Clinical Policy: Pharmacogenetic Testing Reference Number: CP.MP.HN348

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1 Clinical Policy: Pharmacogenetic Testing Reference Number: CP.MP.HN348 Effective Date: 6/07 Last Review Date: 5/17 Coding Implications Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Pharmacogenetic tests are laboratory tests performed for the purpose of determining how an individual s genetic factors may predict a response to specific medications and the effectiveness of treatment. The goal of pharmacogenomics testing is to reduce the incidence of adverse medication reactions while improving an individual s positive response to the medication. Policy/Criteria I. It is the policy of Health Net of California that the following tests are considered medically necessary as noted: Test HLA-B*5701 allele HLA-B* 1502 Genotyping for CYP2C19 polymorphisms BRAF V600E mutation (e.g., the Cobas 4800 BRAF mutation test) BRAF V600E and/or V600K mutations (e.g., the THxID BRAF test MGMT (0-6-methylguanine- DNA methyltransferase) gene methylation assay Anaplastic lymphoma kinase (ALK) gene rearrangement testing [e.g., the Vysis ALK Break Apart FISH Probe Kit; Ventana ALK (D5F3) CDx Assay] Indication Prior to initiation of abacavir (Ziagen; ABC) For persons of Asian ancestry before commencing treatment with carbamazepine (Tegretol). One time, in individuals being considered for treatment with clopidogrel (Plavix) or currently receiving clopidogrel When considering vemurafenib (Zelboraf) for the treatment of unresectable or metastatic melanoma. For individuals with unresectable or metastatic melanoma who are being considered for treatment with either dabrafenib* (Tafinlar) or trametinib** (Mekinist). For predicting response to the chemotherapeutic agent temozolomide (i.e., Temodar) in individuals with glioblastoma For metastatic Non-Small Cell Lung Cancer (NSCLC) for prediction of response to crizotinib (Xalkori) and ceritinib (Zykadia) II. It is the policy of Health Net of California that any of the following pharmacogenetic testing (pharmacogenomic profiling) are considered investigational, because although there are ongoing studies, the efficacy and clinical value have not been established A. Genotyping for other cytochrome P450 polymorphism (including genetic testing panels that include multiple CYP450 mutations) other than noted CYP2C9, CPY450, Page 1 of 14

2 CYP3A4, CYP2D6, and VKORC1) to determine reduced/enhanced effect or severe side effects of drugs metabolized by the cytochrome P450 system such as opoid analgeics, warfarin, tamoxifen, proton pump inhibitors, beta blockers, antipsychotic medications, and selective serotonin reuptake inhibitors; B. For genotyping panels (e.g., GeneSight Psychotropic, PsychiaGene, YouScript Psychotropic, Mental Health DNA Insight, STA2R SureGene GeneSightRx or PHARMAchip assay genotyping, Genecept Assay): CYP450, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, HTR2A, and SCL6A4 to help guide administration of antidepressants and antipsychotics (e.g. poor response to treatment, adverse side effects) and treatment recommendations for patients with neuropsychiatric disorders; C. Invader UGT1A1 molecular assay to determine the proper dosage of irinotecan for persons with cancer (e.g., colorectal,); D. Genotyping for apolipoprotein E (Apo E) to determine therapeutic response to lipidlowering medications; E. Genotyping for methylenetetrahydrofolate reductase (MTHFR) to determine therapeutic response to antifolate chemotherapy; F. For Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) testing in patients with chronic hepatitis C virus (HCV) genotype 1 being considered for treatment with triple therapy (i.e., pegylated interferon alpha (PegIFN), ribavirin (RBV), and a protease inhibitor); G. For Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) testing in patients with chronic hepatitis C virus (HCV) genotype 2 or 3 being considered for treatment with pegylated interferon alpha (PegIFN), ribavirin (RBV), with or without a protease inhibitor; H. For the use of HLA-B*1502 genotyping in patients of other ethnicities (non-asian) for whom treatment with carbamazepine (Tegretol), or with phenytoin (Dilantin) is being considered; I. For the use of HLA-B*1502 genotyping in patients for whom treatment with lamotrigine (Lamictal) is being considered; J. For the use of genotyping for HLA-B variants other than HLA-B*1502 in patients for whom treatment with carbamazepine (Tegretol), phenytoin (Dilantin), or lamotrigine (Lamictal) is being considered. K. The Comprehensive Personalized Medicine Panel L. Cyp3A4 genotyping for Ivacaftor metabolism and toxicity in the clinical care of patients with cystic fibrosis. M. Genoyping for statin associated myopathy (i.e., SLCO1B1 testing) Background Even though it is practically impossible to determine the contribution of all factors that affect drug response, pharmacogenetic studies on inter-individual polymorphisms (i.e. nucleotide mutations, insertions, repeats and deletions) of genes that code for drug-metabolizing enzymes and drug targets (e.g. cytochrome P450 mono-oxygenase and its subtypes, N-acetyl transferase Page 2 of 14

