Coverage Policy Manual
Policy #: 2011061
Category: Laboratory
Initiated: September 2011
Last Review: July 2022
  Genetic Test: Melanoma and Glioma, Testing to Predict Response to Targeted Therapy

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. BRAF and MEK inhibitors, alone or in combination with checkpoint 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 RAF-MEK-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. Checkpoint inhibitors are monoclonal antibodies that were initially developed to target tumors expressing high levels of PD-L1. Tumors with a high tumor mutational burden (TMB) may also predict benefit from checkpoint inhibitor immunotherapy.
 
Overall incidence rates for melanoma have been increasing for at least 30 years. In advanced (Stage 4) melanoma, the disease has spread beyond the original area of skin and nearby lymph nodes. Although only a small proportion of cases are Stage 4 at diagnosis, prognosis is extremely poor; 5-year survival is about 15-20%.
 
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, 50-70% of melanoma tumors harbor a BRAF mutation and of these, 80% are positive for BRAFV600E, and 16% are positive for BRAF V600K (Vultur, 2011). Thus, 405-60% of advanced melanoma patients might 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 (trade name Zelboraf®, 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 BRAFV600E mutated kinase and with significantly lower potency to inhibit most of many other kinases tested (Bollag, 2010). Preclinical studies demonstrated that vemurafenib selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells (Sondergaard, 2010; Joseph, 2010; Yang, 2010) and caused regression of BRAF mutant human melanoma xenografts in murine models (Bollag, 2010). 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, (Sondergaard, 2010; Joseph, 2010; Yang, 2010) 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, as the supportive clinical trials were enrichment trials, enrolling only patients with tumors positive for the BRAFV600E mutation.
 
Gliomas encompass a heterogeneous group of tumors and the 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 (Louis, 2016). 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 indicating that these agents might be potential therapies for primary brain tumors (Dummer, 2014; Long, 2012).
 
Tumor mutational burden (TMB), a measure of gene mutations within cancer cells, is an emerging biomarker of outcomes with immunotherapy in multiple solid tumor types. Initially, assessments of TMB involved whole exome sequencing (WES). More recently, targeted next-generation sequencing (NGS) panels are being adapted to estimate TMB. Currently, FoundationOne CDx is the only U.S. Food and Drug Administration (FDA)-approved panel for estimating TMB, but others are in development (Merino, 2020).
 
Regulatory Status
 
Targeted treatments approved by the U.S. Food and Drug Administration (FDA) for patients with melanoma along with the concurrently approved diagnostic tests:
 
Pembrolizumab (Keytruda®; Merck)
 
Indication:
2020: treatment of adult and pediatric patients with unresectable or metastatic tumor mutation burden-high (TMB-H) [10 mutations/megabase] solid tumors, that have progressed following prior treatment and who have no satisfactory treatment options
 
FDA Approval of Companion Diagnostic Test:
2020: FoundationOne CDx™ (Foundation Medicine)
 
Atezolizumab (Tecentriq®; Genentech)
 
Indication:
2020: treatment of patients with unresectable or metastatic melanoma with BRAF V600 variants in combination with cobimetinib and vemurafenib3
 
FDA Approval of Companion Diagnostic Test:
For cobimetinib in combination with vemurafenib:
2016: cobas® 4800 BRAF V600 Mutation Test (Roche)
2017: FoundationOne CDx™ (Foundation Medicine)
 
Entrectinib (Rozyltrek®; Genentech)
 
Indication:
2019: treatment of adults and pediatric patients 12 years of age and older with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are metastatic or where surgical treatment is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy
 
FDA Approval of Companion Diagnostic Test:
No FDA-approved companion diagnostic
 
Larotrectinib (Vitrakvi®; Loxo Oncology/Bayer)
 
Indication:
2018: treatment of adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment
 
FDA Approval of Companion Diagnostic Test:
2020: FoundationOne CDx™ (Foundation Medicine)
 
Vemurafenib (Zelboraf®; Roche/Genentech and Plexxikon)
 
Indication:
2011: treatment of patients with unresectable or metastatic melanoma with BRAF V600 variants
 
FDA Approval of Companion Diagnostic Test:
2011: cobas® 4800 BRAF V600 Mutation Test (Roche)
2017: FoundationOne CDx™ (Foundation Medicine)
 
Dabrafenib (Tafinlar®; GlaxoSmithKline)
 
Indication:
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
 
FDA Approval of Companion Diagnostic Test:
2013: THxID™ BRAF kit (bioMérieux)
2017: FoundationOne CDx™ (Foundation Medicine)
 
Trametinib (Mekinist™; GlaxoSmithKline)
 
Indication:
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
 
FDA Approval of Companion Diagnostic Test:
2013: THxID™ BRAF kit (bioMérieux)
2017: FoundationOne CDx™ (Foundation Medicine)
 
Cobimetinib (Cotellic®; Genentech)
 
Indication:
2015: Used in combination with vemurafenib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K variants
 
FDA Approval of Companion Diagnostic Test:
2017: FoundationOne CDx™ (Foundation Medicine)
 
Binimetinib (Mektovi®; Array BioPharma)
 
Indication:
2018: Used in combination with encorafenib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
 
FDA Approval of Companion Diagnostic Test:
2013: THxID™ BRAF kit (bioMérieux)
 
Encorafenib (Bravtovi®; Array BioPharma)
 
Indication:
2018: Used in combination with binimetinib to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
 
FDA Approval of Companion Diagnostic Test:
2013: THxID™ BRAF kit (bioMérieux)
 
FDA product code: OWD.
 
