MEDICAL POLICY

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APPENDIX
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BRAF Gene Mutation Testing To Select Melanoma Patients for BRAF Inhibitor Targeted Therapy

Number 12.04.77

Effective Date December 9, 2013

Revision Date(s) 12/09/13; 12/11/12

Replaces 2.04.77

Policy

Testing for BRAFV600 mutations in tumor tissue of patients with stage IIIC or IV melanoma may be considered medically necessary to select patients for treatment with FDA-approved BRAF inhibitors (See Policy Guidelines).

Testing for BRAFV600 mutations for all other patients with melanoma, including but not limited to use in patients with lesser stage melanoma, is considered investigational.

Related Policies

5.01.534

Multiple Receptor Tyrosine Kinase Inhibitors

12.04.91

General Approach to Genetic Testing

Policy Guidelines

Currently only vemurafenib, dabrafenib, and trametinib are FDA-approved specifically for the treatment of advanced BRAF-mutated melanoma.

There are FDA-approved BRAF testing kits intended to be used to select patients for treatment with vemurafenib and with dabrafenib and trametinib. There are also commercial labs that perform BRAF testing using non-FDA approved testing. The full prescribing information states that confirmation of the BRAFV600E mutation using an FDA-approved test is required for selection of patients appropriate for therapy. The intent of the FDA-approval of these testing kits is to minimize the potential for inappropriate treatment based on an inaccurate test.

The Phase III clinical trial of vemurafenib selected all patients with a BRAFV600 mutation using the FDA-approved test. The majority of these mutations were BRAFV600E mutations, and a small number (19/675, 2.8%) were BRAFV600K mutations. The authors stated that patients with the BRAFV600K also appeared to respond to vemurafenib, but no formal subgroup analysis was performed. Therefore, the results of the trial refer primarily to patients with the BRAFV600E mutation. The efficacy of vemurafenib for patients with other mutations, including BRAFV600K, is less certain.

A Phase II, single-arm study of dabrafenib enrolled 172 patients with either BRAF V600E–or BRAF V600K-mutated melanoma with brain metastasis. Overall intracranial response was limited to patients with the BRAF V600E mutation and was negligible in patients with the BRAF V600K mutation.

Coding

Effective for 2012, there is a specific CPT code:

81210 BRAF (v-raf murine sarcoma viral oncogene homolog B1) (e.g., colon cancer), gene analysis, V600E variant

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 BRAF kinase results in constitutive activity, which is believed to promote 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 2013, more than 75, 000 new cases will have been diagnosed. (1) 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. (2) 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 with ipilimumab of 10 months versus 6.4 months with control medication. However, side effects of ipilimumab can include severe and fatal immune-mediated adverse reactions, especially in patients who are already immune-compromised.

BRAF is a human gene that makes a protein called B-RAF. Approximately half of all melanomas have mutations in the BRAF gene. Mutations are common in tumors of patients with advanced melanoma and result in activation of a key signaling pathway (the RAF-MEK-ERK [also called MAPK] pathway) that is associated with oncogenic proliferation. In general, 50-70% of melanoma tumors harbor a BRAF mutation; of these, 80% are positive for BRAFV600E and 16% are positive for BRAFV600K. (3) Thus, approximately 45-60% of advanced melanoma patients may 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. (4). Preclinical studies demonstrated that vemurafenib selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells (5-7) and caused regression of BRAF mutant human melanoma xenografts in murine models. (4) 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, (5-7) 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 (trade name Tafinlar®, also known as GSK2118436 or SB-590885) is a BRAF inhibitor developed by GlaxoSmithKline (GSK). (8, 9) Dabrafenib inhibits several kinases, including mutated forms of BRAF kinase, with greatest activity against V600E-mutated BRAF. In vitro and in vivo studies demonstrated dabrafenib’s ability to inhibit growth of BRAF V600-mutated melanoma cells. (10)

Trametinib (trade name Mekinist™) is an inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 developed by GSK. MEK kinases regulate extracellular signal-related kinase (ERK), which promotes cellular proliferation. BRAF V600E and V600K mutations result in constitutive activation of MEK1 and MEK2. (11) Trametinib inhibits growth of BRAF V600 mutation-positive melanoma cells in vitro and in vivo. (12)

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, (13) to address the “emergence of new technologies that can distinguish subsets of populations that respond differently to treatment.” As stated, 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, 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.

