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 BRAF kinase gene are common in tumors of patients with advanced melanoma and result in constitutive activation of a key signaling pathway (RAF-MEK-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.^1, 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 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.^2, Preclinical studies have demonstrated that vemurafenib selectively blocked the RAF-MEK-ERK pathway in BRAF mutant cells^3,4,5,and caused regression of BRAF mutant human melanoma xenografts in murine models.^2, 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,^3,4,5, 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 classification of gliomas has changed over time. In 2016, the World Health Organization (WHO) updated its classification of gliomas based on both histopathologic appearance and molecular parameters.^6, The classification ranges from grade I to IV, corresponding to the degree of malignancy (aggressiveness), with WHO grade I being least aggressive and grade IV being most aggressive.

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.^7,8, indicating that these agents might be potential therapies for primary brain tumors.

Regulatory Status

Table 1 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.

The FDA maintains a list of 'Cleared or Approved Companion Diagnostic Devices'.^9,

Table 1. FDA-Approved Targeted Treatments for Melanoma and Approved Companion Diagnostic Tests

Treatment	Indication	FDA Approval of Companion Diagnostic Test
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)
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	2013: THxID™ BRAF kit (bioMérieux) 2017: FoundationOne CDx™ (Foundation Medicine)
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	2013: THxID™ BRAF kit (bioMérieux) 2017: FoundationOne CDx™ (Foundation Medicine)
Cobimetinib (Cotellic®; Genentech)	2015: Used in combination with vemurafenib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K variants	2017: FoundationOne CDx™ (Foundation Medicine)
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)
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)

FDA: Food and Drug Administration.

FDA product code: OWD.

Related Policies

• Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes (Policy #015 in the Pathology Section)
• Molecular Analysis for Targeted Therapy for Non-Small-Cell Lung Cancer (Policy #053 in the Pathology Section)

For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

I. Testing for BRAF V600 variants in tumor tissue of members with unresectable or metastatic melanoma is considered medically necessary to select members for treatment with Food and Drug Administration-approved BRAF or MEK inhibitors.

II. Testing for BRAF V600 variants in tumor tissue of members with resected stage III melanoma is considered medically necessary to select members for treatment with Food and Drug Administration-approved BRAF or MEK inhibitors.

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

IV. Testing for BRAF V600 variants in members with glioma to select members for targeted treatment is considered investigational.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.


Medicare Coverage:
There is no National Coverage Determination (NCD) for BRAF Gene Mutation Testing To Select Melanoma or Glioma Patients for Targeted Therapy. In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that this service is covered when LCD L35396 criteria and A52986 are met. Please refer to Novitas Solutions Inc, LCD Biomarkers for Oncology (L35396) and Local Coverage Article: Billing and Coding: Biomarkers for Oncology (A52986)for eligibility and coverage. Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46.

Additionally, per the Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N), effective March 16, 2018, and NCD 90.2, NGS is covered if the test is performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following criteria are met:

· The Individual has either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and
· The Individual has either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and
· The Individual has decided to seek further cancer treatment (e.g., therapeutic chemotherapy) AND

· FDA approval or clearance as a companion in vitro diagnostic; and
· an FDA approved or cleared indication for use in that patient’s cancer; and
· results provided to the treating physician for management of the patient using a report template to specify treatment options.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Unresectable or Metastatic Melanoma

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 phase 3 clinical trials of treatments in which testing for the BRAF variant was required for selection into the trial. In the absence of clinical trials in which both patients with and without BRAF variants are entered into randomized controlled trials (RCTs) of novel therapies, we cannot be certain that the test has clinical utility because it is unknown whether the treatment would be effective in patients without BRAF variant. However, patients without BRAF variants have not been enrolled in clinical trials of BRAF inhibitors.

Clinical Context and Test Purpose

The purpose of testing for BRAF pathogenic variants in individuals with unresectable or metastatic melanoma is to inform a decision whether to treat with BRAF or MEK tyrosine kinase inhibitors or with other standard treatments for metastatic melanoma. At the time of the early trials of targeted therapy for metastatic melanoma, cytotoxic chemotherapy (eg, dacarbazine, temozolomide) was widely used to treat metastatic melanoma and was therefore considered a comparator, although it was never demonstrated to improve survival. Chemotherapy is now generally used only in second- or third-line settings or not at all. The current standard treatment for patients with metastatic melanoma includes immunotherapy, which is effective in patients with and without BRAF V600 variants. Patients whose tumors contain a BRAF V600 pathogenic variant may receive a BRAF inhibitor and/or a MEK inhibitor instead of or following immunotherapy..

The question addressed in this policy is: Does testing for BRAF V600 pathogenic variants to select treatment improve the net health outcome in individuals with unresectable or metastatic melanoma?

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

Patients

The relevant population of interest is patients with stage IIIC or stage IV unresectable or metastatic melanoma.

Interventions

The cobas 4800 BRAF V600 test, THxID BRAF kit and FoundationOne CD test are companion diagnostics approved by the U.S. Food and Drug Administration (FDA) for selecting patients for treatment with FDA-approved BRAF or MEK inhibitors.

Comparators

The comparator of interest is the standard treatment for metastatic melanoma without genetic testing for BRAF variants.

Unresectable or Metastatic Melanoma

For several decades after its approval in 1975, cytotoxic chemotherapy with dacarbazine was considered the standard systemic therapy but has provided disappointingly low response rates of only 15% to 25% and median response duration of 5 to 6 months; less than 5% of responses are complete.² Temozolomide has similar efficacy and, unlike dacarbazine, has much better efficacy with central nervous system tumors. Recently immunotherapy with ipilimumab or with checkpoint inhibitors such as pembrolizumab and nivolumab has demonstrated superior efficacy to chemotherapy^{10,11,12,13,14,} regardless of BRAF status and is now recommended as a potential first-line treatment of metastatic or unresectable melanoma.