Coding
 
Effective January 2012, there is a specific CPT code for this testing:
81210 BRAF (v-raf murine sarcoma viral oncogen homolog B1) (e.g., colon cancer), gene analysis, V600E variant.

Policy/
Coverage:
Effective July 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 variants in tumor tissue of individuals with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib), MEK inhibitors, or immunotherapy.
 
Testing for BRAF V600 variants in tumor tissue of individuals with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors.
 
Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to BRAF and MEK-inhibitor combination therapy (e.g., dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with BRAF V600E–mutated melanoma.
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in individuals with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600 variants for all other indications, including but not limited to, use in individuals with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage
 
Testing for tumor mutational burden (TMB) in individuals with unresectable or metastatic melanoma or glioma to select individuals for treatment with FDA-approved immunotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, testing for tumor mutational burden (TMB) in individuals with unresectable or metastatic melanoma or glioma to select individuals for treatment with FDA-approved immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Effective Prior to July 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib), MEK inhibitors, or immunotherapy.
 
Testing for BRAF V600 variants in tumor tissue of patients with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors.
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage
 
Testing for tumor mutational burden (TMB) in patients with unresectable or metastatic melanoma or glioma to select patients for treatment with FDA-approved immunotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, testing for tumor mutational burden (TMB) in patients with unresectable or metastatic melanoma or glioma to select patients for treatment with FDA-approved immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to November 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
 
Testing for BRAF V600 variants in tumor tissue of patients with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
 
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to July 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 2014 - September 2017
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 mutations in tumor tissue of patients with unresectable or metastatic  melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 2013- September 2014
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 mutations in tumor tissue of patients with stage IIIC or IV melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors is considered investigational.  Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to October 2013
Testing for the BRAF V600E mutation in tumor tissue of patients with stage IIIC or IV melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with vemurafenib.
 
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
 
Testing for the BRAF V600E mutation for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for the BRAF V600E mutation for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors is considered investigational.  Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
Analytic Validity
The analytic validity of a genetic test is its ability to accurately and reliably measure the genotype (or analyte) of interest in the clinical laboratory, and in specimens representative of the population of interest (Teutsch, 2009). Submission to the Office of In Vitro Diagnostics of the FDA for marketing clearance or approval of a diagnostic test requires an extensive demonstration of the analytic validity of the test. Data for cleared or approved tests are summarized in the kit insert (prepared by the manufacturer) and in the Summary of Safety and Effectiveness of the test (prepared by the FDA and publicly available).
 
The cobas® 4800 BRAF V600 Mutation Test is a real-time polymerase chain reaction (PCR) test intended for the qualitative detection of the BRAFV 600E mutation specifically in DNA that has been extracted from formalin-fixed, paraffin-embedded (FFPE) human melanoma tissue.
 
Correlation of cobas 4800 BRAF V600 Mutation Test results to Sanger sequencing was tested in the Phase III trial of vemurafenib (Chapman, 2011) on 596 consecutive patients, of which 449 were evaluable. The percent agreement of the BRAF V600 mutation test with Sanger sequencing is shown in the first line of Table 1 when only V600E results were counted as positive. The cobas 4800 BRAF V600 Mutation Test detected 27 V600 mutations (primarily V600K) that were not V600E by Sanger Sequencing. Limited evidence suggests that patients with V600K mutated tumors may also respond to vemurafenib.
 
Tumor specimens from the patients enrolled in the phase II trial (Ribas, 2011) were also sequenced by Sanger sequencing; specimens that were invalid by Sanger, or that were identified as V600K mutation or as V600 wild type by Sanger were re-sequenced by the more sensitive 454 pyrosequencing method to resolve differences. Correlation to 454 pyrosequencing was 100% if V600K-positive samples were counted as true positives.
 
Regulatory documents contain additional data detailing the evaluation of analytic sensitivity and specificity, cross reactivity, interference, reproducibility, repeatability, and additional studies of test robustness. In general, correlation with sequencing and extensive analytic validation data support that the test is a sensitive, specific, and robust assay for the detection of the V600E mutation in FFPE melanoma specimens. Patients with V600K mutations will also be identified as positive, although it is not clear that all patients with V600K mutations will be positive. There is very limited evidence that patients with V600K mutations may respond to vemurafenib. Infrequently, patients with V600E2 and V600D mutations may also be detected. Additionally, the method is available as a kit and is partially automated, which should result in wide access and rapid turnaround time relative to the reference standard of sequencing.
 
Clinical Validity and Utility
The clinical validity of a genetic test is its ability to accurately and reliably predict the clinically defined disorder or phenotype of interest; the clinical utility of a genetic test is the evidence of improved measurable clinical outcomes, and its usefulness and added value to patient management decision-making compared with current management without genetic testing (Teutsch. 2009).
 
