Medical Policy

Policy Num:      11.003.011
Policy Name:    Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF, NTRK, IDH1, IDH2)
Policy ID:          [11.003.011]  [Ac / B / M+ / P+]  [2.04.77]

Last Review:       July 16, 2025
Next Review:      July 20, 2026
 

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, NTRK, IDH1, IDH2)

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.

The 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.^1, 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 is a kinase inhibitor of TRK A, B, and C protein. Entrectinib additionally inhibits 2 other kinases: anaplastic lymphoma kinase and proto-oncogene tyrosine-protein kinase. The presence of NTRK gene fusions can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry.^2,

Mutations in isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) genes lead to accumulation of the proto-oncogenic metabolite D-2-hydroxyglutarate, disrupting gene expression and cellular differentiation. WHO grade 2 and 3 astrocytomas and oligodendrogliomas are defined by IDH mutations, distinguishing lower-grade gliomas from glioblastomas. IDH1 and IDH2 mutations are generally associated with a favorable prognosis, and have been important biomarkers for stratification in clinical trials. IDH mutations are detected in over 50% of gliomas in patients aged 55 or older.^3,

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 relapsed or refractory pediatric low-grade glioma who receive BRAF gene variant or BRAF fusion rearrangement testing to select treatment with FDA-approved therapeutics, the evidence includes the single-arm FIREFLY-1 trial. Relevant outcomes are overall survival, disease-specific survival, functional outcomes, treatment-related morbidity, and test accuracy. Tovorafenib demonstrated a objective response rate (ORR) ranging from 51-53% across three response assessment criteria among individuals who had received a median of 3 lines of prior systemic therapy, exceeding the historical ORR of 21% observed for single-agent vinblastine chemotherapy in this setting. Notably, patients previously progressing on a MEK or BRAF inhibitor demonstrated ORRs of 30-33% across assessment criteria. Data showing treatment effects of tovorafenib in patients with wild-type BRAF do not exist; therefore, BRAF variant or fusion rearrangement testing is required to identify patients for whom these trial results apply. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

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.

For individuals with glioma who receive IDH1 or IDH2 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.

Additional Inform

Objective

The objective of this review is to summarize the evidence and guidelines on testing for BRAF variants, BRAF fusions,NTRK fusions, IDH1 variants, and IDH2 variants 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 or BRAF fusion rearrangements (e.g., KIAA1549::BRAF) in individuals with relapsed or refractory pediatric low-grade glioma may be considered medically necessary to select individuals for targeted treatment with tovorafenib.

Testing for BRAF V600 variants or BRAF fusion rearrangements 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.

Testing for IDH1 or IDH2 gene variants in individuals with glioma (i.e., grade 2 astrocytoma or oligodendroglioma following surgery including biopsy, sub-total resection, or gross total resection) may be considered medically necessary to select individuals for targeted treatment with vorasidenib.

Testing for IDH gene variants for all other individuals with glioma to select targeted treatment is considered investigational (see Policy Guidelines).

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 varies from National Comprehensive Cancer Network (NCCN)-Pediatric CNS guidelines for pediatric gliomas, which endorse use of several off-label therapies. Plans might locally consider coverage of BRAF V600E testing to inform coverage of vemurafenib and ALK rearrangement testing to inform coverage of lorlatinib and alectinib. The NCCN guidelines for CNS cancers also endorse off-label use of ivosidenib in recurrent or progressive adult oligodendroglioma after radiotherapy and chemotherapy harboring IDH1 mutations. NCCN notes that IDH mutation testing is required for the workup of all gliomas, as IDH mutation status defines WHO grade 2 and 3 astrocytomas and oligodendrogliomas, and grade 4 astrocytomas. The presence of these mutations distinguishes lower-grade gliomas from glioblastomas, which are IDH wild-type. IDH-mutant gliomas are considered adult-type diffuse gliomas and are addressed in the NCCN non-pediatric CNS cancer guidelines. This review does not address genetic testing for purposes of diagnosis or staging in melanoma or glioma.

NCCN Guidelines on Cutaneous Melanoma (v.2.2025) 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.5.2024) 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.

This evidence review does not directly evaluate targeted therapies classified as monoclonal or bispecific antibodies as stand-alone interventions. These therapeutics may be listed in Table 1 of the Regulatory Status section if approved for combination treatment with BRAF, MEK, or other small molecule kinase inhibitors.

For expanded panel testing, see evidence review 2.04.115.

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 2.04.157.

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.^4, 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.^5, Preclinical studies have demonstrated that vemurafenib selectively blocked the RAF-MEK-ERK pathway in BRAF mutant cells^6,7,8, and caused regression of BRAF mutant human melanoma xenografts in murine models.^5, 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,^6,7,8, 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).^9,

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.^10,11, indicating that these agents might be potential therapies for primary brain tumors.

