FEP Medical Policy Manual

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1 FEP Medical Policy Manual FEP BRAF Gene Mutation Testing to Select Melanoma or Glioma Patients for Targeted Effective Date: October 15, 2017 Related Policies: None BRAF Gene Mutation Testing to Select Melanoma or Glioma Patients for Targeted Description BRAF and MEK inhibitors are drugs designed to target a somatic variant in the BRAF gene. The inhibitors were originally developed to be used in 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 retard significantly tumor growth and may improve patient survival. FDA REGULATORY STATUS In August 2011, vemurafenib (Zelboraf ; Roche/Genentech and Plexxikon) and a class III companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test (Roche), were coapproved by the U.S. Food and Drug Administration (FDA). The cobas 4800 BRAF V600 test was approved through the premarket approval process as an aid in selecting melanoma patients whose tumors carry BRAF V600 variants for treatment with vemurafenib.32 Vemurafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 variants. Vemurafenib s prescribing information states that confirmation of the BRAF V600 variants using an FDA-approved test is required to select patients appropriate for therapy. In May 2013, dabrafenib (Tafinlar ; GlaxoSmithKline) was approved by FDA through the new drug application process for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E variants, as detected by an FDA-approved test. Dabrafenib is specifically not indicated to treat patients with wild-type BRAF melanoma. In May 2013, trametinib (Mekinist ; GlaxoSmithKline) was approved by FDA through the new drug application process for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K variants, as detected by an FDA-approved test. Trametinib is specifically not indicated to treat patients who previously received BRAF inhibitor therapy. The companion diagnostic test coapproved for both dabrafenib and trametinib is the THxID BRAF kit (biomérieux). The kit is intended as an aid in selecting melanoma patients whose tumors carry the BRAF V600E variants for treatment with dabrafenib and as an aid in selecting melanoma patients whose tumors carry the BRAF V600E or V600K variants for treatment with trametinib. Original Policy Date: March 2012 Page: 1

2 Effective Policy Date: October 15, 2017 Page: 2 of 7 In January 2014, the combination of dabrafenib (Tafinlar ) and trametinib (Mekinist ; both GlaxoSmithKline) were approved by FDA through the accelerated approval process for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K variants, 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 (see Rationale section).16,18 Continued approval is contingent on results from a phase 3 trial comparing combination therapy with dabrafenib monotherapy in patients with metastatic or unresectable melanoma. In December 2015, cobimetinib (Cotellic ; Genentech) was approved by FDA after priority review for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K variants, in combination with vemurafenib. POLICY STATEMENT Testing for BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma may be considered medically necessary to select patients for treatment with Food and Drug Administration- approved BRAF or MEK inhibitors (see Policy Guidelines section). Testing for BRAF V600 variants for all other patients with melanoma, including but not limited to use in patients with resectable melanoma, is considered investigational. Testing for BRAF V600 variants in patients with glioma to select patients for targeted treatment is considered investigational. POLICY GUIDELINES Vemurafenib, dabrafenib, trametinib, and cobimetinib are currently approved by the U.S. Food and Drug Administration (FDA) specifically to treat advanced BRAF-variant melanoma. There are no FDA-approved targeted therapies for BRAF V600 variant positive glioma. FDA-approved BRAF testing kits are intended to select melanoma patients for treatment with vemurafenib, dabrafenib, trametinib, and cobimetinib. Prescribing information for these drugs states that confirmation of BRAF V600 variants using an FDA-approved test is required for selection of patients with melanoma appropriate for therapy. Pivotal trials for vemurafenib, dabrafenib, trametinib, and cobimetinib have enrolled patients with unresectable, stage III or IV melanoma. BENEFIT APPLICATION Benefits are available for specialized diagnostic genetic testing when it is medically necessary to diagnose and/or manage a patient s existing medical condition. Benefits are not provided for genetic panels when some or all of the tests included in the panel are not covered, are experimental or investigational, or are not medically necessary. Experimental or investigational procedures, treatments, drugs, or devices are not covered (See General Exclusion Section of brochure). RATIONALE Summary of Evidence For individuals who have unresectable or metastatic melanoma who receive BRAF gene variant testing to select treatment with BRAF or MEK inhibitors, the evidence includes studies of analytic validity and

