Pharmacogenetic/Pharmacogenomic Testing And

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Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 1 of 19

PURPOSE: The purpose of this clinical policy is to provide guidelines for coverage of pharmacogenetic/ pharmacogenomic testing for heritable and somatic conditions, and serological testing for inflammatory conditions.

Please refer to the member’s benefit document for specific information. To the extent there is any inconsistency between this policy and the terms of the member’s benefit plan or certificate of coverage, the terms of the member’s benefit plan document will govern.

POLICY: Benefits must be available for health care services. Health care services must be ordered by a provider. Licensed Genetic Counselors may also order genetic tests if it is within the scope of practice of their state licensure. Health care services must be medically necessary, applicable conservative treatments must have been tried, and the most cost effective alternative must be requested for coverage consideration.

COVERAGE:

I. Requests for pharmacogenetic/pharmacogenomic testing - must satisfy the following:

A. A genetic counselor, medical geneticist, or other health care professional trained in genetics, independent of the laboratory performing the testing, has reviewed and documented family history, advised the member of the potential harms/benefits of the testing and implications of the test results, and obtained written formal consent; and [Note: Genetic counseling is not required for the following well-defined populations.]

B. After history, physical examination and completion of conventional diagnostic studies, a definitive diagnosis remains uncertain and a valid specific test exists for the suspected condition; and

C. Member is at direct risk of inheriting the mutation in question (presymptomatic), eg, based on family history or pedigree analysis; or

D. Member displays clinical features of a specific inheritable cancer/cancer syndrome (symptomatic). [Note: Members who have no knowledge of their genetic family history (such as, members who are adopted) will be considered to be at high risk.]

II. Characteristics of covered tests

A. Each test has been approved for its intended use by the appropriate regulatory/oversight body (implies analytic validity).

B. Each test has sufficient sensitivity or specificity (clinical validity) for targeting the member’s specific clinical condition.

C. The results of each test will directly impact clinical decision-making and clinical care (clinical utility) for the individual.

III. Requests for pharmacogenetic/pharmacogenomic testing and serological testing for inflammatory conditions are appropriate, for the member’s condition and indication stated in the table in Attachment A, based on the following:

A. Is a companion diagnostic or required test, as listed on the U.S. Food and Drug Administration (FDA) List of Cleared or Approved Companion Diagnostic Devices or on the package insert under Indications and Usage; or

B. Other reliable evidence.

EXCLUSIONS (not limited to): Refer to member’s Certificate of Coverage or Summary Plan Description.

I. The following tests are considered investigative (see Investigative List):

A. Inflammatory Bowel Disease (IBD), antibody marker testing to diagnose disease or to differentiate UC from Crohn’s. Includes but not limited to, ACCA, ALCA, AMCA, Anti-C, Anti- L, ANCA, ASCA, ASMA, anti-OmpC, anti-Cbir1, l2 antibodies, Prometheus IBD sgi Diagnostic panel

B. NOD2/CARD15 genetic testing to assess for complicated ulcerative colitis

C. Pharmacogenetic/pharmacogenomic testing for any of the following (Includes panel testing, such as but not limited to, AmpliChip™, GeneSight® ADHD, GeneSight® Analgesic, GeneSight® MTHFR, GeneSight®, Psychotropic, Millennium PGTSM, and YouScript® , Focused Pharmacogenomics Panel, Warfarin Response Genotype, INFINITI® Neural Response Panel, Psych HealthPGxPanel, Genomind Professional PGx Express™) • ABCB1 genotyping to determine drug metabolizer status for all drugs • ADRA2A genotyping to determine drug metabolizer status for all drugs • ANKK1 genotyping to determine drug metabolizer status for all drugs • BDNF genotyping to determine drug metabolizer status for all drugs • COMT genotyping to determine drug metabolizer status for all drugs • Cytochrome P450 (CYP450) genotyping to determine drug metabolizer status for all drugs except for the CYP2C19 variant used for clopidogrel (Plavix), CYP2D6 variants used for eliglustat (Cerdelga) in persons with Gaucher disease type 1, and CYP2D6 variants used for tetrabenazine (Xenazine) doses greater than 50mg per day • CYP3A4, CYP3A5 • DRD2 genotyping to determine drug metabolizer status for all drugs • FKBP5 genotyping to determine drug metabolizer status for all drugs • GRIK4 genotyping to determine drug metabolizer status for all drugs • HLA-A*31:01 genotyping to determine drug metabolizer status for all drugs • HLA-B*1502, 15:13 genotyping to determine drug metabolizer status for all drugs except for members of Asian ancestry before initiating treatment with carbamazepine (Tegretol) • HLA-B*5701 screening except for persons with HIV-1 before starting treatment with abacavir (Ziagen) • HTR1A genotyping to determine drug metabolizer status for all drugs • HTR2A genotyping to determine drug metabolizer status for all drugs • HTR2C genotyping to determine drug metabolizer status for all drugs Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 3 of 19

