What Is BRAF Mutation Analysis? - CLINICAL GUIDELINES. Lab Management Program. Effective Januar

• BRAF is part of a cell signaling pathway that helps control cell growth. Mutations in the BRAF gene can cause out of control cell growth, which may lead to

cancer.1,2 The most common BRAF mutation is called V600E (previously known as V599E), which accounts for about 70-90% of mutations in this gene.1,3

• About 40-60% of cutaneous melanomas have a V600E BRAF mutation.1 • Vemurafenib (Zelboraf®

), dabrafenib (Tafinlar®), and trametinib (Mekinist®) are orally-administered kinase inhibitors that are able to block the function of the mutated BRAF protein.1,2 They are specifically indicated for the treatment of patients with metastatic or unresectable melanoma whose tumors have a BRAF V600E mutation. 1,2 They are not recommended for use in patients with wild type BRAF melanoma.2,4-6

Test Information

• Targeted mutation analysis: Laboratories most commonly test for the BRAF V600E mutation, which accounts for about 90% of activating BRAF

mutations.4 Mutation analysis requires relatively little tumor material for testing and has high sensitivity. It is also relatively inexpensive.2,3

BRAF mutation analysis is done on fresh, frozen, or paraffin-embedded tissue from either a primary tumor or metastasis.1-3 Some molecular diagnostic

laboratories perform BRAF mutation analysis by laboratory-developed methods, while others use FDA-approved test kits. Laboratory-developed tests may vary in the specimen type required, methodology used, mutations tested, sensitivity, and other test-specific data.

• Vemurafenib was approved in 2011 for use along with an FDA approved companion diagnostic developed by Roche molecular diagnostics called the cobas® 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 mutation test was clinically validated in the trials conducted for approval of vemurafenib. This testing specifically checks for the V600E mutation in formalin-fixed, paraffin- embedded melanoma tumor tissue.2

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• In 2013, dabrafenib and trametinib were approved for use along with an FDA approved companion diagnostic developed by Roche molecular diagnostics called the THxID BRAF test. The THxID BRAF test was clinically validated in the clinical studies supporting the approval of dabrafenib and trametinib.

Guidelines and Evidence

• The National Comprehensive Cancer Network (NCCN, 2015) includes

vemurafenib, dabrafenib and trametinib as options for treatment of advanced or metastatic melanoma which require companion diagnostic testing. The

guidelines state “Vemurafenib, dabrafenib, and trametinib are recommended only for patients with documented V600 BRAF mutations.”

• The US Food and Drug Administration (FDA) approved each of these drugs with a companion diagnostic:

o Zelboraf: "ZELBORAF® is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use:

ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma."2

o Tafinlar: “TAFINLAR is a kinase inhibitor indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. TAFINLAR in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with trametinib… Limitation of Use:

TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma."5

o Trametinib (Mekinist): "MEKINIST is a kinase inhibitor indicated as a single agent and in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for MEKINIST in combination with dabrafenib…. MEKINIST as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy.”6

Criteria

Requests for testing will be authorized if the following criteria are met. Requests not meeting the criteria will result with a medical review of the case.

Testing may be considered in individuals who meet the following criteria:

• Individual has been diagnosed with metastatic or unresectable melanoma, and

Lab Management Guidelines V1.0.2016

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• At least one of the following treatment is being considered: Zelboraf® (vemurafenib), Tafinlar® (dabrafenib), or Mekinist® (trametinib), and • BRAF V600 testing has not been performed previously

Exclusions

BRAF V600E tumor marker testing is not currently indicated as a companion diagnostic or for therapy selection for any other tumor types and is therefore not covered for these uses.

References

1. Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun

30;364(26):2507-16. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1103782 2. Vemurafenib (ZELBORAF™) prescribing information. August 2011. Available at:

http://www.gene.com/gene/products/information/zelboraf/pdf/pi.pdf

3. Long G, Menzie AM , Nagrial AM, et al. Prognostic and clinicopathic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239-46.

4. National Comprehensive Cancer Network: Practice Guidelines in Oncology. Melanoma (v.3.2015). Available at: http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf 5. Dabrafenib (Tafinlar®) prescribing information. Jan 2014. Available at:

http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf 6. Trametinib (Mekinist®) prescribing information. Jan 2014. Available at:

http://www.pharma.us.novartis.com/product/pi/pdf/mekinist.pdf

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In document CLINICAL GUIDELINES. Lab Management Program. Effective January 15, 2016 (Page 87-90)