Although the guidance is not yet finalized, it represents FDA’s current thinking on the topic and likely the direction given to sponsors of applicable treatments and companion diagnostics in development at the 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. (14) 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. (15)

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. (10)

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. (12)

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.” (14)

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

N/A

Rationale

Literature Review

This policy was originally created in 2011 based on a Special Report by the Technology Evaluation Center. (16) For the TEC Special Report, the MEDLINE® database was searched (via PubMed) for articles using the terms “PLX4032,” “vemurafenib,” “V600E,” and “BRAF inhibitor,” all coupled with the term “melanoma.” The reference lists of relevant study publications and review articles were also examined. Meeting abstracts for the 2011 annual meeting of the American Society of Clinical Oncology were searched using the MEDLINE® search terms. If available, virtual presentations and slides were reviewed for key abstracts. The “grey literature” was consulted in the form of drug and laboratory test approval information released by the FDA, ongoing clinical trials from online site www.clinicaltrials.gov, and online searches for status and ancillary information. The most recent searches using updated search terms included the period through August 2013. Following is a summary of the key publications and regulatory documents to date.

Since the TEC Special Report, two additional Phase III randomized controlled trials (RCT) have been published. These trials, which evaluated dabrafenib and trametinib for advanced melanoma in BRAF-positive patients, are summarized below. Additionally, a Phase II single-arm study of combination dabrafenib plus trametinib is reviewed briefly.

The components of the evidence evaluation are analytic validity, clinical validity, and clinical utility, as defined in the methods of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. (17)

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. (17) 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).

Vemurafenib

The cobas® 4800 BRAF V600 Mutation Test is a real-time polymerase chain reaction (PCR) test intended for the qualitative detection of the BRAFV600E 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 (18) on 596 consecutive patients, 449 of whom 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 patients enrolled in the Phase II trial (19) were also sequenced by Sanger sequencing; specimens that were invalid by Sanger, or that were identified as V600K mutated 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 (see Table 1).

Tumor specimens from 55 patients enrolled in a Phase I clinical trial (20) of vemurafenib were subjected to cobas 4800 BRAF V600 Mutation Test and to Sanger sequencing. The limit of detection was 5% mutant allele for cobas 4800 BRAF V600 Mutation Test and 20% for Sanger sequencing. The cobas 4800 BRAF Mutation Test is highly predictive for V600E; however, it also detects other BRAFV600 mutations (V600K; 65.8% agreement with Sanger sequencing, V600D, V600E2, and V600R; not determined) with less sensitivity. Data presented on study 3 are presented in Table 1. (21)

Halait et al. (2012) analyzed the analytical performance of cobas 4800 BRAF V600 Mutation Test and Sanger sequencing in 219 melanoma specimens. A greater than 96% correct call rate was obtained across all specimen types with 5% mutation sequences. The cobas 4800 BRAF V600 Mutation Test and Sanger sequencing correlation results for V600E in study 4 are presented in Table 1. After discrepant analysis with 454 pyrosequencing, the positive percent agreement increased to 100%, the negative percent agreement increased to 93%, and the overall percent agreement increased to 96%. (22)

A similar study by Anderson et al. (2012) used screening specimens from Phase II and Phase III trials of vemurafenib. (23) Of 477 available specimens, 433 had both a valid cobas result and valid Sanger sequencing. Correlation results were similar to those obtained by Halait et al. (22) and are shown in Table 1. Of 42 discordant results (cobas mutation-positive/Sanger V600E-negative), 17 (40%) were V600E-positive and 24 (57%) were V600K-positive by 454 pyrosequencing; one sample with a V600D mutation on Sanger sequencing was wild-type by 454 pyrosequencing. Reproducibility was assessed across 3 sites. Correct interpretations were made for all wild-type specimens and for specimens with more than 5% mutant allele, the limit of detection of the cobas test.

