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

POLICY NUMBER

A.2.04.77

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.

Melanoma

Overall incidence rates for melanoma have been increasing for at least 30 years. In advanced (Stage 4) melanoma, the disease has spread beyond the original area of skin and nearby lymph nodes. Although only a small proportion of cases are Stage 4 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. 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. Preclinical studies have demonstrated that vemurafenib selectively blocked the RAF-MEK-ERK pathway in BRAF mutant cells and caused regression of BRAF mutant human melanoma xenografts in murine models. 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, suggesting that it might 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.

Neurotrophic receptor tyrosine kinase (NTRK) gene fusions are uncommon kinase fusion events that drive tumorigenesis in a small fraction of solid tumors, regardless of tissue type. The tropomyosin receptor kinases (TRK) proteins A, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 respectively. In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that are oncogenic, promoting tumor cell proliferation and their survival. Larotrectinib and entrectinib are kinase inhibitors of TRK A, B, and C protein. However, entrectinib additionally inhibits 2 other kinases: anaplastic lymphoma kinase and proto-oncogene tyrosine-protein kinase.

The annual incidence of NTRK fusion-driven tumors is estimated to be 1,500 to 5,000 cases in the United States. NTRK fusions may be more characteristic of rare cancers such as mammary analogue secretory carcinoma, secretory breast carcinoma, or infantile fibrosarcoma. The incidence of NTRK fusions is below 1% for most common cancers such as melanoma.

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).

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, indicating that these agents might be potential therapies for primary brain tumors.

The incidence of NTRK fusions ranges from 10.3% in patients with high-grade gliomas to <1% in low-grade gliomas.

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.

The table below summarizes the targeted treatments approved by the U.S. Food and Drug Administration (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.

FDA-Approved Targeted Treatments for Melanoma and Approved Companion Diagnostic Tests¹

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.¹Please consult the FDA list of 'Cleared or Approved Companion Diagnostic Devices' for most current information.

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.

Related policies are –

• Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

• Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)

• 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)

POLICY

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 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 use of BRAF testing for the purpose of Central Nervous System (CNS) tumor diagnosis.

This policy on BRAF testing varies from National Comprehensive Cancer Network (NCCN)-Pediatric CNS guidelines for pediatric gliomas.

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 individual genes (not gene panels) associated with Food and Drug Administration (FDA)-approved therapeuticsfor therapies with 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 expanded panel testing, see the Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies medical policy.

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

Note that TMB is often included in panel tests and might not have separate coding.

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 National Comprehensive Cancer Network (NCCN) management algorithms.

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

03/22/2012: Approved by Medical Policy Advisory Committee.

01/09/2013: The medically necessary policy statement was revised to replace “vemurafenib” with “FDA-approved BRAF inhibitors.” Intent unchanged of policy statement unchanged. Added the following to the policy guidelines: Currently only vemurafenib has FDA approval for treatment of advanced melanoma.

02/26/2013: Policy guidelines updated to add the following: The vemurafenib full prescribing information states that the drug is indicated for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test. The only testing kit that is approved by the FDA as an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with vemurafenib is the cobas® 4800 BRAF V600 Mutation Test. 

12/13/2013: Policy reviewed; no changes.

02/02/2015: Policy description updated to add information regarding the following BRAF inhibitors: Dabrafenib and Trametinib. Medically necessary policy statement revised to change "stage IIIC or IV" to "unresectable or metastatic." Investigational statement updated to change "lesser stage melanoma" to "resectable melanoma." Policy guidelines updated to include dabrafenib and trametinib as FDA-approved for the treatment of advanced BRAF-mutated melanoma.

08/21/2015: Code Reference section updated for ICD-10.

12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions. Code Reference section updated to revise the code description for CPT code 81210 with an effective date of 01/01/2016.

02/11/2016: Policy description updated. Policy statements unchanged. Policy guidelines updated regarding clinical trials.

06/06/2016: Policy number A.2.04.77 added.

08/02/2017: Policy title changed from "BRAF Gene Mutation Testing To Select Melanoma Patients for BRAF Inhibitor Targeted Therapy" to "BRAF Gene Mutation Testing to Select Melanoma or Glioma Patients for Targeted Therapy." Policy description updated to include MEK inhibitors and to add information regarding treatment of melanoma and gliomas. Policy section updated to change "mutations" to "variants." Medically necessary statement updated to include FDA-approved MEK inhibitors. Added statement that testing for BRAF V600 variants in patients with glioma to select patients for targeted treatment is considered investigational. Policy Guidelines updated to include cobimetinib as FDA-approved to treat advanced BRAF-variant melanoma. Added genetics nomenclature update.

07/31/2018: Policy title updated to change "Mutation" to "Variant." Policy description updated regarding resected stage III melanoma and FDA-approved targeted treatments for melanoma. Added policy statement that testing for BRAF V600 variants in tumor tissue of patients with resected stage III melanoma may be considered medically necessary to select patients for treatment with FDA-approved BRAF or MEK inhibitors.

07/15/2019: Policy description updated regarding FDA-approved targeted treatments for melanoma and their approved companion diagnostic tests. Policy statements unchanged.

07/14/2020: Policy description revised. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature information.

04/12/2022: Policy title changed from "BRAF Gene Variant Testing to Select Melanoma or Glioma Patients for Targeted Therapy" to "Genetic Testing to Select Melanoma or Glioma Patients for Targeted Therapy." Policy description updated regarding neurotrophic receptor tyrosine kinase gene fusions, tumor mutational burden, and FDA approved targeted treatments for melanoma and approved companion diagnostic tests. Medically necessary statement regarding patients with unresectable or metastatic melanoma updated to include immunotherapy as an indication for treatment. Added investigational statement for testing for tumor mutational burden. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

07/14/2022: Policy title changed from "Genetic Testing To Select Melanoma or Glioma Patients for Targeted Therapy" to "Somatic Genetic Testing To Select Individuals with Melanoma or Glioma for Targeted Therapy or Immunotherapy." Policy description updated regarding laboratory-developed tests and FDA-approved tests. Policy statements updated to change "patients" to "individuals." Policy Guidelines updated regarding testing for individual genes and to add a link to the FDA's list of cleared or approved companion diagnostic devices.

04/01/2024: Policy title changed from "Somatic Genetic Testing To Select Individuals with Melanoma or Glioma for Targeted Therapy or Immunotherapy" to "Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)." Policy description and statements updated to remove information regarding immunotherapy and tumor mutational burden testing as this information has been moved to a separate medical policy. Added information regarding gliomas and updated FDA-approved targeted treatments for melanoma and approved companion diagnostic tests. Updated list of related medical policies. Medically necessary statement regarding unresectable or metastatic melanoma was combined with statement regarding resected stage III melanoma. Policy statement revised to state that 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. Added statement that testing for BRAF V600 variants for all other individuals with glioma to select targeted treatment is considered investigational. Policy Guidelines updated regarding tests addressed in this policy.

08/15/2024: Policy description updated regarding FDA-approved targeted treatments for melanoma and approved companion diagnostic tests. Medically necessary statement regarding testing for BRAF V600 variants revised to include either tissue or liquid biopsy. Added policy statements regarding testing for NTRK gene fusions. Policy Guidelines updated regarding NCCN Guidelines on cutaneous melanoma and CNS tumors. Code Reference section updated to add CPT codes 81191, 81192, 81193, 81194, and ICD-10 diagnosis codes C71.0 - C71.9.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.77

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

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