When a treatment is developed for a specific biological 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 studies are no longer separate and sequential. Rather, the clinical studies of treatment benefit, which use the test to select patients, provide evidence of both clinical validity and clinical utility. The primary evidence of clinical validity and utility for the cobas® 4800 BRAF V600 Mutation Test is provided by the Phase III clinical trial of vemurafenib. In addition, evidence from Phase I and Phase II trials is supportive. All trials were enrichment trial designs, in which all patients were positive for a V600 mutation (with a few exceptions in the Phase I trial). The justification for this was both efficiency and possibly potential for harm to patients with BRAF wild type tumors.
 
Phase III Clinical Trial. This comparative trial, also known as BRIM-3, randomly assigned 675 patients to either vemurafenib (960 mg twice daily orally) or dacarbazine (1,000 mg/m2 body surface area by IV infusion every 3 weeks) to determine whether vemurafenib would prolong the rate of overall or progression-free survival, compared to dacarbazine (Chapman, 2011). All enrolled patients had unresectable, previously untreated stage IIIC or IV melanoma with no active CNS metastases. Melanoma specimens from all patients tested positive for the BRAFV600E mutation on the cobas 4800 BRAF V600 Mutation Test. Included were 19 patients with BRAFV600K mutations and one with a BRAFV600D mutation.
 
Tumor assessments including CT were performed at baseline, at weeks 6 and 12, and every 9 weeks thereafter. Tumor responses were determined by the investigators according to the RECIST, version 1.1. Primary endpoints were the rate of overall survival and progression-free survival. An interim analysis was planned at 98 deaths and a final analysis at 196 deaths; the published report is the interim analysis, reporting 118 deaths. The median survival had not been reached. 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% of patients. The data and safety monitoring board determined that both co-primary endpoints had met prespecified criteria for statistical significance and recommended that patients in the dacarbazine group be allowed to cross over and receive vemurafenib. The results of this trial comprised the data supporting the efficacy and safety of vemurafenib for submission to the FDA, and established the safety and effectiveness of the cobas 4800 BRAF V600 Mutation Test, resulting in co-approval of drug and companion test.
 
Phase II Clinical Trial. A Phase II trial, also known as BRIM-2, is currently ongoing at 13 centers. All patients were selected with the cobas 4800 BRAF V600 Mutation Test; 122 cases had BRAFV600E–positive melanoma and 10 cases were positive for BRAFV600K. The early results of this trial have been published only as a meeting abstract and a meeting slide presentation (Robas. 2011). The target overall response rate (primary outcome) was 30%, with a lower boundary of the 95% confidence interval (CI) of at least 20%. At a median follow-up of 10 months, this target was met with an overall response rate of 53% by IRC (95% CI: 44-62%). At 10 months, 27% of patients were still on treatment; the majority of discontinuations were due to disease progression. The most common adverse events of any grade were arthralgias (58%), skin rash (52%), and photosensitivity (52%). The most common grade 3 adverse event was squamous cell carcinoma; these were seen in about 25% of patients, tended to occur in the first 2 months of treatment, and were managed with local excision. There were very few grade 4 adverse events.
 
Phase I Clinical Trial. The major goals of this trial were to first determine the maximum dose in a dose-escalation phase, then determine the objective response rate and monitor toxicity (Flaherty, 2010). This trial used a PCR assay that was likely a prototype of the final test; only a brief description of the assay was provided in the publication. In the dose-escalation phase, 5 patients with metastatic melanoma tumors who did not have the BRAFV600E mutation received 240 mg or more vemurafenib twice daily (final recommended dose is 960 mg twice daily); of these, none responded. In the extension phase of the trial, 26 of 32 patients with the BRAFV600E mutation responded (81%; 24 partial, 2 complete responses).
 
Ongoing Clinical Trials
Despite impressive response rates in the Phase I trial, the duration of response to vemurafenib was limited to between 2 and 18 months suggesting the development of resistance; in some patients with BRAFV600E-positive tumors there was no response at all, which was interpreted as primary resistance. Investigations of the mechanisms of resistance have reported evidence of different molecular mechanisms potentially responsible for resistance in different patients (16, 17). It is likely that combined inhibition of BRAF and other key molecular targets, and the use of different combinations in different patients, will be needed in the future. For example, a clinical trial is already underway combining treatment with vemurafenib and a MEK inhibitor in patients who have already been treated with vemurafenib (NCT01271803).
 
As noted, the BRAF inhibitor dabrafenib is currently in phase II and III clinical trials (NCT01227889; NCT01266967), and is expected to be submitted to the FDA, along with a companion diagnostic test, relatively quickly.
 
Summary
A large proportion of patients with advanced melanoma have a mutation in the BRAF gene. The Phase III clinical trial of vemurafenib in melanoma patients positive for the BRAFV600E mutation reported a benefit in overall survival and progression-free survival for vemurafenib treatment. These results, which are corroborated by earlier trials, support the clinical validity and clinical utility of the cobas 4800 BRAF V600 Mutation Test, the companion diagnostic test for vemurafenib. Using the test to select patients for treatment results in improved outcomes compared to the usual standard of care, dacarbazine. Thus, this test, and any other tests approved by the FDA to detect the BRAFV600E mutation to select advanced melanoma patients for vemurafenib treatment, may be considered medically necessary.
 