Mutations in isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) genes lead to aberrant accumulated production of D-2-hydroxyglutarate, disrupting gene expression and cellular differentiation. WHO grade 2 and 3 astrocytomas and oligodendrogliomas are defined by IDH mutations, distinguishing lower-grade gliomas from glioblastomas. IDH1 and IDH2 mutations are generally associated with a more favorable prognosis, and have been important biomarkers for stratification in clinical trials. IDH mutations are detected in over 50% of gliomas in patients aged 55 or older.^3,

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 or glioma along with the concurrently approved diagnostic tests as of the most recent policy update (May 19, 2025). This evidence review does not directly evaluate targeted therapies classified as monoclonal or bispecific antibodies as stand-alone interventions. These therapeutics may be listed in Table 1 if approved for combination treatment with BRAF, MEK, or other kinase inhibitors.

The FDA maintains a regularly updated list of 'Cleared or Approved Companion Diagnostic Devices'. New tests may become available between policy updates.^12,

Table 1. FDA-Approved Targeted Treatments for Melanoma or Glioma and Approved Companion Diagnostic Tests¹

  BRAF: b-raf proto-oncogene, serine/threonine kinase; FDA: Food and Drug Administration; IDH1: isocitrate dehydrogenase-1; IDH2: isocitrate dehydrogenase-2; 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.12,

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 May 19, 2025.

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. This evidence review does not directly evaluate targeted therapies classified as monoclonal or bispecific antibodies as stand-alone interventions. These therapeutics may be listed in Table 1 if approved for combination treatment with BRAF, MEK, or other kinase inhibitors.

Population Reference No. 1 

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.

Population Reference No. 2

BRAF Gene Variant or Gene Fusion Rearrangement 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.

When treatment is developed for a specific biologic target that characterizes only some patients with a particular disease, and a test is co-developed to identify diseased patients with that target, clinical validity and clinical utility cannot be evaluated separately. Rather, clinical studies of treatment benefits; that use the test to select patients, provide evidence of both clinical validity and clinical utility. We reviewed the pivotal clinical trials of treatments in which testing for the BRAF gene variant or BRAF gene fusion rearrangement was required for selection into the trial, leading to the regulatory approval of targeted therapies not yet addressed by NCCN guidelines at the time of review.

Clinical Context and Test Purpose

The purpose of testing for BRAF pathogenic gene variants and gene fusion rearrangements in individuals with glioma is to inform a decision whether to treat with targeted small molecule inhibitors. Standard treatment for patients with glioma includes surgical resection followed by radiotherapy and/or chemotherapy.

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.

The following PICO was used to select literature to inform this review:

Population Reference No. 3 

Populations

The relevant population of interest is patients with relapsed or refractory low-grade glioma considering therapy with tovorafenib. Pediatric low-grade glioma represents approximately 30% of pediatric brain tumors. While considered indolent and potentially curable via surgical resection, deep-seated or highly infiltrative tumors may not be amenable to complete resection. As a result, patients may experience disease progression, functional deficits, neurocognitive deficits, and significant treatment morbidity.

Interventions

The intervention of interest is genetic testing for BRAF V600 pathogenic variants and BRAF fusion rearrangements to select targeted therapy. The specific treatment being evaluated is tovorafenib, a type II RAF inhibitor FDA-approved for the treatment of relapsed or refractory pediatric low-grade glioma. At the time of review, NCCN guidelines have not addressed use of tovorafenib following regulatory approval.

Comparators

The comparator of interest is the standard treatment for glioma without genetic testing for BRAF variants or gene fusion rearrangements. BRAF alterations are present in 70% of pediatric low-grade gliomas. Rearrangements or fusions of the KIAA1549 and BRAF genes are the most common somatic driver alterations.

Low-grade gliomas are classified as WHO grade I or II and include pilocytic astrocytoma, diffuse astrocytoma, and oligodendroglioma. Surgical resection of the tumor is generally performed, although additional therapy with radiotherapy and chemotherapy following surgery is usually required, except for pilocytic astrocytoma. The optimal timing of additional therapies is unclear. Many patients will recur following initial treatment, with a clinical course similar to high-grade glioma. While mortality from pediatric low-grade gliomas is generally low, approximately half of patients will recur or progress, resulting in significant morbidity, decreased functional outcomes, and poor quality of life.

BRAF and MEK inhibitors are considered an emerging standard therapy option in the setting of relapsed or refractory disease. However, some of these medications require daily dosing with fasting requirements complicating administration in the pediatric population. Treatment options are limited in patients who have progressed on these therapies.