Resected Stage III Melanoma

Wide local excision is the definitive surgical treatment of melanoma. Following surgery, patients with American Joint Committee on Cancer stage III melanoma may receive adjuvant therapy. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, has been shown to prolong recurrence-free survival by approximately 25% compared with placebo at a median of 5.3 years in patients who had resected stage III disease.^15, Nivolumab, a programmed cell death protein 1 blocking antibody,has been shown to further prolong survival compared with ipilimumab by approximately 35% at 18 months.^16, Before the development of checkpoint inhibitor immunotherapy and targeted therapy, high-dose interferon alfa was an option for adjuvant treatment of stage III melanoma. Interferon alfa has demonstrated an improvement in overall survival but with numerous serious side effects.^17,

Outcomes

The primary outcomes of interest are overall survival (OS) and progression-free survival (PFS). False-positive BRAF test results could lead to inappropriate treatment with BRAF and/or MEK inhibitors, which have not been shown to be effective in patients without BRAF V600 pathogenic variants, and also could lead to delay in treatment with immunotherapy.

Study Selection Criteria

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

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

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.

Review of Evidence
Vemurafenib

The primary evidence of clinical validity and utility for the cobas 4800 BRAF V600 Mutation Test is provided by the phase 3 clinical trial of vemurafenib that enrolled patients testing positive for a V600 variant.

The BRAF Inhibitors in Melanoma 3 trial as reported by Chapman et al (2011) is summarized in Table 2. A total of 675 patients were randomized to vemurafenib (960 mg twice daily orally) or to dacarbazine (1000 mg/m² body surface area by intravenous infusion every 3 weeks) to determine whether vemurafenib would prolong the rate of OS or PFS compared with dacarbazine.^18, All enrolled patients had unresectable, previously untreated stage IIIC or IV melanoma with no active central nervous system metastases. Melanoma specimens from all patients tested positive for the BRAF V600E variant on the cobas 4800 BRAF V600 Mutation Test. Included were 19 patients with BRAF V600K variants and 1 with a BRAF V600D variant.

Tumor assessments, including computed tomography, were performed at baseline, at weeks 6 and 12, and every 9 weeks after that. Tumor responses were determined by investigators using Response Evaluation Criteria in Solid Tumors, version 1.1. Primary endpoints were the rate of OS and PFS. An interim analysis was planned at 98 deaths and a final analysis at 196 deaths; the published report is the interim analysis. The data and safety monitoring board determined that both coprimary endpoints had met prespecified stopping criteria and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. At the time the trial was halted, 118 patients had died; median survival had not been reached. Results for OS strongly favored vemurafenib, with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.26 to 0.55). Adverse events in the vemurafenib group included grade 2 or 3 photosensitivity skin reactions in 12% of patients and cutaneous squamous cell carcinoma in 18%. The results of this trial comprised the efficacy and safety data supporting vemurafenib submission to FDA and established safety and effectiveness of the cobas 4800 BRAF V600 Mutation Test, resulting in approval of both the drug and companion test.

Final OS results from the BRAF Inhibitors in Melanoma 3 trial were reported by Chapman et al (2017).^19, Eighty-four (25%) of the 338 dacarbazine patients crossed over to vemurafenib, and overall 173 (51%) of the 338 patients in the dacarbazine group and 175 of the 337 patients (52%) in the vemurafenib group received subsequent anticancer therapies, most commonly ipilimumab. Median OS without censoring at crossover was 13.6 months (95% CI, 12.0 to 15.4) in vemurafenib vs 10.3 months (95% CI, 9.1 to 12.8 months) in dacarbazine (HR=0.81; 95% CI, 0.68 to 0.96; p=0.01).

Table 2. Phase 3 RCTs of BRAF and MEK Inhibitors for BRAF-Positive Advanced Melanoma

Study/Year	FU, mo	Group	N	OS (95% CI)	PFS (95% CI), mo	ORR (95% CI)
Vemurafenib
Chapman et al (2011)18,	6	Vemurafenib	337	84% (78% to 89%)	5.3a	48% (42% to 55%)
		Dacarbazine	338	65% (56% to 73%)	1.6a	5% (3% to 9%)
		Hazard ratio		0.37 (0.26 to 0.55)	0.26 (0.20 to 0.33)	NA
		p		<0.001	<0.001	NA
Dabrafenib
Hauschild et al (2012)20,	4.9a 0-9.9b	Dabrafenib	187	89%	5.1a	50% (42.4% to 57.1%)
		Dacarbazine	63	86%	2.7a	6% (1.8% to 15.5%)
		Hazard ratio		0.61 (0.25 to 1.48)	0.33 (0.20 to 0.54)	NA
		p		NR	<0.001	NA
Trametinib
Flaherty et al (2012)21,	6	Trametinib	214	81%	4.8 (4.3 to 4.9)a	22% (17% to 28%)
		Chemotherapyc	108	67%	1.5 (1.4 to 2.7)a	8% (4% to 15%)
		Hazard ratio		0.54 (0.32 to 0.92)	0.47 (0.34 to 0.65)	NA
		p		0.01	<0.001	NA
Dabrafenib plus trametinib
Long et al(2015)22,		Dabrafenib plus trametinib	211	74%	11.0	NA
		Dabrafenib	212	68%	8.8	NA
		Hazard ratio		0.71 (0.55 to 0.92)	0.67 (0.53 to 0.84)	NA
		p		0.01	<0.001	NA
Robert et al(2015)23,	NR	Dabrafenib plus trametinib	352	72%	11.4	64%
		Vemurafenib	352	65%	7.3	51%
		Hazard ratio		0.69 (0.53 to 0.89)	0.56 (0.46 to 0.69)	NA
		p		0.005	0.001	0.001
Vemurafenib plus cobimetinib
Ascierto et al(2016)24,	14a	Vemurafenib plus cobimetinib	248	22.3% (20.3% to NE)	12.3 (9.5 to 13.4)	68% (61% to 73%)
		Vemurafenib	247	17.4% (15.0% to 19.8%)	7.2 (5.6 to 7.5)	45% (38% to 51%)
		Hazard ratio		0.70 (0.55 to 0.90)	0.58 (0.46 to 0.72)	NA
		p		0.005	<0.001	<0.001
Encorafenib plus binimetinib
Dummer et al (2018)25,	17a	Encorafenib plus binimetinib	192	NR	14.9 (11.0 to 18.5)	63% (56% to 70%)
		Encorafenib	194	NR	9.6 (7.5 to 14.8)	51% (43% to 58%)
		Vemurafenib	191		7.3 (5.6 to 8.2)	40% (33% to 48%)
		Hazard ratiod			0.54 (0.41 to 0.71)	NR
		p			<0.001

