Approved Companion Diagnostic Tests1
Treatment Indication FDA Approval of Companion Diagnostic Test Pivotal Study NCCN Recommendation Level/Guideline
Atezolizumab (Tecentriq; Genentech)
  • 2020: treatment of patients with unresectable or metastatic melanoma with BRAF V600 variants in combination with cobimetinib and vemurafenib

For cobimetinib in combination with vemurafenib:

  • 2016: cobas® 4800 BRAF V600 Mutation Test (Roche)
  • 2017: FoundationOne CDx™ (Foundation Medicine)

Gutzmer et al (2020)12,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Binimetinib (Mektovi; Array BioPharma)
  • 2018: Used in combination with encorafenib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
  • 2013: THxID™ BRAF kit (bioMérieux)

Dummer et al (2018)14,
 

Dummer et al (2022)15,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Cobimetinib (Cotellic; Genentech)
  • 2015: Used in combination with vemurafenib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K variants
  • 2016: cobas® 4800 BRAF V600 Mutation Test (Roche)
  • 2017: FoundationOne CDx™ (Foundation Medicine)
Ascierto et al (2016)16, 2A or higher/
Cutaneous Melanoma (v.2. 2024)13,
Dabrafenib (Tafinlar; GlaxoSmithKline)
  • 2013: treatment of patients with unresectable or metastatic melanoma with BRAF V600E
  • 2014: Used in combination with trametinib to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K variants
  • 2018: Used in combination with trametinib for adjuvant treatment of patients with resected stage III melanoma with BRAF V600E or V600K variants
  • 2023: Used in combination with trametinib for treatment of pediatric patients 1 year of age and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy.

Melanoma

  • 2013: THxID™ BRAF kit (bioMérieux)
  • 2017: FoundationOne CDx™ (Foundation Medicine)

Glioma

  • No companion FDA approved companion diagnostic

Hauschild et al (2012)17,

Long et al (2015)18,

Long et al (2014)19,

Robert et al (2015)20,

Long et al (2017)21,

Glioma: ClinicalTrials.gov (2023)22,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Central Nervous System Cancers (v.1.2023)23,

Encorafenib (Bravtovi; Array BioPharma)
  • 2018: Used in combination with binimetinib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
  • 2013: THxID™ BRAF kit (bioMérieux)
Ascierto et al (2020)24, 2A or higher/
Cutaneous Melanoma (v.2. 2024)13,
Entrectinib (Rozyltrek; Genentech)
  • 2019: treatment of adults and pediatric patients 12 years of age and with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are metastatic or where surgical treatment is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy
  • 2023: Above indication expanded to pediatric patients older than 1 month of age
  • 2022: FoundationOne CDx (Foundation Medicine)
  • 2022: FoundationOne Liquid CDx (Foundation Medicine)

Doebele et al (2020)25,

Pediatrics:
Desai et al (2022)26,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Central Nervous System Cancers (v.1.2023)23,

Pediatric CNS Cancers (v.1.2024)

Larotrectinib (Vitrakvi; Loxo Oncology/Bayer)
  • 2018: treatment of adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. Select patients for therapy based on an FDA-approved test.
  • 2020: FoundationOne CDx (Foundation Medicine)
     


Drilon et al (2018)27,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Central Nervous System Cancers (v.1.2023)23,

Pediatric CNS Cancers (v.1.2024)

Pembrolizumab (Keytruda; Merck)
  • 2020: treatment of adult and pediatric patients with unresectable or metastatic tumor mutation burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, that have progressed following prior treatment and who have no satisfactory treatment options
  • 2020: FoundationOne CDx™ (Foundation Medicine)

See evidence review 2.04.157

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Vemurafenib (Zelboraf); Roche/Genentech and Plexxikon)
  • 2011: treatment of patients with unresectable or metastatic melanoma with BRAF V600 variants
  • 2011: cobas® 4800 BRAF V600 Mutation Test (Roche)
  • 2017: FoundationOne CDx™ (Foundation Medicine)

Chapman et al (2017)28,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Trametinib (Mekinist; GlaxoSmithKline)
  • 2013: treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K variants
  • 2014: Used in combination with dabrafenib to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K variants
  • 2018: Used in combination with dabrafenib for adjuvant treatment of patients with resected stage III melanoma with BRAF V600E or V600K variants
  • 2023: Used in combination with dabrafenib for the treatment of pediatric patients 1 year of age and older with low-grade
    glioma with a BRAF V600E mutation who require systemic
    therapy
  • 2013: THxID™ BRAF kit (bioMérieux)
  • 2017: FoundationOne CDx™ (Foundation Medicine)

Flaherty et al (2012)29,

Long et al (2015)18,

Long et al (2014)19,

Robert et al (2015)20,

Long et al (2017)21,

Glioma: ClinicalTrials.gov (2023)22,

2A or higher/
Cutaneous Melanoma (v.2. 2024)13,

Central Nervous System Cancers (v.1.2023)23,

BRAF: b-raf proto-oncogene, serine/threonine kinase; FDA: Food and Drug Administration; NCCN: National Comprehensive Cancer Network; NTRK: Neurotrophic tyrosine receptor kinase; TMB: tumor mutational burden; TRK: tropomyosin receptor kinase.
1 Please consult the FDA list of 'Cleared or Approved Companion Diagnostic Devices' for most current information.11,

FDA product code: OWD.