According to the COSMIC database v54 (available at www.sanger.ac.uk/perl/genetics/CGP/cosmic), in tumors originating in the skin, V600E mutations accounted for 92.5%, V600K mutations for 5.6%, V600R mutations for 1%, “V600E2” for 0.7% and all other V600 mutations, 0.2%. Halait et al. analyzed the cross -reactivity of 14 BRAF non-V600E mutant melanoma specimens with the Cobas test. The one V600R mutant specimen did not show cross reactivity. The remaining 13 mutant specimens showed cross reactivity with the test (V600D, 1/1; V600E2, 1/3; and V600K, 6/9).

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.

Table 1. Correlation of Vemurafenib companion test results with Sanger sequencing

Definition of Positive

Positive % Agreement

Negative % Agreement

Overall % Agreement

Phase III trial (18)

Only V600E

97.3

84.6

90.9

All V600

87.7

95.4

90.6

V600E + V600K 

92.7

95.2

91.1

Phase II trial (19)

Only V600E

92.4

   

V600E + V600K 

100

   

Phase I trial (21)

Only V600E (22)

97.3

   

Analytical Performance trial

Only V600E (23)

96

82

88

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. (24) 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. Additional results are shown in Table 2.

Table 2. Correlation of dabrafenib and trametinib companion test results with Sanger sequencing (24)

 

Overall Agreement

V600E and V600K

V600E

V600K

PPA

NPA

PPA

NPA

PPA

NPA

Including invalids and QNS

92.3

96.4

89.9

96.3

99.2

92.2

99.5

Excluding invalids and QNS

95.9

98.1

93.9

NR

NR

NR

NR

NPA, negative percent agreement; NR, not reported; PPA, positive percent agreement; QNS, quantity not sufficient

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. (17)

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, clinical studies of treatment benefit, which use the test to select patients, provide evidence of both clinical validity and clinical utility.

Vemurafenib

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 open-label, comparative trial, also known as BRIM-3, is summarized in Table 3. A total of 675 patients were randomly assigned to either vemurafenib (960 mg twice daily orally) or dacarbazine (1,000 mg/m2 body surface area by intravenous [IV] infusion every 3 weeks) to determine whether vemurafenib would prolong the rate of overall or progression-free survival, compared to dacarbazine. (18) All enrolled patients had unresectable, previously untreated Stage IIIC or IV melanoma with no active central nervous system (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 computed tomography (CT) were performed at baseline, at weeks 6 and 12, and every 9 weeks thereafter. Tumor responses were determined by investigators according to 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. The Data and Safety Monitoring Board determined that both co-primary endpoints had met prespecified stopping criteria and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. At the time the trial was halted, 118 patients had died; median survival had not been reached. Trial results are summarized in Table 3. 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 the FDA and established safety and effectiveness of the cobas 4800 BRAF V600 Mutation Test, resulting in co-approval of both drug and companion test.

Table 3. Phase III RCTs of BRAF Inhibitors for BRAF-Positive Advanced Melanoma

Study/year

F/U

Group

N

OS1(95% CI)

PFS2 months
(95% CI)

ORR3(95% CI)

Vemurafenib

Chapman 2011 (18)

6 months

Vemurafenib

337  

84% (78-89%)

5.3 (median)

48% (42-55%)

Dacarbazine

338  

65% (56-73%)

1.6 (median)

5% (3-9%)

Hazard ratio

 

0.37 (0.26-0.55)

0.26 (0.20-0.33)

NA4

p value

 

<0.001

<0.001

NA

Dabrafenib

Hauschild 2012 (25)

4.9 months (median),
range (0-9.9 months)

Dabrafenib

187

89%

5.1 (median)

50% (42.4-57.1)

Dacarbazine

63

86%

2.7 (median)

6% (1.8-15.5)