CI: confidence interval; FU: follow-up; NA: not applicable; NE: not estimable; NR: not reported; ORR: objective response rate (including complete and partial responses); OS: overall survival; PFS: progression-free survival; RCT: randomized controlled trial.

^a Median value.
^b Range.
^c Either intravenous dacarbazine 1000 mg/m² or intravenous paclitaxel 175 mg/m² every 3 weeks at investigator discretion.
^d Compared encorafenib plus binimetinib with vemurafenib.

One phase 3, open-label RCT of dabrafenib for advanced (stage IV or unresectable stage III) melanoma has been published;^20, the results of this trial are summarized in Table 2. The main objective of this RCT was to compare the efficacy of dabrafenib with standard dacarbazine treatment in patients who had BRAF V600E-variant metastatic melanoma. Two hundred fifty patients were randomized 3:1 to oral dabrafenib 150 mg twice daily or to intravenous dacarbazine 1000 mg/m² every 3 weeks. The primary outcome was PFS, and secondary outcomes were OS, objective response rate, and adverse events.

Median PFS for the dabrafenib and dacarbazine groups was 5.1 months and 2.7 months (p < 0.001), respectively. OS did not differ significantly between groups: 11% of patients in the dabrafenib group died compared with 14% in the dacarbazine group (HR = 0.61; 95% CI, 0.25 to 1.48). However, 28 (44%) patients in the dacarbazine arm crossed over at disease progression to receive dabrafenib. The objective response rate, defined as complete plus partial responses, was higher in the dabrafenib group (50%; 95% CI, 42.4% to 57.1%) than in the dacarbazine group (6%; 95% CI, 1.8% to 15.5%). Treatment-related adverse events of grade 2 or higher occurred in 53% of patients who received dabrafenib and in 44% of patients who received dacarbazine. Grade 3 and 4 adverse events were uncommon in both groups. The most common serious adverse events were cutaneous squamous cell carcinoma (7% vs none in controls); serious noninfectious, febrile drug reactions (3% grade 3 pyrexia vs none in controls); and severe hyperglycemia (> 250-500 mg/dL) requiring medical management in nondiabetic patients or change in management of diabetic patients (6% vs none in controls).

Trametinib

The clinical efficacy and safety of trametinib were assessed in the phase 3, open-label trial, improved survival with MEK inhibition in BRAF-mutated melanoma.^21, Patients with stage IV or unresectable stage IIIC cutaneous melanoma were randomized 2:1 to trametinib 2 mg orally once daily (n = 214) or to chemotherapy (n = 108), either dacarbazine 1000 mg/m² intravenously every 3 weeks or paclitaxel 175 mg/m² intravenously every 3 weeks at investigator discretion. Most patients (67%) were previously untreated. The primary efficacy endpoint was PFS; secondary endpoints included OS, overall response rate, and safety. Tumor assessments were performed at baseline and weeks 6, 12, 21, and 30 and then every 12 weeks.

Median PFS was 4.8 months (95% CI, 4.3 to 4.9 months) in the trametinib arm and 1.5 months (95% CI, 1.4 to 2.7 months) in the chemotherapy arm (p < 0.001) (see Table 2). Although median OS had not been reached at the time of the report publication, 6-month survival was statistically longer in the trametinib group than in the chemotherapy group (p = 0.01); 51 (47%) of 108 patients in the chemotherapy group had crossed over at disease progression to receive trametinib. Decreased ejection fraction or ventricular dysfunction was observed in 14 (7%) patients in the trametinib group; 2 patients had grade 3 cardiac events that led to permanent drug discontinuation. Twelve percent of the trametinib group and 3% of the chemotherapy grouped experienced grade 3 hypertension. Nine percent of patients in the trametinib group experienced ocular events (mostly grade 1 or 2), most commonly blurred vision (4%). The most common adverse events in the trametinib group were rash, diarrhea, peripheral edema, and fatigue; rash was grade 3 or 4 in 16 (8%) patients. Cutaneous squamous cell carcinoma was not observed during treatment.