3 (NAT), genes creating 'slow' and 'fast' metabolizers, etc) have been able to show that these account for a significant proportion of the heterogeneous response to medicines that is observed across populations. Variability in drug response is, therefore, at least in part inherited and is likely to be associated with patterns of multiple polymorphically expressed traits, rather than with single causative polymorphisms. It is, therefore, to a certain extent predictable through pharmacogenomics, which is the study that investigates the inherited basis of such different responses to drugs. Drug response may, however, also depend significantly on the cause, severity and course of the condition being treated and may be influenced by concomitant medications and drug interactions, by patient age, sex and organ function, lifestyle (e.g. smoking, alcohol consumption), education, socioeconomic status, environmental factors and accompanying illnesses. Many of these factors are difficult to control for and are likely to be affected, at least in some parts of the world, by a person's ethnic background. Apolipoprotein E (Apo E), a member of the apolipoprotein gene family, is essential in the formation of very low-density lipoprotein (VLDL) and chylomicrons. Among the variants of this gene, alleles e2, e3, and e4 are the common polymorphism found in most populations. However, the available evidence in peer-reviewed studies of Apo E genotype (e2, e3, and e4) and statin treatment has not determined that genotyping for Apo E has shown improvements in clinical management of hypercholesterolemia patients. Additional data in randomized controlled studies on the benefits, potential adverse effects, and efficacy on patients from subsequent therapeutic management after pharmacogenetic testing for the three Apo E genotypes, is necessary. Cytochrome P450, subfamily IIC, polypeptide 9 (CYP2C9) and Vitamin K epoxide reductase subunit protein 1 (VKORC1) are two genes that together with environmental factors could partly explain the inter-individual variation in warfarin dose requirements. Three single nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one in the VKORC1 gene, have been found to play key roles in determining the effect of warfarin therapy on coagulation. Although studies have shown that genetic polymorphisms in CYP2C9 and VKORC1 may affect warfarin dosing, additional randomized controlled trials are necessary to link the use of pharmacogenomic testing to improvements in clinical outcomes. SLCO1B1 variants have been the most studied in statin metabolism, however, other genes have also been studied, including ABCB1, which encodes ATP-binding cassette (ABC) transporters subfamily B member 1 (ABCB1/P-glycoprotein 1), ABCG2, which encodes ABC transporters subfamily G member 2 (ABCG2/breast cancer resistance protein), and the coenzyme Q2 (COQ2) homolog gene. Guidelines from the American College of Cardiology/American Heart Association, "2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults" do not address statin myopathy genotyping. The guideline recommends that creatine kinase (CK) should not be routinely measured in individuals receiving statin therapy. (A strong recommendation). Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events because of a personal or Page 3 of 14