2012 Update
A literature search conducted through September 2012 did not reveal any new information that would prompt a change in the coverage statement.
 
2013 Update
Two new BRAF inhibitors received FDA approval since the last policy update. This update contains information relating to these new treatments.
 
Dabrafenib
The THxID™ BRAF kit is a real-time PCR test intended for the qualitative detection of BRAF V600E and V600K mutations in DNA samples extracted from formalin-fixed paraffin-embedded (FFPE) human melanoma tissue (FDA, 2013). Two oligonucleotide probes labeled with different fluorescent dyes (one for internal controls and the other for mutation sequence alleles) are measured at characteristic wavelengths and compared by an autoanalyzer. Results are reported as either “mutation(s) detected” or “mutation(s) not detected” (or “invalid,” which requires troubleshooting and a repeat of the test). The threshold of detection, defined as the smallest proportion of mutated alleles for which the assay yields a positive result in 95% of tests, is 5% for V600E and V600K mutations.
 
Correlation of the THxID BRAF assay with Sanger sequencing was tested in 898 consecutive clinical trial samples. Forty-three samples (5%) were invalid or quantity not sufficient. Excluding these samples, there were 35 discordant cases (4%). The THxID BRAF kit detected as V600E mutation-positive 2 samples determined by Sanger sequencing to be V600D mutation-positive.
 
One Phase III randomized, controlled, open-label trial of dabrafenib for advanced (stage IV or unresectable stage III) melanoma has been published (Hauschild, 2012); the results of this trial are summarized in Table 3. The main objective of this RCT was to study the efficacy of dabrafenib vs. standard dacarbazine treatment in patients selected to have BRAF V600E mutated metastatic melanoma. Two-hundred-fifty patients were randomized 3:1 to receive oral dabrafenib 150 mg twice daily versus intravenous dacarbazine 1,000 mg/m2 every 3 weeks. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival, objective response rate, and adverse events.
 
Median progression-free survival for the dabrafenib and dacarbazine groups was 5.1 months and 2.7 months, respectively. Overall survival did not differ significantly between groups; 11% of patients in the dabrafenib group died compared to 14% in the dacarbazine group (hazard ratio: 0.61, 95% CI: 0.25–1.48). However, 28 patients (44%) in the dacarbazine arm crossed over at disease progression to receive dabrafenib. The objective response rate, defined as complete plus partial responses, was greater in the dabrafenib group (50%, 95% CI: 42.4–57.1%) compared to the dacarbazine group (6%, 95% CI: 1.8–15.5%). Treatment-related adverse events grade 2 or higher occurred in 53% of patients who received dabrafenib and in 44% of patients who received dacarbazine. Grade 3-4 adverse events were uncommon in both groups. The most common serious adverse events were cutaneous squamous cell carcinoma (7% vs. none in controls); serious non-infectious, febrile drug reactions (3% grade 3 pyrexia vs. none in controls); and severe hyperglycemia (>250-500 mg/dL), requiring medical management in non-diabetic patients or change in management of diabetic patients (6% vs. none in controls). Results demonstrated that targeting dabrafenib against BRAF V600E mutated melanoma results in a benefit in progression-free survival. Patients were allowed to cross over at the time of progression, and the effect of dabrafenib on overall survival was favorable but not statistically significant.
 
All tissue specimens from patients screened for enrollment in the clinical trial were analyzed centrally by a clinical trial assay. Outcomes were linked retrospectively to BRAF testing by the THxID BRAF kit. Of 250 patients enrolled in the trial, specimens from 237 patients (177 [95%] in the dabrafenib arm and 55 [87%] in the dacarbazine arm) were retested with the THxID BRAF kit. Reanalysis of the primary end point, PFS, in patients who were V600E positive by the THxID BRAF kit showed a treatment effect that was nearly identical to the overall result by central assay.  Additional analysis for discordant results assumed a worst case scenario, i.e., a hazard ratio of 1 for patients V600E-mutation-positive by the THxID BRAF test but mutation negative by central assay. The hazard ratio was 0.34 (95% CI: 0.23–0.50) (FDA, 2013).
 
Trametinib.
The clinical efficacy and safety of trametinib was assessed in the Phase III, open-label METRIC trial (Flaherty, 2012). Patients with stage IV or unresectable stage IIIC cutaneous melanoma were randomized 2:1 to receive trametinib 2 mg orally once daily (n=214) or chemotherapy (n=108), either dacarbazine 1,000 mg/m2 IV every 3 weeks or paclitaxel 175 mg/m2 IV every 3 weeks at investigator discretion. Most patients (67%) were previously untreated. The primary efficacy endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Tumor assessments were performed at baseline and at weeks 6, 12, 21, and 30 and then every 12 weeks.
 