Combination BRAF Plus MEK Inhibitors
Dabrafenib and Trametinib

The efficacy of combination dabrafenib plus trametinib treatment has been established with two, phase 3 clinical trials.^23,22,26, This combination agent was evaluated in the phase 3, open-label trial by Long et al (2014, 2015).^22,26, In this trial, 4234 patients with unresectable stage IIC or stage IV melanoma with a BRAF V600E or V600K variant were randomized to dabrafenib plus trametinib or dabrafenib plus placebo. The primary endpoint was PFS, as reported in a first publication,^26, followed by a second publication in which longer-term OS was reported.^22,

Median PFS was 11.0 months in the dabrafenib plus trametinib group and 8.8 months in the dabrafenib-only group. The overall response rate was 67% in the dabrafenib plus trametinib group and 51% in the dabrafenib-only group. An interim OS analysis showed a statistically significant difference using standard statistical criteria, but the difference did not cross the prespecified stopping boundary. The rate of cutaneous squamous cell carcinoma was lower in the dabrafenib plus trametinib group (2% vs 9%), whereas pyrexia occurred in more patients (51% vs 28%). In the longer-term study assessing OS, median survival was 25.1 months in the dabrafenib plus trametinib group and 18.7 months in the dabrafenib-only group.

Another phase 3 RCT, by Roberts et al (2015), compared dabrafenib plus trametinib with vemurafenib.^23, A total of 704 patients with metastatic melanoma with BRAF V600E or V600K variants were randomized equally. The trial was terminated at a preplanned interim OS analysis. The OS rate at 12 months was 72% for dabrafenib plus trametinib and 65% for vemurafenib (p = 0.005) (see Table 2). Median PFS was 11.4 months for dabrafenib plus trametinib and 7.3 months for vemurafenib (p < 0.001). The objective response rate was 64% for dabrafenib plus trametinib and 51% for vemurafenib (p < 0.001). Rates of severe adverse events were similar in both groups. Cutaneous squamous cell carcinoma and keratoacanthoma occurred in 1% of dabrafenib plus trametinib subjects and 18% of vemurafenib subjects.

Vemurafenib Plus Cobimetinib

A multicenter, randomized, double-blinded, placebo-controlled phase 3 trial evaluated vemurafenib plus cobimetinib in 495 patients with previously untreated, BRAF V600 variant-positive, unresectable or metastatic melanoma.^24, All patients received vemurafenib 960 mg orally twice daily on days 1 to 28 and were randomized 1:1 to also receive cobimetinib 60 mg once daily on days 1 to 21 or to receive placebo. The primary outcome was PFS. Analyses were done on the intention-to-treat population. Median follow-up was 14 months (see Table 2). PFS was significantly increased with vemurafenib plus cobimetinib compared with vemurafenib plus placebo (median PFS, 12.3 months vs 7.2 months; HR = 0.58; 95% CI, 0.46 to 0.72; p < 0.001). Median OS was 22 months for vemurafenib plus cobimetinib and 17 months for vemurafenib plus placebo (HR = 0.70; 95% CI, 0.55 to 0.90; p = 0.005). Serious adverse events were reported in 92 (37%) patients in the vemurafenib plus cobimetinib group and 69 (28%) patients in the vemurafenib plus placebo group. The most common serious adverse events in the vemurafenib plus cobimetinib group were pyrexia and dehydration. The most common grade 3 or 4 adverse events occurring in the vemurafenib plus cobimetinib group were γ-glutamyl transferase increase, blood creatine phosphokinase increase, and alanine transaminase.

Encorafenib Plus Binimetinib

Dummer et al (2018) reported on results of COLUMBUS, a phase 3 RCT comparing encorafenib, a BRAF inhibitor, alone or in combination with the MEK inhibitor binimetinib, with vemurafenib in patients who had advanced BRAF V600-variant unresectable or metastatic melanoma.^25, The COLUMBUS trial was conducted in 162 hospitals in 28 countries between 2013 and 2015; patients were randomized (1:1:1) to oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (n = 192), oral encorafenib 300 mg once daily (n = 194), or oral vemurafenib 960 mg twice daily (n = 191). The primary outcome was PFS for encorafenib plus binimetinib vs vemurafenib. Analyses were done on the intention-to-treat population. Median follow-up was 17 months. PFS was significantly increased with encorafenib plus binimetinib compared with vemurafenib (median PFS = 14.9 months vs 7.3 months in the vemurafenib group; HR = 0.54; 95% CI, 0.41 to 0.71; p < 0.001; see Table 2). OS was not reported. The most common grade 3 or 4 adverse events were increased γ-glutamyltransferase (9%), increased creatine phosphokinase (7%), and hypertension (6%) in the encorafenib plus binimetinib group; palmoplantar erythrodysesthesia syndrome (14%), myalgia (10%), and arthralgia (9%) in the encorafenib group; and arthralgia (6%) in the vemurafenib group.

Section Summary: Clinical Validity and Clinical Utility

RCTs of BRAF and MEK inhibitor therapy in patients selected by BRAF V600 variant testing have shown improvements in OS and PFS. Single-agent BRAF inhibitor treatment with vemurafenib and dabrafenib compared with chemotherapy has shown superior outcomes for response and PFS. Combination BRAF and MEK inhibitor treatment with vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown superior OS compared with vemurafenib alone or dabrafenib alone. There are no RCTs directly comparing BRAF and MEK inhibitor therapy with immunotherapy as a first-line treatment for patients with BRAF pathogenic variants. Network meta-analyses including indirect comparisons have suggested that BRAF and MEK combination therapy might prolong PFS but with higher toxicity compared with immunotherapy.

Resected Stage III Melanoma

As was stated, clinical validity and clinical utility are evaluated together when treatments are 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. Therefore, phase 3 RCTs of targeted treatments are reviewed in this section in which either (1) testing for the BRAF variant was required for enrollment into the trial, or (2) RCTs in which both patients with and without BRAF variants were enrolled and treatment effects stratified by variant status are reported.