4 family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy.(e-expert Opinion). They also note that during statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. (E- Expert Opinion). The guideline provides a management algorithm to evaluate and treat muscle symptoms. The Comprehensive Personalized Medicine Panel is a pharmacogenetic test that assays variants in 19 genes, including CYP1A2 and CYP2D6, as well as CYP3A4, CYP3A5, and others, and uses this information to predict patient response to medications. Although there are many studies investigating the impact of variants in individual genes on response to individual drugs, there are no published studies evaluating the use of variant information for the set of genes included in the Comprehensive Personalized Medicine Panel to predict patient response to drugs. Therefore, it is currently not possible to assess the impact of using this test in patient care. The STA2R SureGene Test is a pharmacogenetic test that assays variants in 7 genes, including CYP1A2, CYP2C19, and CYP2D6, as well as the serotonin receptor (SLC6A4) gene, the sulfotransferase 4A1 (SULT4A1) gene, CYP3A4, and CYP3A5, and uses this information to predict patient response to a large number of antidepressant and antipsychotic drugs (click here). Although there are many studies investigating the impact of variants in individual genes on response to individual drugs, there is a paucity of peer-reviewed studies evaluating the use of variant information for the 7 genes included in the STA2R SureGene Test to predict patient response to a wide range of antidepressant and antipsychotic drugs. Therefore, the impact of using this test in the care of patients being prescribed antidepressant or antipsychotic drugs cannot be determined at this time. Genetic testing for detecting variants of the VKORC1 genes is available to help clinicians assess whether a patient may be especially sensitive to warfarin, and require a lower starting dose; they also test for genetic variants in CYP2C9 that influence warfarin metabolism. However, routine genotyping of patients prior to starting warfarin is not widely accepted or recommended in guidelines from the American College of Chest Physicians because of the limited evidence from prospective randomized trials that pharmacogenetic-based individualized dosing improves clinical outcomes. Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype. Genetic polymorphism of the UGT1A1 gene is related to severe toxicity caused by the drug, such as leukopenia and diarrhea. In order to identify the group of patients with aberration of the UGT1A1 gene who will need a reduced dose of irinotecan, a pharmacodiagnostic test was developed (Invader UGT1A1 Molecular Assay). National Cancer Comprehensive Network (NCCN) Guidelines Version for Colon Cancer state the following: Page 4 of 14

5 Irinotecan should be used with caution in patients with Glbert s disease or elevated serum bilirubin. There is a commercially available test for UGT1A1. Guidelines for the use has not been clinically established. Peer-reviewed studies regarding the use of UGT1A1 molecular assay to determine the proper dosage of irinotecan for individuals with colon cancer, are ongoing. However, efficacy and long-term outcomes have not been determined. Additional studies are necessary. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating intracellular folate levels, which in turn affects DNA synthesis and methylation. Two MTHFR gene polymorphisms, C677T and A1298C, influence the metabolism of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. Several studies have shown these two polymorphisms may reduce cancer susceptibility and increase drug-related toxicity when folate antagonists (e.g., methotrexate, fluorouracil) are utilized, but data are inconsistent and contradictory. According to the National Cancer Institute, 5 of 6 patients who experienced grade-4 toxicity in their first cycle of adjuvant chemotherapy with cyclophosphamide, methotrexate and fluorouracil (5-FU) for early breast cancer had the variant C677T MTHFR genotype. Studies have shown that MTHFR polymorphisms may affect the sensitivity to antifolate chemotherapy however, there is insufficient evidence of its clinical effectiveness. Polymorphisms in the IL28B gene, which encodes interferon lambda 3, effectively predicted responses to treatment with interferon-based therapies and accounted for a significant proportion of the differential response observed in patients of certain races, such as patients of African descent In contrast, neither non-cc IL28B genotype nor race has consistently been associated with lower SVR rates in multiple trials and cohort studies of contemporary DAA combination regimens. Although some studies have suggested a limited impact of IL28 genotype or race on SVR rates with DAA regimens [the magnitude of the impact is small when appropriate regimens are used and not sufficient enough to recommend IL28B genotype testing in routine clinical practice. HLA-B is a human gene that plays a critical role in the immune system, and is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by viruses or bacteria. The HLA- B gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign invaders. Hundreds of versions, or alleles of HLA-B are known, each of which is given a particular number (i.e., HLA-B 1502). It was discovered that some reactions to aromatic antiepileptic drugs (AEDs) are associated with specific variants in the human leukocyte antigen (HLA) genes. The HLA genes encode cell surface proteins that function in immune response. The most common HLA allele, or version of an HLA gene, linked to the development of ADRs in patients taking aromatic AEDs, is the HLA- B*1502 allele. The HLA-B*1502 allele is most common among individuals from Southeast Page 5 of 14

