BRAF Testing for Melanoma Kinase Inhibitor Responses

Lab Management Guidelines v2.0.2019 BRAF Testing for Melanoma Kinase Inhibitor Response

MOL.TS.134.A v2.0.2019 Introduction

BRAF testing for melanoma kinase inhibitor response is addressed by this guideline.

Procedures addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.

Procedure addressed by this guideline Procedure code BRAF V600 Targeted Mutation Analysis 81210

What is BRAF

Definition

BRAF is a gene that forms a part of a cell-signaling pathway to help control cell growth. Changes or mutations in the BRAF gene can cause out of control cell growth, which may lead to cancer.1,2

BRAF V600E

About 40-60% of cutaneous melanomas have a BRAF mutation.1 The most common BRAF mutation is called V600E which was previously known as V599E. This mutation accounts for about 70-90% of mutations in this gene.1,3

Treatment options

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

Test information

Introduction

Laboratories most commonly perform targeted mutation analysis for the BRAF V600E mutation, which accounts for about 90% of activating BRAF mutations.1,4 Mutation analysis requires relatively little tumor material for testing and has high sensitivity. It is also relatively inexpensive.2,3

Targeted mutation analysis

BRAF mutation analysis is done on fresh, frozen, or paraffin-embedded tissue from either a primary tumor or metastasis.1-4 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 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.4 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

Dabrafenib and trametinib In 2013, dabrafenib and trametinib were approved for use along with an FDA approved companion diagnostic developed by Roche Molecular Diagnostics called the THxIDTM BRAF test.4 The THxID BRAF test was clinically validated in the clinical studies supporting the approval of dabrafenib and trametinib.5,6 a Guidelines and evidence m

Introduction o n

This section includes relevant guidelines and evidence pertaining to BRAF testing for a l melanoma kinase inhibitor response. e

National Comprehensive Cancer Network M

- The National Comprehensive Cancer Network (NCCN, 2018) includes vemurafenib, dabrafenib, dabrafenib in combination with trametinib, and vemurafenib in combination F with cobimetinib as options for the treatment of advanced or metastatic melanoma A

which require companion diagnostic testing. R B

400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com

Lab Management Guidelines v2.0.2019

The guidelines state that “For patients with BRAF-mutant metastatic disease, BRAF- targeted therapy first-line options include BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib or vemurafenib/cobimetinib, or single-agent BRAF inhibitor therapy with vemurafenib or dabrafenib.” 4

FDA

The FDA approved each of the following drugs with a companion diagnostic:  Zelboraf (vemurafenib) — “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  Tafinlar (dabrafenib) — “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  Mekinist (trametinib) — “MEKINIST is a kinase inhibitor indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. MEKINIST is indicated, 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 and the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detecetd by an FDA- approved test, and involvement of lymph node(s), following complete resection. Limitation of use: MEKINIST is not indicated for treatment of patients who have progressed on prior BRAF-inhibitor therapy.” 6 a

 Cotellic (cobimetinib) — “COTELLIC is a kinase inhibitor indicated for the m

treatment of patients with unresectable or metastatic melanoma with a BRAF o

V600E or V600K mutation, in combination with vemurafenib. Limitation of use: n

COTELLIC is not indicated for treatment of patients with wild-type BRAF a l melanoma.” 7 e M

Criteria

Testing may be considered in individuals who meet the following criteria: F A  Individual has been diagnosed with metastatic or unresectable melanoma, AND R B

400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com

Lab Management Guidelines v2.0.2019

 At least one of the following treatments is being considered: Zelboraf® (vemurafenib), Tafinlar® (dabrafenib), Mekinist® (trametinib) in combination with Tafinlar® (dabrafenib), or Zelboraf® (vemurafenib) in combination with Cotellic® (cobimetinib), AND  BRAF V600 testing has not been performed previously

References

Introduction

These references are cited in this guideline.

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. Revised Nov 2017. 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: NCCN Clinical Practice Guidelines in Oncology. Melanoma (v.2.2018). Available at http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. 5. Dabrafenib (Tafinlar® ) prescribing information. Revised Jan 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf. 6. Trametinib (Mekinist® ) prescribing information. Revised May 2018. Available at: http://www.pharma.us.novartis.com/product/pi/pdf/mekinist.pdf. 7. Cobimetinib (Cotellic® ) prescribing information. Revised Nov 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf. a m o n a l e M

F A R B

400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com