Clinical Context and Test Purpose

The purpose of testing for BRAF pathogenic variants in individuals with resected stage III melanoma is to inform a decision whether to use adjuvant treatment with BRAF and/or MEK tyrosine kinase inhibitors after surgical resection. Observation, as well as treatment with nivolumab or ipilimumab, are also options for resected, stage III melanoma.

The question addressed in this policy is: Does testing for BRAF V600 pathogenic variants to select treatment improve the net health outcome in individuals with resected stage III melanoma?

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

Patients

The relevant population of interest is patients with stage III resected melanoma.

Interventions

The cobas 4800 BRAF V600 test, THxID BRAF kit and FoundationOne CDx™ test are FDA-approved companion diagnostics for selecting patients for treatment with FDA-approved BRAF or MEK inhibitors.

Comparators

The comparator of interest is the standard treatment for resected stage III melanoma without genetic testing for BRAF variants, which includes observation, checkpoint inhibitor immunotherapy, or high-dose interferon alfa.

Outcomes

The primary outcome of interest is a recurrence. False-positive BRAF test results could lead to inappropriate treatment with BRAF and/or MEK inhibitors, which have not been shown to be effective in patients without BRAF V600 pathogenic variants, and also could lead to delay in treatment with immunotherapy.

The time point of interest for outcomes is at least three years.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility

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.

Review of Evidence

Two RCTs of BRAF and/or MEK inhibitors in patients with resected stage III BRAF-variant melanoma have been reported. Trial design characteristics are reported in Table 3; results are reported in Table 4. An appraisal of study relevance as well as design and conduct gaps are reported in Tables 5 and 6.

Long et al (2017) reported on results of COMBI-AD, a phase 3 RCT comparing adjuvant combination therapy using dabrafenib plus trametinib with placebo in 870 patients who had stage III melanoma with BRAF V600E or V600K variants.^27, In 2013 and 2014 when patients were being enrolled in COMBI-AD, observation was the standard of care after resection of stage III melanoma in most countries. With a median follow-up of 2.8 years, the 3-year rate of relapse-free survival was 58% in the combination group and 39% in the placebo group (HR = 0.47; 95% CI, 0.39 to 0.58; P < 0.001). OS rates at 3 years were 86% and 77%, respectively (HR = 0.57; 95% CI, 0.42 to 0.79; P < 0.001).

Maio et al (2018) reported on results of BRIM8, a phase 3 RCT comparing adjuvant vemurafenib monotherapy with placebo in 498 patients who had stage IIC, IIIA, IIIB, or IIIC BRAF V600 variant-positive melanoma.^28, Patients with stage IIC, IIIA, or IIIB disease were enrolled in cohort 1 (n = 314), and patients with stage IIIC disease were enrolled in cohort 2 (n = 184). As stated previously, during enrollment, observation was standard care for stage III melanoma. A hierarchical testing strategy was prespecified for the primary outcome (disease-free survival) based on the assumption that observing a biologic effect in higher risk disease (ie, cohort 2) would suggest a treatment effect across the continuum of melanoma given the effect is already established in metastatic melanoma. In the hierarchical strategy, only a P value of 0.05 or less in cohort 2 would allow for results in cohort 1 to be considered significant. The median trial follow-up was 34 months (interquartile range, 26-42 months) in cohort 2 and 31 months (interquartile range, 26-41 months) in cohort 1. In cohort 2, median disease-free survival was 23 months (95% CI, 19 to 27 months) in the vemurafenib group and 15 months (95% CI, 11 to 36 months) in the placebo group (HR = 0.80; 95% CI, 0.54 to 1.18; P = 0.26). In cohort 1, median disease-free survival was not reached (95% CI, not estimable) in the vemurafenib group and 37 months (95% CI, 21 to not estimable) in the placebo group (HR = 0.54; 95% CI, 0.37 to 0.78); however, this result cannot be considered statistically significant because of the prespecified hierarchical testing strategy.

Table 3. Characteristics of RCTs of BRAF and/or MEK Inhibitors for BRAF-Positive Stage III Melanoma

Study	Countries	Sites	Dates	Participants	Interventions
					BRAF and/or MEK Inhibitor	Control
Long et al (2017)27,; COMBI-AD (NCT01682083)	26 countries including U.S.	169	2013- 2014	Adults with completely resected stage III melanoma with BRAF V600E or V600K variants: Stage IIIA: 19% Stage IIIB: 39% Stage IIIC: 41% Stage III unspecified: 1%	Dabrafenib (150 mg bid) plus trametinib (2 mg qd) for 12 mo (n=438)	Matching placebos (n=432)
Maio et al (2018)28,; BRIM8 (NCT01667419)	23 countries including U.S.	124	2012- 2015	Adults with completely resected stage IIC, IIIA, or IIIB (cohort 1) or stage IIIC (cohort 2) melanoma with BRAF V600E or V600K variants Cohort 1: Stage IIC: 9% Stage IIIA: 24% Stage IIIB: 68% Cohort 2: Stage IIIC: 100%	Cohort 1: n=157 Cohort 2: n=93 Vemurafenib (960 mg bid) for 12 mo	Cohort 1: n=157 Cohort 2: n=91 Matching placebo

bid: twice daily; qd: every day; RCT: randomized controlled trial.