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 October 2011 with a search of the PubMed database. The most recent literature update was performed through April 30, 2024.

Testing for individual genes (not gene panels) associated with 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 1 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.

BRAF Gene Variant Testing to Select Targeted Treatment in Melanoma

For individuals with melanoma who receive BRAF gene variant testing to select treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with melanoma who receive BRAF gene variant testing to select treatment with Food and Drug Administration (FDA)-approved targeted therapy, the evidence includes 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.

Testing for BRAF V600 variants in individuals with unresectable or metastatic melanoma, or with resected stage III melanoma may be considered medically necessary to select individuals for treatment with FDA-approved BRAF inhibitors or MEK inhibitors (see Policy Guidelines).

Testing for BRAF V600 variants for all other individuals with melanoma is considered investigational.

Population

Reference No. 1

Policy Statement

[X] Medically Necessary [ ] Investigational

BRAF Gene Variant Testing to Select Targeted Treatment in Glioma

For individuals with glioma who receive BRAF gene variant testing to select treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with glioma who receive BRAF gene variant testing to select treatment with FDA-approved targeted therapy, 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 BRAF V600E variants in individuals with glioma may be considered medically necessary to select individuals for targeted treatment with dabrafenib in combination with trametinib.

Testing for BRAF V600 variants for all other individuals with glioma to select targeted treatment is considered investigational.

Population

Reference No. 2

Policy Statement

[X] Medically Necessary [ ] Investigational

NTRK Fusion Testing to Select Targeted Treatment in Melanoma

For individuals with melanoma who receive NTRK fusion testing to select treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with melanoma who receive NTRK gene fusion testing to select treatment with Food and Drug Administration (FDA)-approved targeted therapy, the evidence includes 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.

Testing for NTRK gene fusions in individuals with unresectable or metastatic melanoma may be considered medically necessary to select individuals for treatment with FDA-approved kinase inhibitors (see Policy Guidelines).

Population

Reference No. 3

Policy Statement

[X] Medically Necessary [ ] Investigational

NTRK Fusion Testing to Select Targeted Treatment in Glioma

For individuals with glioma who receive NTRK fusion testing to select treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with glioma who receive NTRK gene fusion testing to select treatment with Food and Drug Administration (FDA)-approved targeted therapy, the evidence includes 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.

Testing for NTRK gene fusions in individuals with glioma may be considered medically necessary to select individuals for treatment with FDA-approved kinase inhibitors.

Population

Reference No. 4

Policy Statement

[X] Medically Necessary [ ] Investigational

SUPPLEMENTAL INFORMATION

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

National Comprehensive Cancer Network

Note: Guidelines are updated frequently; refer to the source material for most recent guidelines.

National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma (v.2. 2024) include the following recommendations on somatic genetic testing relevant to this reference medical policy:13,

NCCN guidelines on central nervous system cancers (v.1.2023) include the following recommendation on somatic genetic testing in glioma relevant to this evidence review:23,

NCCN guidelines on pediatric central nervous system cancers ( v.1.2024) include a recommendation for testing of BRAF V600E mutation and BRAF fusion for pediatric gliomas, and further recommend that preferred systemic therapy options for recurrent disease include, but are not limited to, dabrafenib/trametinib or vemurafenib for BRAF V600E mutated tumors.30,The guidelines also recommend NTRK fusion testing for pediatric diffuse high-grade gliomas and TRK inhibitors for tumors with NTRK gene fusion.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

In January 2020, the Centers for Medicare and Medicaid Services (CMS) determined that next generation sequencing (NGS) is covered for patients with somatic (acquired) cancer when the diagnostic test is performed in a CLIA-(Clinical Laboratory Improvement Amendments) certified laboratory, when ordered by a treating physician, and when all of the following requirements are met:31,

  1. Patient has:

    1. either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; and

    2. not been previously tested with the same test using NGS for the same cancer genetic content, and

    3. decided to seek further cancer treatment (eg, therapeutic chemotherapy).

  2. The diagnostic laboratory test using NGS must have:

    1. Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,

    2. an FDA-approved or -cleared indication for use in that patient’s cancer; and,

    3. results provided to the treating physician for management of the patient using a report template to specify treatment options.

CMS states that local Medicare carriers may determine coverage of next generation sequencing as a diagnostic laboratory test for patients with advanced cancer only when the test is performed in a CLIA-certified laboratory, when ordered by a treating physician, and when the patient meets criteria in (a) above.