Outcomes

The primary outcomes of interest are OS, PFS, ORR (overall response rate), functional outcomes, treatment morbidity, and quality of life. While survival outcomes are also of interest, most pediatric low-grade gliomas do not undergo malignant transformation, resulting in a 10-year overall survival rate exceeding 90%. In contrast, the 5-year PFS rate is approximately 50%. Radiologic and clinical response to treatment in individuals with glioma may be assessed by several assessment criteria, including the Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) or low-grade gliomas (RANO-LGG), and the Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria.

Study Selection Criteria

As stated previously, we will include pivotal clinical trials of treatments in which testing for the BRAF variant or gene fusion rearrangement was required for selection or phase 3 trials which provided treatment by BRAF variant interaction analyses.

Clinically Valid and Clinically Useful

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Tovorafenib

Tovorafenib is a CNS-penetrant type II RAF kinase inhibitor, inhibiting both RAF monomers and dimers. Its treatment efficacy as monotherapy was evaluated in the international, multicenter, single-arm, phase 2 FIREFLY-1 trial. Arm 1 enrolled 77 children and young adults (median age, 8 years; range, 2-21 years) with BRAF-altered relapsed or refractory pediatric low-grade glioma (pLGG). Subjects had a median of 3 prior lines of systemic therapy (range, 1-9), with more than half previously receiving BRAF and/or MEK inhibitors. The majority of patients harbored tumors in the optic pathway or deep midline structures. KIAA1549::BRAF fusions were identified in 73% of patients, whereas BRAF V600E mutations were identified in 17%. Subtotal resection was previously performed in 47% of patients, and a prior resection was not attempted in 52%. Tumor responses were evaluated across three response assessment criteria by an independent review committee (IRC). The primary trial outcome was IRC-assessed ORR based on RANO-HGG criteria, as this was considered the only validated assessment criteria at the time of trial initiation. Secondary endpoints included efficacy assessments by RAPNO criteria. Efficacy by RANO-LGG criteria was added as a post hoc exploratory outcome per regulatory authority request. The ORR based on RANO-HGG criteria was 53% (95% CI, 41-64), meeting the primary endpoint by rejecting the null hypothesis ORR of 21% observed for single-agent vinblastine in this setting. ORR based on RAPNO and RANO-LGG criteria were 51% (95% CI, 40-63) and 53% (95% CI, 41-64), respectively. Responses to tovorafenib among patients who progressed on prior treatment with a MAPK pathway MEK or BRAF inhibitor ranged from 30-33% across assessment criteria. Time to response in patients with tumors harboring BRAF V600E mutations were shorter by RAPNO and RANO-LGG criteria (2.8 months and 2.9 months, respectively) compared to those harboring BRAF fusions (5.5 months and 5.5 months, respectively. The investigators noted that a delayed treatment response pattern in patients initially assessed with early radiographic evidence of progressive disease may represent a tumor flare or pseudoprogression, a phenomenon previously observed with immune checkpoint inhibitor administration, highlighting the challenge of efficacy evaluation in this patient population. Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 63% of patients in the safety population (n=137), with anemia, elevated CPK, maculopapular rash, and decreased growth velocity most commonly identified. Grade 3 or higher treatment-related adverse events (TRAEs) were reported in 42% of the safety population, with anemia, elevated CPK, maculopapular rash, increased ALT, and decreased growth velocity most commonly identified. Investigators noted that there has been no evidence of bone age advancement or premature growth plate closure. Recovery of growth velocity was observed in patients with available height data off-treatment. Nine patients (7%) had TRAEs leading to tovorafenib discontinuation. One patient death was observed, due to disease progression. There were no treatment-related deaths during the trial period. Adherence to treatment with tovorafenib was deemed favorable due to the availability of a liquid formulation and absence of a food effect. Limitations of the trial include the single-arm design; however, this approach was considered sufficient and necessary due to the lack of consensus on standard of care for most patients with relapsed and refractory pLGG. The phase 3 LOGGIC/FIREFLY-2 RCT of tovorafenib monotherapy versus current standard of care chemotherapy in children and adults with pLGG harboring activating RAF alterations who require frontline systemic treatment is ongoing (NCT05566795).

Section Summary: BRAF Testing in Low-Grade Glioma

The FIREFLY-1 trial of tovorafenib in children and young adults with relapsed or refractory and BRAF-altered pLGG demonstrated ORRs ranging from 51-53% across three response assessment criteria. Patients previously progressing on a MEK or BRAF inhibitor demonstrated ORRs of 30-33% across assessment criteria, exceeding the ORR of 21% observed for single-agent vinblastine chemotherapy in this setting. Tovorafenib represents the first available systemic therapy for the treatment of pLGG in individuals with BRAF fusions or rearrangements and is undergoing further study for use as frontline therapy.