Table 4. Results of RCTs of BRAF and/or MEK Inhibitors for BRAF-Positive Stage III Melanoma

Study	Median Recurrence-Free Survival, mo	Distant Metastasis	Death	SAEs
	Recurrence or Death	% Over Study Period	% Over Study Period
Long et al (2017)27,
N	870	870	870	867
Dabrafenib plus trametinib (95% CI)	Not yet reached(44.5 to NE)	25%	14%	36%
Control (95% CI)	16.6 (12.7 to 22.1)	35%	22%	10%
TE (95% CI); p	HR=0.47(0.39 to 0.58); <0.001	HR=0.51(0.40 to 0.65); <0.001	HR=0.57(0.42 to 0.79); <0.001	NR
	Recurrence, New Primary Melanoma, or Death	Median, mo	% at 2 Years
Maio et al (2018)28,
Cohort 1 (stage IIC, IIIA, IIIB)
N	314	314	314	494b
Vemurafenib	Not yet reached (NE)	Not yet reached (NE)	93 (89% to 98%)	16%
Control	36.9 (21.4 to NE)	Not yet reached (NE)	87 (81% to 92%)	10%
TE (95% CI); p	HR=0.54(0.37 to 0.78)a	HR=0.58(0.37 to 0.90); 0.01	NR	NR
Cohort 2 (stage IIIC)
N	184	184	184	See aboveb
Vemurafenib	23.1 (18.6 to 26.5)	37.2 (22.1 to NE)	84% (76% to 92%)
Control	15.4 (11.1 to 35.9)	30.7 (24.5 to NE)	85% (78% to 93%)
TE (95% CI); p	HR=0.80(0.54 to 1.18); 0.26a	HR=0.91(0.57 to 1.44); 0.68	NR

CI: confidence interval; HR: hazard ratio; NE: not estimable; NR: not reported; RCT: randomized controlled trial; SAE: serious adverse event; TE: treatment effect.

^a Hierarchical testing of cohort 2 before cohort 1 was prespecified for this outcome. Because the HR in cohort 2 was not statistically significantly different than 1, the test in cohort 1 cannot be regarded as significant.
^b Cohorts 1 and 2 combined for safety analyses.

RCTs of BRAF and MEK inhibitor therapy in stage III melanoma patients selected byRAF V600 variant testing have shown reductions in recurrence risk. One well-conducted RCT of combination BRAF and MEK inhibitor treatment with dabrafenib plus trametinib has shown superiority for recurrence risk and OS in BRAF variant-positive, stage III patients compared with placebo. Single-agent BRAF inhibitor treatment using vemurafenib compared with placebo showed numeric benefit for disease-free survival in patients with stage IIC, IIIA, or IIIB BRAF V600 variant-positive melanoma, but this result must be considered exploratory given the lack of statistically significant benefit in stage IIIC disease and the hierarchical statistical testing strategy. There are no RCTs directly comparing BRAF and MEK inhibitor therapy with immunotherapy as an adjuvant treatment for stage III patients with BRAF pathogenic variants.

Glioma

When treatment is developed for a specific biologic target that characterizes only some patients with a particular disease, and a test is codeveloped to identify diseased patients with that target, clinical validity and clinical utility cannot be evaluated separately. Rather, clinical studies of treatment benefit; that use the test to select patients provide evidence of both clinical validity and clinical utility We reviewed the phase 3 clinical trials of treatments in which testing for the BRAF variant was required for selection into the trial. In the absence of clinical trials in which both patients with and without BRAF variants are entered into RCTs of novel therapies, we cannot be certain that the test has clinical utility because it is unknown whether the treatment would be effective in patients without BRAF variant. However, patients without BRAF variants have not been enrolled in clinical trials of BRAF inhibitors.

Clinical Context and Test Purpose

The purpose of testing for BRAF pathogenic variants in individuals with glioma is to inform a decision whether to treat with BRAF or MEK inhibitors or with other standard treatments for glioma. Standard treatment for patients with glioma includes surgical resection followed by radiotherapy and/or chemotherapy with temozolomide.

The question addressed in this policy is: Does testing for BRAF pathogenic variants to select treatment improve the net health outcome in individuals with glioma?

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

Patients

The relevant population of interest is patients with glioma, particularly patients for whom adjuvant therapy following resection is indicated or for whom resection is not possible.

Interventions

The intervention of interest is genetic testing for BRAF V600 pathogenic variants to select treatments.

Comparators

The comparator of interest is the standard treatment for glioma without genetic testing for BRAF variants.

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.

High-grade gliomas (WHO grade III/IV) include anaplastic gliomas and glioblastoma. Maximal surgical resection is the initial treatment followed by combined adjuvant chemoradiotherapy. Temozolomide, an oral alkylating agent, is considered standard systemic chemotherapy for malignant gliomas. The prognosis for patients with high-grade gliomas is poor; the 1-year survival in U.S. patients with anaplastic astrocytoma is about 63% and with glioblastoma is about 38%.^29,

There is a high frequency of BRAF V600E variants in several types of gliomas. For example, BRAF V600E variants have been found in 5% to 10% of pediatric diffusely infiltrating gliomas, 10% to 15% of pilocytic astrocytoma, 20% of ganglioglioma, and more than 50% of pleomorphic xanthoastrocytoma.^{30,31,32,33,34,35,} However, it may be rare in adult glioblastoma.^36,

Outcomes

The primary outcomes of interest are OS and PFS. False-positive BRAF test results could lead to inappropriate treatment with BRAF and/or MEK inhibitors, may not be effective in patients without BRAF V600 pathogenic variants, and could also lead to delay in treatment with chemotherapy.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

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.

Review of Evidence
Sorafenib

Sorafenib is a multikinase inhibitor with potent in vitro activity against both BRAF wild-type and V600E variants as well as vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and c-KIT. Several phase 2, single-arm prospective studies have investigated the use of sorafenib in newly diagnosed and recurrent, adult and pediatric, and low- and high-grade gliomas in various combinations with other treatments. Results have not shown sorafenib to be effective. Most studies did not report BRAF V600 variant status. Table 5 describes select prospective studies of sorafenib in glioma.

