Coverage Policy Manual
Policy #: 2011061
Category: Laboratory
Initiated: September 2011
Last Review: July 2018
  Genetic Test: Melanoma, V600 Mutation Testing to Predict Response to BRAF Inhibitor Targeted Therapy

Description:
BRAF inhibitors are drugs designed to target a somatic mutation in the BRAF gene of patients with advanced melanoma. BRAF codes for a kinase component in the RAF-MEK-ERK signal transduction phosphorylation cascade. The mutated version of the BRAF kinase results in constitutive activity, which is believed to be actively involved in oncogenic proliferation. Direct and specific inhibition of the mutated kinase has been shown to significantly retard tumor growth and may improve patient survival.
 
Background
Overall incidence rates for melanoma have been increasing for at least 30 years; in 2011, more than 70,000 new cases will have been diagnosed (ACS, 2011). 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%. Dacarbazine has long been considered the treatment standard for systemic therapy but has disappointingly low response rates of only 15 to 25% and median response durations of 5 to 6 months; less than 5% of responses are complete (Gogas, 2007). Temozolomide has similar efficacy with the exception of a much greater ability to penetrate the central nervous system. Combination regimens increase response rates, but not overall survival. Very recently, ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma. For the first time, a survival advantage was demonstrated in previously treated patients: median survival on ipilimumab of 10 months versus 6.4 months on control medication. However, side effects of ipilimumab can include severe and fatal immune-mediated adverse reactions, especially in patients who are already immune-compromised.
 
Mutations in the BRAF kinase gene are common in tumors of patients with advanced melanoma and result in constitutive activation of a key signaling 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 (Vultur, 2011). Thus, 40-60% of advanced melanoma patients might respond to a BRAF inhibitor targeted to this mutated kinase.
 
Three BRAF inhibitors have been developed for use in patients with advanced melanoma. Vemurafenib (trade name Zelboraf®, also known as PLX4032 and RO5185426) was co-developed under an agreement between Roche (Genentech) and Plexxikon. Vemurafenib 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.
 
Dabrafenib (also known as GSK2118436 or SB-590885) is a BRAF inhibitor developed by GlaxoSmithKline (GSK) (King, 2006; Takle, 2006). The results of a Phase III clinical trial of dabrafenib have recently been published. On August 3, 2012, GSK submitted a new drug application to the U.S. Food and Drug Administration for dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation, as detected by an FDA-approved test. BioMérieux has filed for FDA premarket approval of the molecular theranostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma.
 
Regulatory Status
The FDA Centers for Devices and Radiological Health (CDRH), for Biologics Evaluation and Research (CBER), and for Drug Evaluation and Research (CDER) developed a draft guidance on in vitro companion diagnostic devices, which was released on July 14, 2011, (FDA, 2011) to address the “emergence of new technologies that can distinguish subsets of populations that respond differently to treatment.” As stated, the FDA encourages the development of treatments that depend on the use of companion diagnostic devices “when an appropriate scientific rationale supports such an approach.” In such cases, the FDA intends to review the safety and effectiveness of the companion diagnostic test as used with the therapeutic treatment that depends on its use. The rationale for co-review and approval is the desire to avoid exposing patients to preventable treatment risk.
 
While the guidance is not yet finalized, it represents the FDA’s current thinking on the topic and likely the direction given to sponsors of applicable treatments and companion diagnostics in development at the same time this guidance was being prepared. Important points from the guidance include that a new therapeutic product and its corresponding companion diagnostic test should be developed together, and that both diagnostic test and therapeutic product should be approved or cleared at the same time by the FDA. While the guidance allows for the development of competitor companion tests, those tests must be submitted to the FDA for review and approval or clearance.
 
Vemurafenib and a Class III companion diagnostic test, the cobas® 4800 BRAF V600 Mutation Test, were co-approved by the FDA in August 2011. The test is approved as an aid in selecting melanoma patients whose tumors carry the BRAFV600 mutation for treatment with vemurafenib. Vemurafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600 mutation. The vemurafenib full prescribing information states that confirmation of the BRAFV600 mutation using an FDA-approved test is required for selection of patients appropriate for therapy.
 
Dabrafenib was FDA-approved in May 2013 for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDA-approved test. Dabrafenib is specifically not indicated for the treatment of patients with wild-type BRAF melanoma.  
 
Trametinib was FDA-approved in May 2013 for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Trametinib is specifically not indicated for the treatment of patients previously treated with BRAF inhibitor therapy.  
 
The companion diagnostic test co-approved for both dabrafenib and trametinib is the THxID™ BRAF Kit manufactured by bioMérieux. The kit is intended “as an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with dabrafenib and as an aid in selecting melanoma patients whose tumors carry the BRAF V600E or V600K mutation for treatment with trametinib” (FDA, 2013).
 
In January 2014, the combination of dabrafenib (Tafinlar®) and trametinib (Mekinist™; both GlaxoSmithKline) were approved by FDA through the accelerated approval process for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K variants, as detected by an FDA-approved test. Continued approval is contingent on results from a phase 3 trial comparing combination therapy with dabrafenib monotherapy in patients with metastatic or unresectable melanoma.
 
In December 2015, cobimetinib (Cotellic®; Genentech) was approved by FDA after priority review for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K variants, in combination with vemurafenib (Genentech, 2016).
   
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 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).
 
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.

CPT/HCPCS:
81210BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

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