Hazard ratio

 

0.61 (0.25-1.48)

0.30 (0.18-0.51)

NA

p value

 

NR

<0.0001

NA

Trametinib

Flaherty 2012 (26)

6 mo

Trametinib

214

81%

4.8 (median)

22% (17-28%)

Chemotherapy5

108

67%

1.5 (median)

8% (4-15%)

Hazard ratio

 

0.54 (0.32-0.92)

0.47 (0.34-0.65)

NA

P Value

 

0.01

<0.001

NA

1 Overall survival.

2 Progression-free survival.

3 Objective response rate, including complete and partial responses.

4 NA, not applicable.

5 Either dacarbazine 1,000 mg/m2 IV or paclitaxel 175 mg/m2 IV every 3 weeks at investigator discretion.

Phase II Clinical Trial

A Phase II single-arm study, known as BRIM-2, enrolled patients from 13 centers who had failed at least one previous treatment for metastatic melanoma. (19) All patients were selected with the cobas 4800 BRAF V600 Mutation Test; 122 cases were BRAFV600E-positive, and 10 cases were BRAFV600K-positive. The target overall response rate (primary outcome) was 30%, with a lower boundary of the 95% confidence interval (CI) of 20%. At a median follow-up of 7 months, this target was met with an overall response rate of 52% by independent review committee (IRC) (95% CI: 43-61). 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 study were first to determine the maximum dose in a dose-escalation phase, then determine the objective response rate and monitor toxicity. (20) This study used a polymerase chain reaction (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 study, 26 of 32 patients with the BRAFV600E mutation responded (81%; 24 partial, 2 complete responses).

Dabrafenib

One Phase III randomized, controlled, open-label trial of dabrafenib for advanced (stage IV or unresectable stage III) melanoma has been published (25); 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 noninfectious, febrile drug reactions (3% grade 3 pyrexia vs. none in controls); and severe hyperglycemia (>250-500 mg/dL), requiring medical management in nondiabetic patients or change in management of diabetic patients (6% vs. none in controls). 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. (Table 4) 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). (24)

Table 4. PFS in patients testing V600E-mutation positive by central assay and by THxID BRAF kit (24)

 

Central assay

THxID–BRAF kit

 

N

Median PFS (95% CI), months

N

Median PFS (95% CI), months

Dabrafenib

187

5.1 (4.9-6.9)

177

5.0 (4.9-6.8)

Dacarbazine

63

2.7 (1.5-3.2)

55

2.7 (1.5-3.2)

Hazard ratio (95% CI)

 

0.33 (0.20-0.54)

 

0.34 (0.20-0.57)

p value

 

<0.001

 

<0.001

Trametinib

The clinical efficacy and safety of trametinib was assessed in the Phase III, open-label METRIC trial. (26) 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 (Table 5). 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). (24)

Table 5. PFS in patients testing V600E- or V600K-mutation positive by central assay and by THxID BRAF kit (24)

 

Central assay

THxID–BRAF kit

 

N

Median PFS (95% CI), months

N

Median PFS (95% CI), months

Trametinib

214

4.8 (4.3-4.9)

196

4.8 (4.2-4.9)

Chemotherapy

108

1.5 (1.4-2.7)

93

1.5 (1.4-2.7)

Hazard ratio (95% CI)

 

0.47 (0.34-0.65)

 

0.48 (0.34-0.68)

p value

 

<0.001

 

<0.001

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; (18-20) 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. (27, 28) 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. (29) 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

Table 6 shows active Phase III trials of BRAF inhibitor therapy in melanoma currently listed at online site ClinicalTrials.gov. 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. (See table notes for details.)