6 Asia. It is significantly less common among Japanese and Korean individuals, and is essentially absent in those of European, African, and Hispanic descent. Per the U.S. FDA site, The risk of Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) from carbamazepine and other aromatic anticonvulsants (eg, phenytoin, phenobarbital) is significantly increased in patients positive for the HLA-B*1502 allele. This allele is found almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Due to wide variability in rates of HLA-B*1502 even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry, screening for HLA-B*1502 should be performed for most patients of Asian ancestry. Kalydeco (i.e., generic name ivacaftor) received FDA approval on January 31, 2012, for the treatment of cystic fibrosis related symptoms in patients with the p.gly551asp variant in the cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7) (CFTR) gene. On March 3, 2015, the FDA includes expanded indications for genetic testing to detect the presence of other additional CFTR variants. The FDA also states that some in vitro studies have suggested that drug interactions may occur with CYP3A enzyme inducers or inhibitors, but there is no indication that cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) genotyping should be performed. The main evidence deficiencies for CYP3A4 genotyping for ivacaftor metabolism and toxicity are insufficient data on analytical validity, clinical validity, and clinical utility. There is currently insufficient published peer-reviewed evidence to evaluate the impact of using CYP3A4 genotyping in the clinical care of patients with cystic fibrosis prescribed ivacaftor. It is therefore considered investigational at this time. Coding Implications This clinical policy references Current Procedural Terminology (CPT ). CPT is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2015, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. CPT Codes Description Tier 1 Molecular Pathology CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17) CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, Page 6 of 14

7 CPT Codes Description drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6) FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; internal tandem duplication (ITD) variants (i.e., exons 14, 15) FLT3 (fms-related tyrosine kinase 3) (e.g., acute myeloid leukemia), gene analysis; tyrosine kinase domain (TKD) variants (e.g, D835, I836) MGMT (0-6-mrthylguanine-DNA methyltransferase (eg. Glioblastoma multiforme), methylation analysis MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis PCA3/KLK3 (prostate cancer antigen 3[non-protein coding]/kallilrein-related peptidase 3 [prostate specific antigen]) ratio (e.g, prostate cancer) HLA-A, -B, and DRB1 (e.g., verification typing) HLA Class 11 typing, low resolution. One locus (e.g, HLA-DRB1, - DRB3/4/5, -DQB1, -DQA1, -DPB1, OR DPA1), each Molecular pathology procedure, Level 1 (e.g., identification of single germline variant [e.g, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) Molecular pathology procedure, Level 2 (e.g., 2-10 SNPS, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) Molecular pathology procedure, Level 3 (e.g., >10 SNPs, 2-10 methylated variants, or 2-10 somatic variants, [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity (LOH), uniparental disomy (UPD]) Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons), regionally targeted cytogenomic array analysis Molecular pathology procedure, Level 7 (e.g., analysis of exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, cytogenomic array analysis for neoplasia) Molecular pathology procedure, Level 8 (e.g., analysis of exons by DNA sequence analysis, mutation scanning or duplication/deletion variants Page 7 of 14

8 CPT Codes Description of >50 exons, sequence analysis of multiple genes on one platform) Molecular pathology procedure, Level 9 (e.g., analysis of >50 exons in a single gene by DNA sequence analysis Unlisted microbiology procedure HCPCS Codes G9143 Description Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s) ICD-10-CM Diagnosis Codes ICD-10-CM Description Code B2Ø Human immunodeficiency virus [HIV] disease C17-C17.9 Malignant neoplasm of colon C22-C22.9 Malignant neoplasm of liver and intrahepatic bile ducts C34-C34.92 Malignant neoplasm of bronchus and lung I I25.9 Chronic ischemic heart disease Z21 Asymptomatic human immunodeficiency virus [HIV] infection status Z79.Ø1 Long term (current) use of anticoagulants Z79-Z Long term current drug therapy Z Long term (current) use of opiate analgesic Z Other long term (current) drug therapy Reviews, Revisions, and Approvals Date Approval Date HLA-B*5701 allele prior to initiation of abacavir (Ziagen; ABC) therapy as medically necessary to reduce the risk of hypersensitivity reaction. Added genotyping for HLA-B* 1502 as medically necessary for persons of Asian ancestry before commencing treatment with carbamazepine (Tegretol). 8/08 Page 8 of 14