Median PFS was 4.8 months (95% CI: 4.3–4.9) in the trametinib arm and 1.5 months (95% CI: 1.4-2.7) in the chemotherapy arm, a statistically significant difference. (Table 3) Although median overall survival 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 of 108 patients (47%) in the chemotherapy group crossed over at disease progression to receive trametinib. In the trametinib and chemotherapy groups, adverse events led to dose interruption in 35% and 22% of patients, respectively, and to dose reduction in 27% and 10% of patients, respectively. Decreased ejection fraction or ventricular dysfunction was observed in 14 patients (7%) 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 patients (8%). Cutaneous squamous cell carcinoma was not observed during treatment.
 
Tumor tissue was evaluated for BRAF mutations at a central site using a clinical trial assay. Retrospective THxID BRAF analysis was conducted on tumor samples from 289 patients (196 [92%] in the trametinib arm and 93 [86%] in the chemotherapy arm). Reanalysis of PFS in patients who were V600E or V600K-positive by the THxID BRAF kit showed a treatment effect that was almost identical to the overall result by central assay. Additional analysis for discordant results assuming a worst case scenario as above yielded a hazard ratio of 0.48 (95% CI: 0.35–0.63) (FDA, 2013).
 
Resistance to BRAF inhibitors
Median duration of response in the Phase I (extension), II, and III studies of vemurafenib was approximately 6 months, 6.7 months, and 5.5 months, respectively, suggesting the development of resistance; (Chapman, 2011; Sosman, 2012; Flaherty, 2010) in some patients with BRAFV600E-positive tumors, there was no response at all, which was interpreted as primary resistance. Investigations of the mechanisms of resistance have reported evidence of different molecular mechanisms potentially responsible for resistance in different patients (Johannessen, 2010; Nazarian, 2010).  It is likely that combined inhibition of BRAF and other key molecular targets, and the use of different combinations in different patients, will be needed in the future. For example, MEK proteins are also components of the MAP kinase signal-transduction pathway; like BRAF inhibitors, MEK inhibitors, such as trametinib, have been designed to interfere with this pathway and may be used in combination. An open-label Phase I/II trial examined the pharmacokinetics, safety, and efficacy of dabrafenib plus trametinib combination therapy in 247 patients with metastatic (stage IV) melanoma and BRAF V600E or V600K mutations (Flaherty, 2012). Maximum tolerated combination dosing was not reached. One dose-limiting toxic effect, recurrent neutrophilic panniculitis, occurred in 24 patients who received the highest dose level (dabrafenib 150 mg twice daily plus trametinib 2 mg daily), and this was the recommended dose for efficacy testing. Median PFS, the primary efficacy endpoint, was 9.4 months in the combination therapy group (n=54) and 5.8 months in the dabrafenib (150 mg twice daily) monotherapy group (n=54; hazard ratio 0.39, 95% CI: 0.25–0.62; p<0.001). Complete or partial response occurred in 76% of patients in the combination therapy group and 54% of the monotherapy group (p=0.03). Median duration of response was 10.5 (95% CI: 7.4–14.9) months and 5.6 months (95% CI: 4.5–7.4), respectively. Cutaneous squamous cell carcinoma occurred in 7% of the combination therapy group and 19% of the monotherapy group (p=0.09). Fever was more common in the combination therapy group (71% vs. 26% monotherapy; p=<0.001). Other trials of vemurafenib, dabrafenib, and trametinib in combination with each other and with other treatments (e.g., high-dose interleukin-2) are currently in progress, as listed below.
 
Ongoing Clinical Trials
A search of the ClinicalTrials.gov website identified a number of ongoing Phase III trials of BRAF inhibitor therapy in melanoma. Most trials study combination therapy. All trials are in patients with unresectable stage III or stage IV melanoma, except for NCT01667419 under “Single agents” and NCT01682083 under “Combination treatments,” which are in patients with completely resected melanoma.
 
Currently active Phase III trials of BRAF inhibitor therapy for melanoma:
    • NCT01898585- An Open-Label Study of Zelboraf (Vemurafenib) in Patients with BRAF V600-Mutation Positive Metastatic Melanoma. This is a single-arm study with an estimated completion date of June 2015.
    • NCT01667419- BRIM8: A Study of Vemurafenib Adjuvant Therapy in Patient s With Resected Cutaneous BRAF Mutant Melanoma. This double-blind RCT has an estimated completion date of June 2016.
    • NCT01683188- High-Dose Interleukin-2 + Vemurafenib in Patients with BRAF Mutation Positive Metastatic Melanoma (PROCLIVITY 01). Estimated completion date of April 2016.
    • NCT01584648- A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma.  This is a double-blind, RCT with a completion date of September 2013.
    • NCT01597908- Dabrafenib Plus Trametinib vs. Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-V).  Open-label, RCT with estimated completion date of March 2014.
    • NCT01682083- The BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Mutation-positive Melanoma After Surgical Resection (COMBI-AD). Double-blind, RCT with a completion date of July 2015.
    • NCT01689519- coBRIM: A Phase 3 Study Comparing GDC-0973 (Cobimetinib), a MEK Inhibitor, in Combination With Vemurafenib vs. Vemurafenib Alone in Patients With Metastatic Melanoma. Double-blind RCT with scheduled completion date of August 2016.
    • NCT01909453- Study Comparing Combination of the RAF Kinase Inhibitor LGX818 Plus the MEK Inhibitor MEK 162 and LGX818 Monotherapy Versus Vemurafenib in Unresectable or Metastatic BRAF V600 Mutant Melanoma (COLUMBUS). Open-label RCT with an estimated scheduled completion date of June 2017.
 