3 Effective Policy Date: October 15, 2017 Page: 3 of 7 randomized trials. Relevant outcomes are overall survival, disease-specific survival, and test accuracy. Studies of analytic validity have shown that BRAF variant testing kits have high concordance with the Studies of analytic validity have shown that BRAF variant testing kits have high concordance with the reference standard (Sanger sequencing). Randomized phase 3 trials of BRAF inhibitor therapy in patients selected on the basis of BRAF variant testing have shown improvements in overall survival and progression-free survival. Single-agent BRAF inhibitor treatment compared with nontargeted treatments have shown superior outcomes for most end points. Combination BRAF and MEK inhibitor treatment with vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown superior overall survival compared with either vemurafenib or dabrafenib alone. Data showing treatment effects in patients without BRAF variants do not exist; therefore, BRAF variant testing is required to identify patients to whom these trial results apply. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. For individuals who have glioma who receive BRAF gene variant testing to select treatment with BRAF or MEK inhibitors, the evidence includes small, prospective, uncontrolled studies and case reports. Relevant outcomes are overall survival, disease-specific survival, and test accuracy. Studies assessing the use of sorafenib in patients with newly-diagnosed and recurrent gliomas combined with various other treatments have not shown benefit, although most did not report BRAF V600 variant status. Evaluation of the BRAF and MEK inhibitors vemurafenib, dabrafenib, and trametinib in patients with gliomas has been limited to 1 phase 2 basket study, including 8 patients with glioma, case reports, and small case series. Early reports have suggested clinical benefit but confirmatory randomized controlled trials are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes. SUPPLEMENTAL INFORMATION Practice Guidelines and Position Statements National Comprehensive Cancer Network (NCCN) Guidelines for melanoma (v ) recommend BRAF-targeted therapy only for patients with V600 mutation of the BRAF gene, as documented by an FDA-approved [Food and Drug Administration] or CLIA-approved [Clinical Laboratory Improvement Amendments] facility. 8 Combination dabrafenib plus trametinib and combination vemurafenib plus cobimetinib therapies have a category 1 recommendation as a preferred regimen for advanced or metastatic melanoma. Vemurafenib and dabrafenib also have category 1 recommendations for advanced or metastatic melanoma. NCCN guidelines for central nervous system cancers (v ) does not discuss BRAF-targeted therapy for primary brain cancers. Not applicable. U.S. Preventive Services Task Force Recommendations Medicare National Coverage There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. REFERENCES 1. American Cancer Society. Cancer Facts & Figures research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed June 2, Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. Feb ;109(3): PMID

4 Effective Policy Date: October 15, 2017 Page: 4 of 7 3. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumabrefractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. Aug 2015;16(8): PMID Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. Apr ;33(10): PMID Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. Jan ;372(4): PMID Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. Jun ;364(26): PMID Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-ctla-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. Apr 2015;16(4): PMID National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Melanoma Version Accessed May 17, Vultur A, Villanueva J, Herlyn M. Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res. Apr ;17(7): PMID Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. Sep ;467(7315): PMID Sondergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39. PMID Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. Aug ;107(33): PMID Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. Jul ;70(13): PMID King AJ, Patrick DR, Batorsky RS, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB Cancer Res. Dec ;66(23): PMID Takle AK, Brown MJ, Davies S, et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. Jan ;16(2): PMID GlaxoSmithKline. Tafinlar (dabrafenib) capsules prescribing information, January Accessed August 13, Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8:67. PMID GlaxoSmithKline. Mekinist (trametinib) tablets prescribing information, January Accessed August 13, Genentech, Inc. Cotellic(r) (cobimetinib) highlights of prescribing information, May Accessed May 24, Central Brain Tumor Registry of the United States CBTRUS Fact Sheet. n.d.; Louis DN, Ohgaki H, Wiestler HOD, et al. WHO Classification of Tumours of the Central Nervous System. Revised. 4th ed. Lyon: WHO Press; Chien LN, Gittleman H, Ostrom QT, et al. Comparative brain and central nervous system tumor incidence and survival between the United States and Taiwan based on population-based registry. Front Public Health. 2016;4:151. PMID Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric lowgrade gliomas. Neuro Oncol. Jul 2010;12(7): PMID Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. Mar 2011;121(3): PMID Myung JK, Cho H, Park CK, et al. Analysis of the BRAF(V600E) mutation in central nervous system tumors. Transl Oncol. Dec 2012;5(6): PMID Zhang J, Wu G, Miller CP, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. Jun 2013;45(6): PMID