9 Reviews, Revisions, and Approvals Date Approval Date Update. Added FDA-approved test (e.g., the THxID BRAF test) as 3/14 medically necessary for detecting mutation of the BRAF gene (V600E or V600K) in persons with unresectable or metastatic melanoma who are being considered for treatment with either dabrafenib (Tafinlar) (Tafinlar) or trametinib (Mekinist)(Mekinist). (NCCN Category 1 recommendation) Added MGMT, gene methylation assay as medically necessary for predicting response to the chemotherapeutic agent temozolomide for glioblastoma, aged 70 years or younger, with a good PS (KPS>70). (NCCN Category 1 recommendation). Codes updated. Added pharmacogenetic testing as investigational for the following: 5/14 HLA-B*1502 genotyping in patients of other ethnicities (non-asian) for whom treatment with carbamazepine (Tegretol), or with phenytoin (Dilantin) is being considered; HLA-B*1502 genotyping in patients for whom treatment with lamotrigine (Lamictal) is being considered; Genotyping for HLA-B variants other than HLA-B*1502 in patients for whom treatment with carbamazepine (Tegretol), phenytoin (Dilantin), or lamotrigine (Lamictal) is being considered. Codes updated. Added SureGene Test for Antipsychotic and Antidepressant Response 2/15 (STA2R), GeneSightRx and PHARMAChip as investigational. Codes updated. Added Comprehensive personalized Medicine Panel as investigational 4/15 since there is a paucity of peer reviewed studies to evaluate the genes in this panel and to predict patient responses to the drugs. Codes reviewed. Update Added anaplastic lymphoma kinase (ALK) gene 5/15 rearrangement testing in NSCLC, for prediction of response to crizotinib and ceritinib therapy in ALK-positive NSCLC patients, as medically necessary. Added Genecept Assay as investigational to assist in making treatment recommendations for patients with neuropsychiatric disorders, since there is a paucity of peer reviewed literature. Codes updated. Added Cytochrome P450 (CYP450) genotyping to predict response to 6/15 antidepressant and antipsychotic medications as investigational since the evidence supporting the clinical validity is limited. Additional peer reviewed studies are necessary. Added CYP3A4 genotyping for patients with cystic fibrosis prescribed ivacaftor, as investigational since there is a paucity of peer reviewed studies to support this. Update Added Genoyping for statin associated myopathy (i.e., 4/16 SLCO1B1 testing) as investigational. References 1. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer: Page 9 of 14

10 2. Agency for Healthcare Research and Quality (AHRQ). Testing of CYP2C19 variants and platelet reactivity for guiding antiplatelet treatment. Draft Comparative Effectiveness Review. Rockville, MD: AHRQ; Amstutz U, Ross CJ, Castro-Pastrana LI, et al.; CPNDS Consortium. HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin Pharmacol Ther. 2013;94 (1): Azer MF, Menzies AM, Haydu LE, et al. Patterns of Response and Progression in Patients with BRAF-mutant Melanoma Metastatic to the Brain treated with Dabrafenib (Tafinlar). Cancer: Berm EJ, Looff Md, Wilffert B, et al. Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature. PLoS One Jan 11;11(1):e Blue Cross Blue Shield Technology Evaluation Center. CYP2D6 pharmacogenomics of tamoxifen treatment. TEC Assessment Program January. Volume 28, No. 8. Available at: 7. Chang KL, Weitzel K, Schmidt S. Pharmacogenetics: Using Genetic Information to Guide Drug Therapy. Am Fam Physician Oct 1;92(7): Clinicaltrial.gov. A Study Comparing Trametinib (Mekinist)and Dabrafenib (Tafinlar) Combination Therapy to Dabrafenib (Tafinlar) Monotherapy in Subjects With BRAFmutant Melanoma. Clinicaltrial.gov identifier: NCT August 22, Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. Clin Pharmacol Ther Jan Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2012; 91: Ferrari M, Guasti L, Maresca A, et al. Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2. Eur J Clin Pharmacol May;70(5): Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 2012;367(18): Flaherty, KT, Robert, C, Hersey, P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med Jul 12;367(2): Frederick DT, Piris A, Cogdill AP, et al. (2013) BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma. Clinical Cancer Research 19: doi: / ccr Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenet Genomics. 2014;24(2): Gusti R. Bope & Kellerman: Conn's Current Therapy 2013, 1st ed Saunders, An Imprint of Elsevier. Cystic Fibrosis. 17. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib (Tafinlar) in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet Jul 28;380(9839): Page 10 of 14

