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BRAF 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.
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, 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 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 patients with tumors positive for the BRAF V600E mutation.
Dabrafenib (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 (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.
In August 2011, vemurafenib and a Class III companion diagnostic test, the cobas® 4800 BRAF V600 Mutation Test, were co-approved by the FDA through the premarket approval process 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.
In May 2013, dabrafenib (GlaxoSmithKline) was FDA-approved through the premarket approval process 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.
In May 2013, trametinib (GlaxoSmithKline) was FDA-approved through the premarket approval process 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 (GlaxoSmithKline) 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. 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 –
Testing 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.
The Phase 3 clinical trial of vemurafenib selected all patients with a BRAF V600 mutation using the FDA-approved test. Most of these mutations were BRAF V600E mutations, and a small number (19/675 [2.8%]) were BRAF V600K mutations. The authors stated that patients with BRAF V600K mutations also appeared to respond to vemurafenib, but no formal subgroup analysis was performed. Therefore, results of the trial refer primarily to patients with the BRAF V600E mutation. Efficacy of vemurafenib for patients with other mutations, including BRAF V600K, is less certain.
Pivotal trials for vemurafenib, dabrafenib, and trametinib enrolled patients in the following stages of advanced melanoma:
A Phase 2, 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 BRAF V600E mutations and was negligible in patients with BRAF V600K mutations.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
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.
12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions. Code Reference section updated to revise the code description for CPT code 81210 with an effective date of 01/01/2016.
02/11/2016: Policy description updated. Policy statements unchanged. Policy guidelines updated regarding clinical trials.
06/06/2016: Policy number added.
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.