5 Effective Policy Date: October 15, 2017 Page: 5 of Horbinski C, Nikiforova MN, Hagenkord JM, et al. Interplay among BRAF, p16, p53, and MIB1 in pediatric lowgradegliomas. Neuro Oncol. Jun 2012;14(6): PMID Forshew T, Tatevossian RG, Lawson AR, et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. Jun 2009;218(2): PMID Behling F, Barrantes-Freer A, Skardelly M, et al. Frequency of BRAF V600E mutations in 969 central nervous system neoplasms. Diagn Pathol. Jun ;11(1):55. PMID Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. Feb 2014;50(3): PMID Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. Nov 2012;13(11): PMID Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) (May 3); Accessed June 5, Genentech, Inc. Zelboraf (vemurafenib) tablet prescribing information, March Accessed August 13, Blue Cross and Blue Shield Technology Evaluation Center (TEC). Special Report. Companion diagnostics: Example of BRAF testing to select patients with melanoma for BRAF kinase inhibitors. TEC Assessment Program. 2011;Volume 26:Tab Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med. Jan 2009;11(1):3-14. PMID Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. Jun ;364(26): PMID Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. Feb ;366(8): PMID Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. Aug ;363(9): PMID Luke JJ, Hodi FS. Vemurafenib and BRAF inhibition: a new class of treatment for metastatic melanoma. Clin Cancer Res. Jan ;18(1):9-14. PMID Halait H, Demartin K, Shah S, et al. Analytical performance of a real-time PCR-based assay for V600 mutations in the BRAF gene, used as the companion diagnostic test for the novel BRAF inhibitor vemurafenib in metastatic melanoma. Diagn Mol Pathol. Mar 2012;21(1):1-8. PMID Anderson S, Bloom KJ, Vallera DU, et al. Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed, paraffin-embedded tissue specimens of malignant melanoma. Arch Pathol Lab Med. 2012/11/ ;136(11): PMID 42. Food and Drug Administration. THxID -BRAF kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument - P BioMérieux labeling. 2013; Accessed August 13, Anwar MA, Murad F, Dawson E, et al. Immunohistochemistry as a reliable method for detection of BRAF-V600E mutation in melanoma: a systematic review and meta-analysis of current published literature. J Surg Res. Jun ;203(2): PMID O'Brien O, Lyons T, Murphy S, et al. BRAF V600 mutation detection in melanoma: a comparison of two laboratory testing methods. J Clin Pathol. Apr PMID Huang WK, Kuo TT, Wu CE, et al. A comparison of immunohistochemical and molecular methods used for analyzing the BRAF V600E gene mutation in malignant melanoma in Taiwan. Asia Pac J Clin Oncol. Dec 2016;12(4): PMID Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. Jul ;380(9839): PMID Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2): PMID Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. Aug ;386(9992): PMID

6 Effective Policy Date: October 15, 2017 Page: 6 of Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. Jan ;372(1): PMID Ascierto PA, McArthur GA, Dreno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)- mutant melanoma (cobrim): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. Sep 2016;17(9): PMID Food and Drug Administration (FDA). FDA Summary of Safety and Effectiveness Data (SSED): THxID BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument. 2013; Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. Nov ;371(20): PMID Amdahl J, Chen L, Delea TE. Network meta-analysis of progression-free survival and overall survival in first-line treatment of BRAF mutation-positive metastatic melanoma. Oncol Ther. 2016;4(2): PMID Devji T, Levine O, Neupane B, et al. Systemic therapy for previously untreated advanced BRAF-mutated melanoma: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncol. Mar ;3(3): PMID Pasquali S, Chiarion-Sileni V, Rossi CR, et al. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis. Cancer Treat Rev. Mar 2017;54: PMID Karajannis MA, Legault G, Fisher MJ, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. Oct 2014;16(10): PMID Hottinger AF, Aissa AB, Espeli V, et al. Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma. Br J Cancer. May ;110(11): PMID Galanis E, Anderson SK, Lafky JM, et al. Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. Clin Cancer Res. Sep ;19(17): PMID Zustovich F, Landi L, Lombardi G, et al. Sorafenib plus daily low-dose temozolomide for relapsed glioblastoma: a phase II study. Anticancer Res. Aug 2013;33(8): PMID Den RB, Kamrava M, Sheng Z, et al. A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas. Int J Radiat Oncol Biol Phys. Feb ;85(2): PMID Peereboom DM, Ahluwalia MS, Ye X, et al. NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme. Neuro Oncol. Apr 2013;15(4): PMID Lee EQ, Kuhn J, Lamborn KR, et al. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study Neuro Oncol. Dec 2012;14(12): PMID Hainsworth JD, Ervin T, Friedman E, et al. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme. Cancer. Aug ;116(15): PMID Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. Aug ;373(8): PMID National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version Accessed May 24, 2017.

7 Effective Policy Date: October 15, 2017 Page: 7 of 7 POLICY HISTORY Date Action Description March 2012 New December 2012 Revise Policy Policy and references updated with literature review, Policy statement modified to read FDA-approved BRAF inhibitors in place of vemurafenib. Added to Policy guidelines: Currently only vemurefenib has FDA approval for treatment of advanced melanoma. December 2013 Revise Policy Policy updated with literature review through August 2013, references 10-12, 14-15, 23-26, and 29 added; references 1, 13, and 30 updated. Policy statements modified to read, Testing for BRAFV600 mutations in place of Testing for the BRAFV600 mutation. December 2014 Revise Policy Policy updated with literature review through September 2, 2014, references were updated, and none were added. Policy statements were revised to align with current FDA approved indication, i.e., unresectable or metastatic rather than stage IIC or IV. September 2017 Revise Policy Policy updated with literature review through April 25, 2017; references 3-7,19-31, 43-45, 50-51, and added. Policy revised with updated genetics nomenclature. Information about additional FDA-approved BRAF inhibitor (nivolumab) added to policy. Policy statements regarding BRAF testing in melanoma unchanged. Information about FDA-approved MEK inhibitor (cobimetinib)added. New policy statement stating BRAF testing in glioma is investigational was added. Policy title changed to BRAF Gene Mutation Testing to Select Melanoma or Glioma Patients for Targeted.