11 18. Hayes. Genetic Test Evaluation (GTE) Overview. Cytochrome P450 3A5 (CYP3A5) Testing for Predict Response to Tacrolimus. November 16, Updated December 4, Hayes. Genetic Test Evaluation (GTE). BRAF p.val600glu Testing in Papillary Thyroid Carcinoma for Papillary Thyroid Carcinoma. May 1, Updated March 13, Hayes. GTE Overview. Anaplastic Lymphoma Kinase (ALK) Gene Rearrangement Testing in Non-Small Cell Lung Cancer (NSCLC). June 18, Hayes. GTE Overview. BRAF p.val600glu (V600E) and p.val600lys (V600K) Testing for Trametinib (Mekinist) and Dabrafenib (Tafinlar) Combination Therapy in Melanoma. January 29, Updated February 12, Hayes. GTE Overview. BRAF p.val600glu (V600E) and p.val600lys (V600K) Testing for Trametinib (Mekinist). Monotherapy in Melanoma. January 29, Updated December 18, Hayes. GTE Overview. BRAF p.val600glu (V600E) Testing for Dabrafenib (Tafinlar) Monotherapy in Melanoma. January 29, Updated January 15, Hayes. GTE Overview. Comprehensive Personalized Medicine Panel. March 12, Hayes. GTE Overview. CYP3A4 Genotyping for Ivacaftor Metabolism and Toxicity. May 21, Hayes. GTE Overview. Cytochrome P450 (CYP450) Genotyping to Predict Response to Antidepressant and Antipsychotic Medications. May 14, Hayes. GTE Overview. HLA-B Testing for Guidance of Treatment with Anticonvulsant Drugs. April 15, Hayes. GTE Overview. STA2R SureGene Test for Antipsychotic and Antidepressant Response. January 15, Hayes. GTE Synopsis. GTE Synopsis. BRAF Testing to Predict Response to Vemurafenib in Malignant Melanoma. July 6, Updated April 23, Updated March 24, Hayes. GTE Synopsis. The Genecept Assay. December Update April Hocum BT, White JR Jr, Heck JW, et al. Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. Am J Health Syst Pharm Jan 15;73(2): Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010; 56(2): Innocenti F, Schilsky RL, Ramírez J, et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol Aug 1;32(22): doi: /JCO Epub 2014 Jun Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013;94(3): Liu X, Cheng D, Kuang Q, et al. Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians. Pharmacogenomics J Mar 26. doi: /tpj [Epub ahead of print] Page 11 of 14

12 36. Martin MA, Klein TE, Dong BJ, et al. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing. Clin Pharmacol Ther 2012; 91: Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16): Meini G, Dello Russo C, Allice T, et al. First external quality assurance program of the Italian HLA-B*57:01 Network assessing the performance of clinical virology laboratories in HLA-B*57:01 testing. J Clin Virol May;78: National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Colon Cancer. Version Updated Version Updated Version Updated Version Update National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Melanoma. Version Updated Version Updated Version Update National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Thyroid Cancer. Version Updated Version Updated Version National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Central Nervous System Cancers. Version Updated Version Update National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version Non-Small Cell Lung Cancer. Updated Version Updated Version Updated Version Update Nirken MH, High WA, Roujeau JC, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. April 15, O'Connor SA, Hulot JS, Silvain J, et al. Pharmacogenetics of clopidogrel. Curr Pharm Des Jun 19. [Epub ahead of print] 46. Pallet N, Etienne I, Buchler M, et al. Long-term clinical impact of adaptation of initial tacrolimus dosing to CYP3A5 genotype. Am J Transplant Mar Ramsey BW. CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 3-NOV-2011; 365(18): Reese ES, Daniel Mullins C, Beitelshees AL, et al. Cost-Effectiveness of Cytochrome P450 2C19 Genotype Screening for Selection of Antiplatelet Therapy with Clopidogrel or Prasugrel. Pharmacotherapy Rosenson RS. Lipoprotein classification; metabolism; and role in atherosclerosis. UpToDate. October 12, Sánchez-Iglesias S, García-Solaesa V, García-Berrocal B, et al. Role of Pharmacogenetics in Improving the Safety of Psychiatric Care by Predicting the Potential Risks of Mania in CYP2D6 Poor Metabolizers Diagnosed With Bipolar Disorder. Medicine (Baltimore) Feb;95(6):e Shi C, Yan W, Wang G, et al. Pharmacogenetics-Based versus Conventional Dosing of Warfarin: A Meta-Analysis of Randomized Controlled Trials. PLoS One Dec 16;10(12):e Shore NJ, Robinson JG, Lichtenstein AH, et al ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Page 12 of 14

13 Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol. 2014;63(25_PA): Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther Jan;95(1): doi: /clpt Epub 2013 Oct 3. Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. Health Plan means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. Page 13 of 14

14 Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services. Note: For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy. Note: For Medicare members, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs, LCDs, and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at for additional information Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation. Page 14 of 14