Summary
A large proportion of patients with advanced melanoma have a mutation in the BRAF gene. There are 2 Phase III randomized controlled trials (RCTs) of BRAF inhibitors (vemurafenib and dabrafenib) in advanced melanoma patients who are positive for the BRAFV600E mutation and 1 Phase III trial of a MEK inhibitor (trametinib) in advanced melanoma patients who are positive for BRAF V600E or V600K mutations. All of the trials reported a benefit in progression-free survival for treatment with a BRAF inhibitor. In addition, the vemurafenib and trametinib trials reported a significant improvement in overall mortality; the dabrafenib trial did not demonstrate a difference in overall survival. These results support the clinical validity and clinical utility of the cobas 4800 BRAF V600 Mutation Test to select patients for treatment with vemurafenib, and the THxID BRAF kit to select patients for treatment with dabrafenib and trametinib.
 
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Combination BRAF (Dabrafenib) and MEK (Trametinib) Inhibition
Efficacy of combination treatment with dabrafenib and trametinib has been established with 2 phase 3 clinical trials (Long, 2015; Robert, 2015; Long, 2014; NCCN, 2016).
 
Clinical efficacy of combination treatment with dabrafenib and trametinib was evaluated in the phase 3 open-label by Long and colleagues (Long, 2015; Long 2014). In this study, 4234 patients with unresectable stage IIC or stage IV melanoma with a BRAF V600E or V600K mutation were randomized to either a combination of dabrafenib and trametinib or dabrafenib and placebo. The primary end point was progression-free survival, reported in a first publication followed by a second publication in which longer term overall survival was reported (Long, 2015).
 
Median PFS was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group. The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenibonly group. An interim overall survival analysis showed a difference in survival which was statistically significant with standard statistical criteria, but did not cross the prespecified stopping boundary. The rate of cutaneous squamous cell carcinoma was lower in the dabrafenib-trametinib group (2% vs 9%), whereas pyrexia occurred in more patients (51% vs 28%). In the longer term study assessing overall survival, median survival was 25.1 months in the dabrafenib-trametinib group versus 18.7 months in the dabrafenib-only group.
  
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
This update focuses on the use of testing for BRAF pathogenic variants in individuals with glioma.
 
Analytic Validity
Currently there is no standard method for testing BRAF status in neuropathology. DNA-based tests for melanomas and IHC are used. The analytic validity of these methods is described in the previous section on melanoma.
 
Clinical Validity and Clinical Utility
Sorafenib is a multikinase inhibitor with potent in vitro activity against both BRAF wild-type and V600E variant as well as vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), and c-KIT. Several phase 2 single-arm prospective studies have investigated the use of sorafenib in newly diagnosed and recurrent, adult and pediatric, 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.
 
Hyman et al (2015) published results of a multicenter phase 2 “basket” study of vemurafenib in BRAF V600 variant–positive nonmelanoma cancers (Hyman, 2015). A total of 122 patients with BRAF V600 pathogenic variants were enrolled, including 8 patients with gliomas. Response was assessed by site investigators using RECIST criteria. Of the 8 glioma patients, 2 died before the 1-month evaluation; 4 had stable disease at 12, 6, 4, and 3 months and 2 had progressive disease at 2 and 7 months, all respectively.
 
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 has been limited to 1 phase 2 “basket” study (including 8 patients with glioma), case reports, and small case series. Several early phase studies are ongoing.   
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. The key identified literature is summarized below.
 
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 BRIM-3 trial as reported by Chapman et al (2011) randomized a total of 675 patients 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 (Chapman, 2011). 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 (RECIST), version 1.1. Primary end points 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 end points 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 coapproval of both the drug and companion test.
 
In 2017, final OS results from BRIM-3 were reported by Chapman et al (Chapman, 2017). 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).
 
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 (Long, 2015; Robert, 2015; Long, 2014). This combination agent was evaluated in the phase 3 open-label trial by Long et al (Long, 2014; Long 2015). 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 end point was PFS, as reported in a first publication, followed by a second publication in which longer term OS was reported (Long, 2014; Long, 2015).
 
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.
 
Encorafenib Plus Binimetinib
 
Dummer et al reported on results of a phase 3 COLUMBUS 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 (Dummer, 2018). 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.
 
Clinically Valid and Clinical Usefulness
 
Two RCTs of BRAF and/or MEK inhibitors in patients with resected stage III BRAF-variant melanoma, have been reported by Long et al in 2017 and Maio et al in 2018.
 
Long et al 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 (Long, 2017). 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 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 (Maio, 2018). 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.
 
In summary, RCTs of BRAF and MEK inhibitor therapy in stage III melanoma patients selected by BRAF 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.
 