Table 6. Currently active Phase III trials of BRAF inhibitor therapy for melanoma

• NCT Number

Sponsor

Title

• Study Design

• N

Completion Date

Single agents

NCT018985851

Hoffmann LaRoche

An Open-Label Study of Zelboraf (Vemurafenib) in Patients With Braf V600-Mutation Positive Metastatic Melanoma

Single-arm study

60

June 2015

NCT01667419

Hoffmann LaRoche

BRIM8: A Study of Vemurafenib Adjuvant Therapy in Patients With Resected Cutaneous BRAF Mutant Melanoma2

Double-blind RCT

725

June 2016

Combination treatments

NCT016831881

Prometheus

High-Dose Interleukin-2 + Vemurafenib in Patients With BRAF Mutation Positive Metastatic Melanoma (PROCLIVITY 01)

Single-arm study

185

April 2016

NCT01584648

GlaxoSmithKline

A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma

Double-blind RCT

340

September 2013

NCT01597908

GlaxoSmithKline

Dabrafenib Plus Trametinib vs. Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-V)

Open-label RCT

694

March 2014

NCT01682083

GlaxoSmithKline

The BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk3 BRAF V600 Mutation-positive Melanoma After Surgical Resection (COMBI-AD)

Double-blind RCT

852

July 2015

NCT01689519

Hoffmann LaRoche

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

500

August 2016

NCT01909453

Novartis

Study Comparing Combination of the RAF Kinase Inhibitor LGX818 Plus the MEK Inhibitor MEK162 and LGX818 Monotherapy Versus Vemurafenib in Unresectable or Metastatic BRAF V600 Mutant Melanoma (COLUMBUS)

Open-label RCT

900

June 2017

1 Phase IV trial.

2 Stage IIc (tumor >4 mm with ulceration) or stage III melanoma with lymph node metastasis >1 mm.

3 Stage III melanoma with lymph node metastasis >1 mm.

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.

Based on the results of phase III trials, BRAF testing that uses a test approved by the FDA may be considered medically necessary to select advanced melanoma patients for treatment with FDA-approved BRAF inhibitors.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Guidelines for melanoma, version 1.2014, recommend vemurafenib, dabrafenib, and trametinib “only for patients with V600 mutation of the BRAF gene, as documented by an FDA-approved or CLIA-approved facility.” (30) Vemurafenib and dabrafenib both have category 1 recommendations as preferred regimens for advanced or metastatic melanoma. Trametinib (monotherapy) has a category 1 recommendation as an “other active regimen.” The Guidelines include no recommendation for combination therapy with these agents but acknowledge that “the clinical efficacy of combination therapy remains under investigation.”

Medicare National Coverage

There is no national coverage determination.