• MC4R genotyping to determine drug metabolizer status for all drugs • MTHFR genotyping for determining therapeutic response to antifolate chemotherapy and for guiding antidepressant therapy • OPRM1 genotyping to determine drug metabolizer status for all drugs • SLC6A4 genotyping to determine drug metabolizer status for all drugs • SLCO1B1 genotyping to determine drug metabolizer status for all drugs • TXNRD2 genotyping to determine drug metabolizer status for all drugs • UGT2B15 genotyping to determine drug metabolizer status for all drugs • VKOR1C genotyping to determine drug metabolizer status for all drugs

II. Direct-to-consumer testing

DEFINITIONS: Analytic Validity: How accurately and reliably the test measures the genotype of interest. A major component in the validation of an analytical technique is the technique's ability to accurately determine the presence of the substance it is seeking. It must measure the target substance without a great range of variation over a number of trials. The technique also must be proven to work reliably at multiple labs to be validated by this testing.

Clinical Utility: The evidence of improved measurable clinical outcomes, and its usefulness and added value to patient management decision-making compared with current management without the testing.

Clinical Validity: How consistently and accurately the test detects or predicts the intermediate or final outcomes of interest.

Companion Diagnostic: A companion diagnostic is a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product. The test helps a health care professional determine whether a particular therapeutic product’s benefits to patients will outweigh any potential serious side effects or risks. Companion diagnostics can: • identify patients who are most likely to benefit from a particular therapeutic product; • identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product; or • monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.

Cytochrome P450 (CYP450): Cytochrome P450 (CYP450) tests to help determine how your body processes (metabolizes) a drug. The human body contains P450 enzymes to process medications. Because of inherited (genetic) traits that cause variations in these enzymes, medications may affect each person differently.

Health care professionals trained in genetics: A genetics professional has experience and an educational background in genetics, counseling, and hereditary syndromes to provide accurate risk assessment and empathetic genetic counseling to patients and their families. Genetics professionals include people certified in any of the following ways: Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 4 of 19

• American Board of Genetic Counseling (ABGC) or American Board of Medical Genetics and Genomics (ABMGG) board certified/board eligible or a licensed genetic counselor • American College of Medical Genetics physician board certified in medical genetics • Advanced Practice Nurse in Genetics (APNG) • Advanced Genetics Nursing Certification (AGN-BC) credentialed through the American Nurses Credentialing Center (ANCC) • Genetics Clinical Nurse (GCN) • Advanced practice oncology nurse or physician assistant who is prepared at the graduate level with specialized education in cancer genetics and hereditary cancer predisposition syndromes • Board-certified/board-eligible physician with experience in cancer genetics • Board-certified specialty care physician with experience in the diagnosis and treatment of the hereditary condition, eg, cardiologist ordering genetic testing for hypertrophic cardiomyopathy • A registered nurse with specialized education in cancer genetics and hereditary cancer predisposition syndromes (defined as education resulting in a certification and undergoing ongoing continuing medical education in cancer genetics and hereditary cancer predisposition syndromes)

Next Generation Sequencing (NGS): Used to analyze specimens for the four main classes of genomic alterations (base substitutions, insertions and deletions, copy number alterations, and rearrangements)

Pharmacogenetics: The role of individual candidate genes (identified by approaches such as genome-wide associated studies [GWAS], genome wide-expression profiling, or methylation studies) to identify markers across the genome that affect drug metabolism, distribution, receptor targets, and biologic effect. Often used interchangeably with pharmacogenomics.

Pharmacogenomics: The study of the role of inherited and acquired genetic variation on drug response. Often used interchangeably with pharmacogenetics.