Ongoing and Unpublished Clinical Trials

Some currently ongoing or unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials
NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
Melanoma      
NCT04722575 NEOadjuvant Plus Adjuvant Therapy With Combination or Sequence of Vemurafenib, cobImetinib, and atezolizuMab in Patients With High-risk, Surgically Resectable BRAF Mutated and Wild-type Melanoma (NEO-TIM) 88 Jun 2027
NCT05768178 DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations Treatment Arm 5: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers 30 Oct 2029
NCT05770544 DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. Treatment Arm 3: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers 30 Oct 2029
Glioma      
NCT01089101 A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma 220 Dec 2025
NCT01748149a PNOC-002: Safety, Phase 0, and Pilot Efficacy Study of Vemurafenib, an Oral Inhibitor of BRAF V600E, in Children and Young Adults With Recurrent/Refractory BRAFV600E- or BRAF Ins T Mutant Brain Tumors 40 Dec 2025
NCT02285439 Phase I Study of MEK162 for Children With Progressive or Recurrent Cancer and a Phase II Study for Children With Low-Grade Gliomas and Other Ras/Raf/MAP Pathway Activated Tumors 105 Feb 2024
NCT02465060 Molecular Analysis for Therapy Choice (MATCH) 6452 Dec 2025
NCT03220035 NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Vemurafenib in Patients With Tumors Harboring BRAF V600 Mutations 49 Sep 2024
NCT04166409 A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine Versus Selumetinib (NSC# 748727) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) Not Associated With BRAF V600E Mutations or Systemic Neurofibromatosis Type 1 (NF1) 220 Dec 2026
NCT03155620 NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) Screening Protocol 2316 Sep 2027
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

REFERENCES

  1. Stransky N, Cerami E, Schalm S, et al. The landscape of kinase fusions in cancer. Nat Commun. Sep 10 2014; 5: 4846. PMID 25204415
  2. TRK Fusion Cancer (Testing). https://trkcancer.com/testing. Accessed May 27, 2024.
  3. Vultur A, Villanueva J, Herlyn M. Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res. Apr 01 2011; 17(7): 1658-63. PMID 21447722
  4. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. Sep 30 2010; 467(7315): 596-9. PMID 20823850
  5. Søndergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. Apr 20 2010; 8: 39. PMID 20406486
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CODES

Codes Number Description
CPT 81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
  0037U Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden (Foundation One CDx)
ICD-10-CM C43.0-C43.9 Malignant melanoma of skin code range
  C71.9 Malignant neoplasm of brain, unspecified
ICD-10-PCS   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.
Type of service Pathology  
Place of service Laboratory/Physician’s Office

POLICY HISTORY

Date Action Description
07/19/2024 Annual Review Policy updated with literature review through April 30, 2024; references added. New indications and MN policy statements added for NTRK gene fusion testing to select targeted treatment. Statement on BRAF V600 variant testing in cutaneous melanoma revised to include either tissue or liquid biopsy, to align with NCCN guidelines.
08/15/2023 Policy Reviewed Policy updated with literature review through May 11, 2023. Policy extensively pruned. Pivotal studies added to Table 1. Policy statements changed to align with PICO. New policy statement added stating BRAF V600E variants in individuals with glioma may be considered medically necessary to select individuals for targeted treatment with dabrafenib in combination with trametinib. Indications related to immunotherapy and tumor mutational burden testing removed and added to new policy 2.04.157.
07/11/2023 Annual Review No changes
07/12/2022 Annual Review Policy updated with literature review through May 9, 2022; references added. Policy scope revised to exclude extensive review of individual gene testing associated with FDA-approved therapeutics (i.e., as companion diagnostics) for therapies with National Comprehensive Cancer Network recommendations of 2A or higher. Policy guidelines updated and policy statement added to reflect this approach. Minor editorial refinements to policy statements; intent unchanged.
07/20/2021 Annual Review Policy updated with literature review through May 7, 2021; references added. New policy statement stating TMB testing in melanoma and glioma is investigational was added. Policy title changed to "Genetic Testing to Select Melanoma or Glioma Patients for Targeted Therapy."
07/09/2020 Policy Reviewed Policy updated with literature review through April 21, 2020; references added. Policy statements unchanged.
 10/21/2019 Policy Reviewed Policy updated with literature review through April 18, 2019; references added. Policy statements unchanged.
 06/14/2018 Policy Reviewed Policy updated with literature review through April 9, 2018; references 36, 38, 41, 44, 50 and 51 added. Policy statements on BRAF testing in unresectable, metastatic melanoma and in glioma unchanged. New policy statement added stating BRAF testing in resected, stage III melanoma is medically necessary. "Mutation" changed to "variant" in policy title.
 09/17/2013 Policy Reviewed  
 03/08/2012 Policy created New policy