2019 Update
A literature search was conducted through June 2019.  There was no new information identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.    
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Ascierto et al published long-term outcomes from the COLUMBUS trial (Ascierto, 2020). The median follow-up for OS was 48.8 months. Compared with vemurafenib, the combination of encorafenib plus binimetinib significantly reduced the risk of death by 39% (HR, 0.61; 95% CI, 0.48 to 0.79) and increased the duration of PFS (HR, 0.51; 95% CI, 0.39 to 0.67). The OS rates at 3 years were 47%, 41%, and 31% for encorafenib plus binimetinib, encorafenib, and vemurafenib groups, respectively. All subgroup analyses favored combination treatment with encorafenib plus binimetinib versus treatment with vemurafenib alone.
 
Gutzmer et al reported primary results from IMspire150, a phase 3, double-blind RCT of atezolizumab, vemurafenib, and cobimetinib (n=256) compared to placebo, vemurafenib, and cobimetinib (n=258) as first-line treatment for unresectable advanced BRAF V600-positive melanoma (Gutzmer, 2020). The primary endpoint was investigator-assessed PFS. The median follow-up in the overall study population was 18.9 months. At data cut-off, 327 patients had progressive disease by investigator assessment or had died, including 148 (58%) of patients in the atezolizumab group and 179 (69%) in the control group. The atezolizumab with vemurafenib and cobimetinib group experienced a median PFS per investigator assessment of 15.1 months (95% CI, 0.63 to 0.97) compared to 10.6 months (95% CI, 9.3 to 12.7) in the control group. A 77% concordance rate for progressive disease assessment by study investigators versus independent review committee was reported. The primary reason for discordant results (n=109) was the assessment of progressive disease per study investigators but not the independent review committee. The prevalence of treatment-related adverse events was comparable between the 2 groups. PD-L1 expression status was not significantly associated with the treatment effect.
 
Marabelle et al reported the association of TMB-high (TMB-H) status to response to pembrolizumab in patients with various previously treated unresectable or metastatic solid tumors enrolled in a prespecified exploratory analysis of the nonrandomized, phase 2 KEYNOTE-158 study (NCT02628067) (Marabelle, 2020). TMB-H was defined as 10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the TMB-H group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the TMB-H group and was 33.1 months in the non-TMB-H group. TMB-H status was associated with improved response irrespective of PD-L1 status. Median PFS and OS did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI, 24 to 48) of 68 participants who had both TMB-H status and PD-L1-positive tumours (ie, PD-L1 combined positive score of 1) and in 6 (21%; 8 to 40) of 29 participants who had TMB-H status and PD-L1-negative tumors.
 
Notably, patients with melanoma or glioma were not included in these analyses. Study eligible cancers were limited to anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar. The prescribing information for pembrolizumab includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Several early phase "basket" studies, case reports, and small case series have suggested clinical benefit with vemurafenib, dabrafenib, and trametinib in patients with glioma and BRAF V600 pathogenic variants (Hyman, 2015; Kaley, 2018; Brown, 2017; Marks, 2018; Wen, 2022). Ongoing phase 3 studies of targeted therapy with these agents were not identified.

CPT/HCPCS:
0037UTargeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
81210BRAF (B Raf proto oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

References: American Cancer Society.(2011) Melanoma Skin Cancer. http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/melanoma-skin-cancer-key-statistics. Last accessed September 12, 2011.

Anderson S, Bloom KJ, Vallera DU et al.(2012) Multisite Analytic Performance Studies of a Real-Time Polymerase Chain Reaction Assay for the Detection of BRAF V600E Mutations in Formalin-Fixed, Paraffin-Embedded Tissue Specimens of Malignant Melanoma. Arch Pathol Lab Med 2012; 136(11):1385-91.

Ascierto PA, Dummer R, Gogas HJ, et al.(2020) Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. Feb 2020; 126: 33-44. PMID 31901705

Brown NF, Carter T, Kitchen N, et al.(2017) Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol. Oct 2017; 6(4): 291-296. PMID 28984141

Center For Drug Evaluation and Research.(2011) Summary review for vemurafenib. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429Orig1s000SumR.pdf Last accessed September 12, 2011.

Chapman PB, Hauschild A, Robert C et al.(2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26):2507-16.

Chapman PB, Hauschild A, Robert C, et al.(2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.

Chapman PB, Robert C, Larkin J, et al.(2017) Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol. Oct 1 2017;28(10):2581-2587. PMID 28961848

Dummer R, Ascierto PA, Gogas HJ, et al.(2018) Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. May 2018;19(5):603-615. PMID 29573941

Dummer R, Goldinger SM, Turtschi CP, et al.(2014) 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): 611-21. PMID 24295639

FDA. Companion diagnostic devices: in vitro and imaging tools. Available online at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Last accessed September 2013.

FDA. Companion diagnostic devices: in vitro and imaging tools. Available online at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Last accessed September 2013.

FDA. Draft guidance for industry and food and drug administration staff: in vitro companion diagnostic devices. Available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm262292.htm.

FDA. Draft guidance for industry and food and drug administration staff: in vitro companion diagnostic devices. July 14, 2011. Available online at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm262292.htm. Last accessed September 2013.

FDA. THxID™-BRAF kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument - P120014. BioMérieux labeling, May 2013. Available online at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p120014. Last accessed September 2013.

Flaherty KT, Infante JR, Daud A et al.(2012) Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367(18):1694-703.