Regulatory/oversight body: Such as, but not limited to, Clinical Laboratory Improvement Amendments (CLIA), Food and Drug Administration (FDA) or The Joint Commission

Reliable Evidence: Reliable evidence shall mean consensus opinions and recommendations reported in the relevant medical and scientific literature, peer-reviewed journals, reports of clinical trial committees, or technology assessment bodies, and professional consensus opinions of local and national health care providers.

BACKGROUND: Pharmacogenomic influences on drug responses have traditionally been divided into four categories based upon the impact of genetic variability on the pharmacologic properties of a drug. • Effect on drug pharmacokinetics; an example is a genetic variant that alters drug metabolism, affecting plasma concentration. • Effects on pharmacodynamics; an example is a genetic variation that reduces binding of the drug to its receptor, thereby decreasing therapeutic efficacy. • Effects on idiosyncratic reactions, such as the likelihood of a hypersensitivity reaction to a certain drug. • Effects on disease pathogenesis or severity and response to specific therapies; these include specific molecular defects related to the pathogenesis of certain malignancies for which specific targeted therapies have been developed

Prior Authorization: Yes, per network provider agreement - for those marked with an *

REFERENCES: 1. Integrated Healthcare Services Process Manual: UR015 Use of Medical Policy and Criteria 2. Clinical Policy: MP/C009 Coverage Determination Guidelines 3. Clinical Policy: MP/L001 Laboratory Tests 4. Clinical Policy: MP/M001 Molecular Testing: Tumor/Neoplasm Biomarkers 5. US. Food and Drug Administration. In Vitro Diagnostics. Last Updated: 08/04/21. 6. Retrieved from https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved- companion-diagnostic-devices-vitro-and-imaging-tools Accessed 08-23-21. 7. Aetna. Clinical Policy Bulletin: Pharmacogenetic and Pharmacodynamic Testing. Last Review: 05/06/21. Retrieved from http://www.aetna.com/cpb/medical/data/700_799/0715.html Accessed 05- 18-21 8. Aetna. Inflammatory Bowel Disease: Serologic Markers and Pharmacogenomic and Metabolic Assessment of Thiopurine Therapy Clinical Policy Bulletin. Last Review 03/12/21. Retrieved from http://www.aetna.com/cpb/medical/data/200_299/0249.html Accessed 05-18-21. 9. Tantisira K, Weiss ST. Overview of pharmacogenomics.(Topic 2904, Version 64.0; last updated: 04/22/21) In: Tirnauer JS and Savarese DMF, eds. UpToDate. Waltham, Mass.: UpToDate; 2021. www.uptodate.com. Accessed 07-23-19. 10. Korf BR, Rehm, HL. New Approaches to Molecular Diagnosis. JAMA. 2013;309(14);1511-1521. 11. Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS). Realizing the potential of pharmacogenomics: opportunities and challenges. 2008 March. Department of Health and Human Services. Rockville (MD). 12. Centers for Disease Control and Prevention. Genomic Testing. ACCE Model List of 44 Targeted Questions Aimed at a Comprehensive Review of Genetic Testing. 2010. 13. Shackelford RE, Whitling NA, McNab P, Japa S, Coppola D. KRAS Testing A Tool for the Implementation of Personalized Medicine. Genes Cancer. 2012 July; 3(7-8): 459–466. 14. Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Associated Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. Gastroenterol. 2017;153:827-834. Retrieved from https://www.gastro.org/guidelines. Accessed 05-18-21. 15. National Comprehensive Cancer Network (NCCN) Guidelines. Anaplastic Gliomas/Glioblastoma. Version 5.2020, 04/15/21. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed 05-18-21. 16. Alecensa [package insert]. South San Francisco, CA: Genentech USA, Inc; 2021 17. Bosulif [package insert]. New York, NY: Pfizer; 2021 18. Braftovi [package insert]. Boulder, CO: Array BioPharma Inc; 2020 19. Cerdelga [package insert]. Waterford, Ireland: Genzyme Ireland, Ltd.; 2018 20. Cotellic [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2018 21. Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020 22. Iclusig [package insert]. Cambridge, MA: Takeda Pharmaceuticals Company Limited; 2020 23. Kalydeco [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2020 24. Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2021 25. Lynparza [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021 26. Mekinist [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 27. Mektovi [package insert]. Boulder, CO: Array BioPharma Inc; 2019 28. Orkambi [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2018 29. Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi; 2021 30. Rubraca [package insert]. Boulder, CO: Clovis Oncology, Inc.; 2020 31. Rydapt [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 7 of 19