Table 5. Prospective Studies of Sorafenib in Patients With Glioma

Study	Populations	N	Treatment(s)	Results (95% CI), mo
				Median PFS	Median OS
Karajannis et al (2014)37,	Children with recurrent or progressive low-grade astrocytomas	11 overall; 5 positive for constitutive BRAF activation (KIAA-BRAF fusion or BRAF-activating variant including BRAFV600E)	Sorafenib bid at 200 mg/m2 per dose in continuous 28-d cycles	2.8 (2.1 to 31.0)a
Hottinger et al (2014)38,	Adults with newly diagnosed high-grade glioma	17; BRAF status not reported	60-Gy RT plus TMZ 75 mg/m2 per day and sorafenib 200 mg qd, 200 mg bid, or 400 mg bid	7.9 (5.4 to 14.6)	17.8 (14.7 to 25.6)
Galanis et al (2013)39,	Adults with recurrent GBM	54; BRAF status not reported	Bevacizumab 5 mg/kg per 2 wk plus sorafenib 200 mg qd or bid	6-mo, 20.4%	5.6 (4.7 to 8.2)
Zustovich et al (2013)40,	Adults with recurrent GBM	53; BRAF status not reported	TMZ 40 mg/m2 per day plus sorafenib 400 mg bid	3.2 (1.8 to 4.8)	7.4 (5.6 to 9)
Den et al (2013)41,	High-grade glioma (primary or recurrent) with at least 2 wk of RT	18; BRAF status not reported	Sorafenib 200-400 mg bid plus: Primary disease, TMZ 75 mg/m2 per day and 60-Gy RT; Recurrent disease, 35 Gy in 10 fractions.		18 (6 to undefined)
Peereboom et al (2013)42,	Adults with recurrent or progressive GBM	56; BRAF status not reported	Erlotinib 150 mg qd plus sorafenib 400 mg bid	2.5 (1.8 to 3.7)	5.7 (4.5 to 7.9)
Lee et al (2012)43,	Adults with recurrent GBM or gliosarcoma	18; BRAF status not reported	Sorafenib 800 mg qd plus temsirolimus 25 mg/wk	8 wk (5-9 wks)a
Hainsworth et al (2010)44,	Adults with newly diagnosed GBM	47; BRAF status not reported	60-Gy RT and TMZ 75 mg/m2 per day followed by TMZ 150 mg/m2 per day plus sorafenib 400 mg bid	6 (3.7 to 7)	12 (7.2 to 16)

bid: twice daily; CI: confidence interval; GBM: glioblastoma multiforme; Gy: gray; OS: overall survival; PFS: progression-free survival; qd: every day: RT: radiotherapy; TMZ: temozolomide.

^a Study terminated early.

Vemurafenib, Dabrafenib, Trametinib and Binimetinib

Several case reports and small case series have suggested clinical benefit with vemurafenib, dabrafenib, trametinib and binimetinib in patients with glioma and BRAF V600 pathogenic variants. Ongoing early-phase studies evaluating BRAF and MEK inhibitors are listed in Table 8.

Hyman et al (2015) published results of a multicenter phase 2 "basket" study of vemurafenib in BRAF V600 variant-positive nonmelanoma cancers.^45, A total of 122 patients with BRAF V600 pathogenic variants were enrolled, including 8 patients with gliomas. The response was assessed by site investigators using Response Evaluation Criteria in Solid Tumors criteria. Of the 8 glioma patients, 2 died before the 1-month evaluation; 4 had a stable disease at 12, 6, 4, and 3 months and 2 had progressive disease at 2 and 7 months, all respectively.

Kaley et al (2018) published results of an open-label, nonrandomized, basket study for BRAF V600-mutant non-melanoma cancers, including 24 patients (median age, 32 years; 18 female and 6 male) with glioma.^46, Patients received vemurafenib 960 mg twice per day. Confirmed objective response rate was 25% (95% CI, 10 to 47) and median PFS was 5.5 months (95% CI, 3.7 to 9.6).

Selumetinib

Selumetinib is an oral kinase inhibitor of MEK1/2 that is FDA-approved for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type who have symptomatic, inoperable plexiform neurofibromas. Case series and phase I have been conducted in pediatric, low-grade glioma and have demonstrated tolerable toxicities. Phase 2 studies are briefly described in Table 6. Phase 3 RCTs are underway; one of the RCTs (NCT04166409) has hypotheses related to BRAF variants.

Table 6. Phase 2 Studies of Selumetinib in Pediatric Patients With Glioma

Study	Populations	N	Treatment(s)	Results (95% CI), mo
				Median PFS	Median OS
Fangusaro et al (2019)47,	Patients with a performance score > 60, presence of recurrent, refractory, or progressive pediatric low-grade glioma after at least one standard therapy	N=50 Stratum 1: 25 with WHO grade I pilocytic astrocytoma with KIAA1549–BRAF fusion or BRAF V600E variant Stratum 3: 25 with NF1-associated pediatric low-grade glioma (WHO grades I and II)	Selumetinib capsules given orally at 25 mg/m2 BID in 28-day courses for up to 26 courses	At 2 years: Stratum 1: 70% (95% CI 47–85) Stratum 3: 96% (95% CI 74–99)	NR

NF1: neurofibromatosis type I

Section Summary: Clinical Validity and Clinically Useful

Studies of sorafenib in patients with newly diagnosed and recurrent gliomas combined with various other treatments have not shown benefit, although most did not report BRAF V600 status. Evaluation of the BRAF and MEK inhibitors vemurafenib, dabrafenib, and trametinib in patients with gliomas have been limited to "basket" study (including less than 40 patients with glioma in total), case reports, and small case series. Several early-phase studies are ongoing and a phase 3 RCT of selumetinib compared to carboplatin/vincristine in previously-untreated low-grade glioma not associated with BRAF V600E variants or systemic NF1 is underway. Phase 3 clinical trials of targeted treatments are needed in which either (1) testing for the BRAF variant was required for selection into the trial or (2) patients with and without a BRAF variant are included, and testing for treatment interactions by variant status are prespecified.

