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DESCRIPTIONBRAF inhibitors are drugs designed to target a somatic mutation in the BRAF gene of patients with advanced melanoma. BRAF encodes a kinase component in the RAF-MEK-ERK signal transduction phosphorylation cascade. Mutated BRAF causes constitutive kinase 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.
Overall incidence rates for melanoma have been increasing for at least 30 years; in 2013, there were more than 76,000 new cases. 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. 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 (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 BRAF V600E and 16% are positive for BRAF V600K. Thus, 45-60% 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 BRAF V600E mutated kinase and with significantly lower potency to inhibit most of many other kinases tested. Preclinical studies demonstrated that vemurafenib selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant human melanoma xenografts in murine models.
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, suggesting that it might 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 those patients with tumors positive for the BRAF V600E mutation.
Dabrafenib (trade name Tafinlar®, also known as GSK2118436 or SB-590885) is a BRAF inhibitor developed by GlaxoSmithKline (GSK). 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.
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. Trametinib inhibits growth of BRAF V600 mutation-positive melanoma cells in vitro and in vivo.
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, 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. FDA issued the finalized version of this document on August 6, 2014.
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 BRAF V600 mutation for treatment with vemurafenib. Vemurafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation. The vemurafenib full prescribing information states that confirmation of the BRAF V600 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.”
In January 2014, FDA granted accelerated approval to dabrafenib and trametinib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Approval was based on response rather than survival outcomes observed in the phase 1/2 trial described next. Continued approval is contingent on results from a phase 3 trial comparing combination therapy with dabrafenib monotherapy in patients with metastatic or unresectable melanoma.
Related policies are –
POLICYTesting for BRAF V600 mutations in tumor tissue of patients with unresectable or metastatic melanoma may be considered medically necessary to select patients for treatment with FDA-approved BRAF inhibitors. (See Policy Guidelines)
Testing for BRAF V600 mutations for all other patients with melanoma, including but not limited to, use in patients with resectable melanoma, is considered investigational.
Currently only vemurafenib, dabrafenib, and trametinib are FDA-approved specifically for the treatment of advanced BRAF-mutated melanoma.
FDA-approved BRAF testing kits are intended to select patients for treatment with vemurafenib and with dabrafenib and trametinib. Prescribing information for these drugs states that confirmation of the BRAF V600E mutation using an FDA-approved test is required for selection of patients appropriate for therapy. The intent of FDA approval of these testing kits is to minimize inappropriate treatment based on an inaccurate test. Commercial labs perform BRAF testing using non-FDA approved tests.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY03/22/2012: Approved by Medical Policy Advisory Committee.
01/09/2013: The medically necessary policy statement was revised to replace “vemurafenib” with “FDA-approved BRAF inhibitors”. Intent unchanged of policy statement unchanged. Added the following to the policy guidelines: Currently only vemurafenib has FDA approval for treatment of advanced melanoma.
02/26/2013: Policy guidelines updated to add the following: The vemurafenib full prescribing information states that the drug is indicated for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test. The only testing kit that is approved by the FDA as an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with vemurafenib is the cobas® 4800 BRAF V600 Mutation Test.
12/13/2013: Policy reviewed; no changes.
02/02/2015: Policy description updated to add information regarding the following BRAF inhibitors: Dabrafenib and Trametinib. Medically necessary policy statement revised to change "stage IIIC or IV" to "unresectable or metastatic." Investigational statement updated to change "lesser stage melanoma" to "resectable melanoma." Policy guidelines updated to include dabrafenib and trametinib as FDA-approved for the treatment of advanced BRAF-mutated melanoma.
08/21/2015: Code Reference section updated for ICD-10.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.77
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.