References

  1. American Cancer Society. Cancer Facts & Figures 2013. Available online at: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2013/index. Last accessed November 2013.
  2. Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer 2007; 109(3):455-64.
  3. Vultur A, Villanueva J, Herlyn M. Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res 2011; 17(7):1658-63.
  4. Bollag G, Hirth P, Tsai J et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010; 467(7315):596-9.
  5. Sondergaard JN, Nazarian R, Wang Q et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med 2010; 8:39.
  6. Joseph EW, Pratilas CA, Poulikakos PI et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A 2010; 107(33):14903-8.
  7. Yang H, Higgins B, Kolinsky K et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 2010; 70(13):5518-27.
  8. King AJ, Patrick DR, Batorsky RS et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006; 66(23):11100-5.
  9. Takle AK, Brown MJ, Davies S et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett 2006; 16(2):378-81.
  10. GlaxoSmithKline. Tafinlar (dabrafenib) capsules prescribing information, May 2013. Available online at: http://www.tafinlar.com/. Last accessed September 2013.
  11. Rubinstein JC, Sznol M, Pavlick AC et al. 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.
  12. GlaxoSmithKline. Mekinist (trametinib) tablets prescribing information, May 2013. Available online at: http://www.mekinist.com/. Last accessed November 2013.
  13. 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 November 2013.
  14. FDA. Companion diagnostic devices: in vitro and imaging tools. Available online at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Last accessed November 2013.
  15. Genentech, Inc. Zelboraf® (vemurafenib) tablet prescribing information, July 2013. Available online at: http://www.zelboraf.com/. Last accessed November 2013.
  16. Blue Cross and Blue Shield Technology Evaluation Center (TEC). Special Report. Companion diagnostics: Example of BRAF testing to select patients with melanoma for BRAF kinase inhibitors. TEC Assesment Program 2011; 26(7).
  17. Teutsch SM, Bradley LA, Palomaki GE et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med 2009; 11(1):3-14.
  18. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26):2507-16.
  19. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366(8):707-14.
  20. Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363(9):809-19.Luke JJ, Hodi FS. Vemurafenib and BRAF inhibition: a new class of treatment for metastatic melanoma. Clin Cancer Res 2012; 18(1):9-14.
  21. Luke JJ, Hodi FS. Vemurafenib and BRAF inhibition: a new class of treatment for metastatic melanoma. Clin Cancer Res 2012; 18(1):9-14.
  22. Halait H, Demartin K, Shah S et al. Analytical performance of a real-time PCR-based assay for V600 mutations in the BRAF gene, used as the companion diagnostic test for the novel BRAF inhibitor vemurafenib in metastatic melanoma. Diagn Mol Pathol 2012; 21(1):1-8.
  23. Anderson S, Bloom KJ, Vallera DU et al. 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.
  24. 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 November 2013.
  25. Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380(9839):358-65.
  26. Flaherty KT, Robert C, Hersey P et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med 2012; 367(2):107-14.
  27. Johannessen CM, Boehm JS, Kim SY et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468(7326):968-72.
  28. Nazarian R, Shi H, Wang Q et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468(7326):973-7.
  29. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367(18):1694-703.
  30. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Melanoma v.1.2014. Available online at: http://www.nccn.org/index.asp. Last accessed November 2013.
  31. 23. BlueCross BlueShield Association (BCBSA) Medical Policy Reference Manual, BRAF Gene Mutation Testing to Select Melanoma Patients for BRAF Inhibitor Targeted Therapy. Medical Policy Reference Manual, Policy No. 2.04.77, 2013.

Coding

Codes

Number

Description

CPT

81210

BRAF (v-raf murine sarcoma viral oncogene homolog B1) (e.g., colon cancer), gene analysis, V600E variant

ICD-9-CM Diagnosis

172.0 – 172.9

Malignant melanoma of skin code range

ICD-10-CM
(effective 10/01/14)

C43.0-C43.9

Malignant melanoma of skin code range

Appendix

N/A

History

Date

Reason

01/10/12

New Policy – Add to Pathology/Laboratory section. Policy created with literature search through August 2011; considered medical necessary in tumor tissue from patients with stage IIIC or IV melanoma to select patients for treatment with vemurafenib and investigational for all other indications.

02/09/12

Code 81210 removed from policy.

05/24/12

Policy renumbered to 12.04.77 (previously 2.04.77) and reassigned to new Genetic Testing category.

09/21/12

Update Related Policy – Add 5.01.534; ICD-10 codes are now effective 10/01/2014.

12/11/12

Replace policy. Policy revised to state “Testing for the BRAFV600 mutation in tumor tissue of patients with stage IIIC or IV melanoma may be considered medically necessary to select patients for treatment with FDA-approved BRAF inhibitors” in place of “vemurafenib”. Sentence added to Policy Guidelines: “Currently only vemurefenib has FDA approval for treatment of advanced melanoma.” Rationale updated based on literature review through August 2012, references 13-18, 21 added; others renumbered or removed. Policy statement changed as noted.

01/14/13

Coding update. CPT codes 83890 – 83913 deleted as of 12/31/12; CPT codes 81210 and 81599, effective 1/1/13, are added to the policy.

05/14/13

Update Related Policies. Add 12.04.91.

12/09/13

Replace policy. Policy statements modified to read, “Testing for BRAFV600 mutations” in place of “Testing for the BRAFV600 mutation.” Rationale updated with literature review through August 2013. References 10-12, 14-15, 23-26, 29 added. References1, 13, 30 updated; others renumbered/removed. Policy statements revised as noted. CPT code 81599 removed as it is not specific to the policy; 83890-83913 removed because they are now deleted.


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