32. Sprycel [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018 33. Talzenna [package insert]. New York, NY: Pfizer; 2020 34. Tafinlar [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 35. Tecentriq [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2021 36. Xenazine [package insert]. Deerfield, IL: Lundbeck; 2017 37. Zelboraf [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2020 38. Trikafta [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2020 39. Spinraza [package insert]. Cambridge, MA: Biogen; 2020 40. Zolgensma [package insert]. Bannockburn, IL: AveXis, Inc.; 2021 41. Ayvakit [package insert]. Cambridge, MA: Blueprint Medicines Corporation; 2020 42. Tegretol [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 43. Ziagen [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2020 44. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. American College of Gastroenterology. ACG Clinical Guideline. Ulcerative Colitis in Adults. Am J Gastroenterol 2019;114:384-413. Retrieved from https://journals.lww.com/ajg/Fulltext/2019/03000/ACG_Clinical_Guideline__Ulcerative_Colitis_in.10.a spx . Accessed 05-18-21. 45. American Gastroenterological Association (AGA). Institute Guidelines for the Identification, Assessment, and Initial Medical Treatment in Crohn’s Disease. Clinical Decision Support Tool. Retrieved from https://www.gastro.org/guidelines/ibd-and-bowel-disorders. Accessed 05-18-21. 46. American College of Gastroenterology. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol 2019;114:384-413. Retrieved from https://gi.org/guidelines/. Accessed 05-18-21. 47. American College of Gastroenterology. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol 2018;113:481-517; doi: 10.1038/ajg.2018.27. Retrieved from https://gi.org/guidelines/. Accessed 05-18-21. 48. Lorbrena [package insert]. New York, NY: Pfizer; 2021 49. Jemperli [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2021 50. Vitrakvi [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals; 2021 51. Tibsovo [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc.; 2019 52. Zejula [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2021 53. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2021 54. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2020 55. Imfinzi [package insert]. Wilmington, DE: AstraZeneca; 2021 56. Xospata [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2019 57. Papamichael K, Cheifetz AS, et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol and Hepatol. 2019;17:1655–1668. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661210/ Accessed 05-21-21. 58. Truseltiq [package insert]. Brisbane, CA: QED Therapeutics, Inc.; 2021

DOCUMENT HISTORY: Created Date: 09/16/13 Reviewed Date: 09/16/14, 09/16/15, 12/14/15, 06/22/16, 06/22/17, 04/24/18, 04/24/19, 04/24/20, 04/23/21 Revised Date: 06/17/14, 10/07/14, 5/19/15, 12/14/15, 06/22/16, 09/14/16, 09/12/17, 12/13/18, 11/14/19, 01/16/20, 02/19/20, 05/08/20, 06/10/20, 09/10/20, 05/17/21, 06/29/21, 08/23/21, 09/14/21

Attachment A Revised 08/23/21 Molecular Marker /Test Indication Coverage Criteria ALK

ALK protein expression by Drug eligibility Medically necessary for members who are Ventana ALK [D5F3] CDx considering Alecensa (alectinib), Lorbrena assay - tissue (lorlatinib), Xalkori (crizotinib) or Zykadia (ceritinib) for the treatment of non-small cell lung cancer (NSCLC)

ALK gene rearrangements Drug eligibility Medically necessary for members who are by Vysis ALK Break Apart considering Alunbrig (brigatinib) or Xalkori probe FISH Kit - tissue (crizotinib) for the treatment of non-small cell lung cancer (NSCLC)

ALK mutation Drug eligibility Medically necessary for members who are considering Opdivo (nivolumab)52 , Tecentriq (atezolizumab)30 or Yervoy (ipilimumab)53 No specific CPT code for the treatment of non-small cell lung

FDA CACDD cancer (NSCLC) *BCR/ABL1 and/or ABL1

BCR/ABL1 translocation Drug monitoring Medically necessary for monitoring and breakpoint analysis treatment of CML with TKIs and by MRDx Monitoring Test identification of CML patients in the chronic - blood phase being treated with Tasigna (nilotinib) CPT 0040U

BCR/ABL1 breakpoint Drug eligibility and monitoring Medically necessary for members who are fusion analysis - blood or considering, already on, or have a history of bone marrow treatment with Bosulif (bosutinib) for CPTs 81206, 81207, Philadelphia chromosome + (Ph+) CML12 ; 81208 0016U Gleevec (imatinib)16 , Iclusig (ponatinib)17, Sprycel (dasatinib)27 for Philadelphia ABL1 CPT 81170 chromosome + (Ph+) ALL or CML (Ph+)

FDA CACDD *BRAF

BRAF V600E and V600K Drug eligibility Medically necessary for members who are mutation by THxID BRAF considering treatment with Braftovi Kit - tissue (encorafenib) in combination with Mektovi (binimetinib), Mekinist (trametinib), or Tafinlar (dabrafenib) for the treatment of melanoma.