For individuals with relapsed or refractory pediatric low-grade glioma who receive BRAF gene variant or BRAF fusion rearrangement testing to select treatment with FDA-approved therapeutics, the evidence includes the single-arm FIREFLY-1 trial. Relevant outcomes are overall survival, disease-specific survival, functional outcomes, treatment-related morbidity, and test accuracy. Tovorafenib demonstrated a objective response rate (ORR) ranging from 51-53% across three response assessment criteria among individuals who had received a median of 3 lines of prior systemic therapy, exceeding the historical ORR of 21% observed for single-agent vinblastine chemotherapy in this setting. Notably, patients previously progressing on a MEK or BRAF inhibitor demonstrated ORRs of 30-33% across assessment criteria. Data showing treatment effects of tovorafenib in patients with wild-type BRAF do not exist; therefore, BRAF variant or fusion rearrangement testing is required to identify patients for whom these trial results apply. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

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.

Population Reference No. 5 

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.

Population Reference No. 6

IDH1 or IDH2 Gene Variant Testing to Select Targeted Treatment in Glioma

For individuals with glioma who receive IDH1 or IDH2 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.

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.2.2025) include the following recommendations on somatic genetic testing relevant to this reference medical policy:^14,

• The panel does not recommend BRAF or next generation sequencing (NGS) testing for resected stage I–II cutaneous melanoma unless it will inform clinical trial participation.

• BRAF mutation testing is recommended for patients with stage III at high risk for recurrence for whom future BRAF-directed therapy may be an option.

• For initial presentation with stage IV disease or clinical recurrence, obtain tissue to ascertain alterations in BRAF, and in the appropriate clinical setting, KIT [receptor tyrosine kinase] from either biopsy of the metastasis (preferred) or archival material if the patient is being considered for targeted therapy.

• Broader genomic profiling (e.g., larger NGS panels, BRAF non-V600 mutations) is recommended if feasible, especially if the test results might guide future treatment decisions or eligibility for participation in a clinical trial.

• If BRAF single-gene testing was the initial test performed, and is negative, clinicians should strongly consider larger NGS panels to identify other potential genetic targets (e.g, KIT, BRAF non-V600).

• Repeat molecular testing upon recurrence or metastasis is likely to be of low yield, unless new or more comprehensive testing methods are used or a larger, more representative sample is available if there is concern for sampling error.

• Repeat testing following progression on targeted therapy (BRAF- or KIT-directed therapy) does not appear to have clinical utility, since the mechanisms of resistance are diverse and do not have prognostic or therapeutic relevance.

• While the V600E mutation is the most common BRAF mutation, other BRAF mutations exist that may respond equally well to BRAF inhibitors. Some tests have lower sensitivity/specificity or detect only particular mutations. If needed for clinical care, repeat testing using a different methodology may be warranted to detect non-V600E BRAF mutations, or other mutations in different genes. If the initially submitted tissue was of poor quality, a new biopsy may be required before repeat testing is ordered.

NCCN guidelines on central nervous system cancers (v.5.2024) include the following recommendation on somatic genetic testing in glioma relevant to this evidence review:^3,

• The panel encourages molecular testing of glioblastoma because if a driver mutation (such as BRAF V600E mutation or NTRK fusion) is detected, it may be reasonable to treat with a targeted therapy on a compassionate use basis and/or the patient may have more treatment options in the context of a clinical trial.

• Molecular testing also has a valuable role in improving diagnostic accuracy and prognostic stratification that may inform treatment selection.

• IDH mutation testing is required for the workup of all gliomas.

• The most common IDH1 mutation (R132H) is reliably screened by mutation-specific immunohistochemistry (IHC), which is recommended for all patients with glioma. If the R132H immunostain result is negative, in the appropriate clinical context, sequencing of IDH1 and IDH2 is highly recommended to detect less common IDH1 and IDH2 mutations. Prior to age 55 years, sequencing of IDH1 and IDH2 is required if the R132H immunostain result is negative, or if the glioma is only grade 2 or 3 histologically. Standard sequencing methods include Sanger sequencing, pyrosequencing, and NGS, and can be performed on formalin-fixed, paraffin-embedded tissue.

NCCN guidelines on pediatric central nervous system cancers (v.2.2025) 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.^29, The guidelines recommend NTRK fusion testing for pediatric diffuse high-grade gliomas and TRK inhibitors for tumors with NTRK gene fusion. The guidelines also recommend the use of lorlatinib or alectinib in pediatric high-grade gliomas harboring ALK rearrangements.

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:^36,

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

References

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20. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. Jul 28 2012; 380(9839): 358-65. PMID 22735384
21. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. Aug 01 2015; 386(9992): 444-51. PMID 26037941
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Codes

Policy History