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Overall incidence rates for melanoma have been increasing for at least 30 years; in 2011, more than 70,000 new cases will be diagnosed. 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 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. Thus, 40-60% of advanced melanoma patients might respond to a BRAF inhibitor targeted to this mutated kinase.

Two companies developed targeted BRAF inhibitors that have proceeded to Phase III clinical trials in melanoma patients. 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 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 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 BRAFV600E mutation.

Dabrafenib (also known as GSK2118436 or SB-590885) is a BRAF inhibitor developed by GlaxoSmithKline and, as of the date of this policy, is under study in a Phase III clinical trial. As few publications detailing preclinical or clinical studies for dabrafenib are available, and neither drug nor companion test (developed by bioMérieux) have as yet been submitted to the FDA, this policy will focus on the vemurafenib companion test.

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.

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.

Related policies are –

• Genetic Testing for Inherited Susceptibility to Colon Cancer, Including Microsatellite Instability Testing

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

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.

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. 

Covered Codes

This is not intended to be a comprehensive list of codes. Some covered procedure codes have multiple descriptions.
The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document.

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