Summary of Evidence

For individuals who have unresectable or metastatic melanoma who receive BRAF gene variant testing to select a treatment with BRAF or MEK inhibitor combination therapy, the evidence includes randomized trials. Relevant outcomes are overall survival (OS), disease-specific survival, and test accuracy. Randomized phase 3 trials of BRAF inhibitor therapy in patients selected on the basis of BRAF variant testing have shown improvements in OS and progression-free survival. Single-agent BRAF inhibitor treatment compared with nontargeted treatments have shown superior outcomes for most endpoints. Combination BRAF and MEK inhibitor treatment with vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown superior OS compared with vemurafenib or dabrafenib alone. Data showing treatment effects in patients without BRAF variants do not exist; therefore, BRAF variant testing is required to identify patients to whom these trial results apply. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have resected stage III melanoma who receive BRAF gene variant testing to select a treatment with BRAF or MEK inhibitors, the evidence includes randomized trials. Relevant outcomes are OS, disease-specific survival, and test accuracy. One randomized phase 3 trial of BRAF and MEK combination therapy with dabrafenib plus trametinib in patients selected by BRAF variant testing has shown improvements in recurrence-free survival and OS compared with placebo. One randomized phase 3 trial of vemurafenib monotherapy did not find statistically significant differences in disease-free survival in patients with stage IIIC disease. In patients with stage IIC, IIIA, or IIIB disease, median disease-free survival was prolonged with vemurafenib, but this result was considered exploratory. Data showing treatment effects in patients without BRAF variants do not exist; therefore, BRAF variant testing is required to identify patients to whom these trial results apply. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have glioma who receive BRAF gene variant testing to select a treatment with BRAF or MEK inhibitors, the evidence includes small, prospective, uncontrolled studies and case reports. Relevant outcomes are OS, disease-specific survival, and test accuracy. Studies assessing the use of sorafenib in patients with newly diagnosed and recurrent gliomas combined with various other treatments have not shown benefit, although most did not report BRAF V600 variant status. Evaluation of the BRAF and MEK inhibitors vemurafenib, dabrafenib, and trametinib in patients with gliomas has been limited "basket" studies, Selumetinib is being investigated in pediatric, low-grade glioma. Confirmatory randomized controlled trials are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements

The National Comprehensive Cancer Network Guidelines for melanoma (v.2.2020) recommends BRAF mutation testing for patients who are sentinel node positive and stage IIIB/C/D and the consideration of BRAF mutation testing for stage IIIA. The guidelines recommend BRAF mutation testing for clinically node positive or clinical satellite/in-transmit stage III. For stage IV patients, the guidelines recommend BRAF mutation testing if the patient is being considered for targeted therapy.^48,

Network guidelines for central nervous system cancers (v.1.2020) indicate the following on the use of BRAF molecular markers to guide treatment decisions for primary brain cancers: "BRAF V600E tumors may respond to BRAF inhibitors such as vemurafenib, but comprehensive clinical trials are still ongoing."^49,The guidelines state that BRAF and MEK inhibitors can be considered for pilocytic astrocytoma, PXA or ganglioglioma with a BRAF V600E activating mutation.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 7.

Table 7. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
Melanoma
Glioma
NCT01089101	A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma	180	Dec 2020
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	54	Dec 2021
NCT01677741a	Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors	86	May 2020
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	120	Feb 2023
NCT02034110a	A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib	206	Jul 2020
NCT02465060	Molecular Analysis for Therapy Choice (MATCH)	6452	Jun 2022
NCT03220035	NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Vemurafenib in Patients With Tumors Harboring Braf V600 Mutations	49	Dec 2023
NCT02684058a	Phase II Open-label Global Study to Evaluate the Effect of Dabrafenib in Combination With Trametinib in Children and Adolescent Patients With BRAF V600 Mutation PositiveLow Grade Glioma (LGG) or Relapsed or Refractory High Grade Glioma (HGG)	142	Jan 2025
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)	200	Dec 2026
NCT03155620	NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) Screening Protocol	1500	Sep 2027

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

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
BRAF Gene Mutation Testing To Select Melanoma or Glioma Patients for Targeted Therapy
BRAF Gene Mutation Testing To Select Melanoma Patients for BRAF/MEK Inhibitor Targeted Therapy
Cobas® 4800 BRAF V600 Mutation Test
Cobas 4800 BRAF V600 Mutation Test
V600
V600E
V600K
BRAF Inhibitor Therapy, BRAF Gene Mutation Testing to Select Melanoma Patients for
MEK Inhibitor Therapy. BRAF Gene Mutation Testing to Select Melanoma Patients for
THxID BRAF Test

References:
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2. 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):596-599. PMID 20823850

3. Sondergaard 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

4. Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. Aug 17 2010;107(33):14903-14908. PMID 20668238

5. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. Jul 1 2010;70(13):5518-5527. PMID 20551065

6. Louis DN, Ohgaki H, Wiestler HOD, et al. WHO Classification of Tumours of the Central Nervous System. Revised. 4th ed. Lyon: WHO Press; 2016.

7. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. Feb 2014;50(3):611-621. PMID 24295639

8. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. Nov 2012;13(11):1087-1095. PMID 23051966

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