Flaherty KT, Puzanov I, Kim KB, et al.(2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19.

Flaherty KT, Robert C, Hersey P et al.(2012) Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med 2012; 367(2):107-14.

Flaherty KT.(2010) Narrative Review: BRAF opens the door to therapeutic advances in melanoma. Ann Intern Med. 2010;153:587-591.

Food and Drug Administration.(2017) SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED): FoundationOne CDx™. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019B.pdf. Accessed April 26, 2018.

Genentech, Inc. Zelboraf® (vemurafenib) tablet prescribing information, July 2013. Available online at: http://www.zelboraf.com/. Last accessed September 2013.

Genentech, Inc. Zelboraf® (vemurafenib) tablet prescribing information, July 2013. Available online at: http://www.zelboraf.com/. Last accessed September 2013.

GlaxoSmithKline. Mekinist (trametinib) tablets prescribing information, May 2013. Available online at: http://www.mekinist.com/. Last accessed September 2013.

GlaxoSmithKline. Tafinlar (dabrafenib) capsules prescribing information, May 2013. Available online at: http://www.tafinlar.com/. Last accessed September 2013.

Gogas HJ, Kirkwood JM, Sondak VK.(2007) Chemotherapy for metastatic melanoma: time for a change? Cancer 2007; 109(3):455-64.

Gutzmer R, Stroyakovskiy D, Gogas H, et al.(2020) Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Jun 13 2020; 395(10240): 1835-1844. PMID 32534646

Hauschild A, Grob JJ, Demidov LV et al.(2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380(9839):358-65.

Hyman DM, Puzanov I, Subbiah V, et al.(2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. Aug 20 2015;373(8):726-736. PMID 26287849

Johannessen CM, Boehm JS, Kim SY et al.(2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468(7326):968-72.

Joseph EW, Pratilas CA, Poulikakos PI et al.(2010) The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A 2010; 107(33):14903-8.

Kaley T, Touat M, Subbiah V, et al.(2018) BRAF Inhibition in BRAF V600 -Mutant Gliomas: Results From the VE-BASKET Study. J Clin Oncol. Dec 10 2018; 36(35): 3477-3484. PMID 30351999

King AJ, Patrick DR, Batorsky RS et al.(2006) Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006; 66(23):11100-5. Cancer Res 2006; 66(23):11100-5.

Label information for ipilimumab.(2011) Center For Drug Evaluation and Research. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Last accessed September 12, 2011.

Long GV, Hauschild A, Santinami M, et al.(2017) Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. Nov 9 2017;377(19):1813-1823. PMID 28891408

Long GV, Stroyakovskiy D, Gogas H, et al.(2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. Nov 13 2014;371(20):1877-1888. PMID 25265492

Long GV, Stroyakovskiy D, Gogas H, et al.(2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. Aug 1 2015;386(9992):444-451. PMID 26037941

Long GV, Stroyakovskiy D, Gogas H, et al.(2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. Aug 1 2015;386(9992):444-451. PMID 26037941

Long GV, Trefzer U, Davies MA, et al.(2012) 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): 1087-95. PMID 23051966

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

Maio M, Lewis K, Demidov L, et al.(2018) Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. Apr 2018;19(4):510-520. PMID 29477665

Marabelle A, Le DT, Ascierto PA, et al.(2020) Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. Jan 01 2020; 38(1): 1-10. PMID 31682550

Marks AM, Bindra RS, DiLuna ML, et al.(2018) Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib. Pediatr Blood Cancer. May 2018; 65(5): e26969. PMID 29380516

Merino DM, McShane LM, Fabrizio D, et al.(2020) Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer. Mar 2020; 8(1). PMID 32217756

National Comprehensive Cancer Network (NCCN).(2016) Clinical Practic Guidelines in Oncology, Melanoma v1.2016. http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.

Nazarian R, Shi H, Wang Q et al.(2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468(7326):973-7.

Ribas A, Kim KB, Schuchter LM et al. Ribas A, Kim KB, Schuchter LM et al.(2011) BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. J Clin Oncol 2011; 29 (Suppl):Abstract 8509.

Robert C, Karaszewska B, Schachter J, et al.(2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. Jan 1 2015;372(1):30-39. PMID 25399551

Rubinstein JC, Sznol M, Pavlick AC et al.(2010) Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 2010; 8:67.

Sondergaard JN, Nazarian R, Wang Q et al.(2010) Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med 2010; 8:39.

Takle AK, Brown MJ, Davies S et al.(2006) The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett 2006; 16(2):378-81.

Teutsch SM, Bradley LA, Palomaki GE et al.(2009) The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med 2009; 11(1):3-14.

Vultur A, Villanueva J, Herlyn M.(2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res. 2011 Apr 1;17(7):1658-1663.

Vultur A, Villanueva J, Herlyn M.(2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Nature 2010; 467(7315):596-9.

Wen PY, Stein A, van den Bent M, et al.(2022) Dabrafenib plus trametinib in patients with BRAF V600E -mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. Jan 2022; 23(1): 53-64. PMID 34838156

Yang H, Higgins B, Kolinsky K et al.(2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 2010; 70(13):5518-27.


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