BRAF V600 mutation by Drug eligibility Medically necessary for members who are cobas 4800 BRAF V600 considering Cotellic (cobenitinib) in Mutation Test – tissue combination with Zelboraf (vemurafenib) or

Molecular Marker /Test Indication Coverage Criteria *BRAF (continued) Zelboraf alone, for the treatment of melanoma.

Therascreen BRAF V600E Drug eligibility Medically necessary for members who are RCQ PCR kit considering treatment with Braftovi (encorafenib) in combination with Erbitux (cetuximab) for treatment of colorectal cancer

BRAF Drug eligibility Medically necessary for members who are considering Zelboraf (vemurafenib)32 for the treatment of Erdheim-Chester disease

Medically necessary for members who are considering Mekinist (trametinib) 25 or Tafinlar (dabrafenib)33 for the treatment of non-small cell lung cancer

CPT 81210 Medically necessary for members who are 25 FDA CACDD considering Mekinist (trametinib) or Tafinlar (dabrafenib)33 for the treatment of anaplastic thyroid cancer (ATC) *BRCA

BRCA mutations by Drug eligibility Medically necessary for members who are BRACAnalysis CDx considering Lynparza (olaparib) or Talzenna (Myriad) - blood (germline (talazoparib) for the treatment of breast mutation) cancer

Medically necessary for members who are considering Lynparza (olaparib) or Rubraca (rucaprib) for the treatment of ovarian cancer Medically necessary for members are considering Lynparza (olaparib) for the treatment of pancreatic cancer

Medically necessary for members are considering Lynparza (olaparib) for the treatment of metastatic castration resistant prostate cancer (mCRPC)

BRCA mutations by Drug eligibility Medically necessary for members who are FoundationFocus considering Rubraca (rucaprib) for the CDxBRCA assay - tissue treatment of ovarian cancer

BRCA mutations by Drug eligibility Medically necessary as an aid in identifying Myriad myChoice CDx - ovarian cancer patients who are candidates tissue CPT 0172U Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 10 of 19

Molecular Marker /Test Indication Coverage Criteria *BRCA 1 (continued) for therapy with Lynparza (olaparib) or

Zejula (niraparib)

BRCA - tissue or blood Drug eligibility Medically necessary for members who are (germline) considering Lynparza (olaparib)24 or

32 Talzenna (talazoparib) for the treatment of breast cancer

Drug eligibility Medically necessary for members who are considering Rubraca (rucaprib)29 or Zejula 51 (niraparib) for the treatment of fallopian tube cancer

Drug eligibility Medically necessary members who are considering Rubraca (rucaprib)29 or Zejula CPTs 81162, 81163, 51 81164, 81165, 81166, (niraparib) for the treatment of primary peritoneal cancer 81167, 81212, 81215, 81216, 81217 Drug eligibility Medically necessary for members who are 29 considering Rubraca (rucaprib) for the

treatment of metastatic castration resistant FDA CACDD prostate cancer (mCRPC) CFTR F508del, G551D, Drug eligibility Medically necessary for members who are G1244E, G1349D, G178R, considering Kalydeco (ivacaftor)22 or G551S, R117H, S1251N, Orkambi (lumacaftor/ivacaftor)27 for the S1255P, S549N, and treatment of cystic fibrosis S549R mutations – blood

Trikafta (elexacaftor, tezacaftor and CFTR F508del Drug eligibility ivacaftor)37 for the treatment of cystic fibrosis CPT 81222

*C-Kit protein/CD 117 Drug eligibility Medically necessary for members who are antigen by Dako c-Kit considering Gleevec/Glivac (imatinib pharmDX assay - tissue mesylate) for the treatment of gastrointestinal stromal tumors (GIST) and CPT 81272 to aid in the differential diagnosis of GIST

FDA CACDD Cytochrome P450 (CYP) polymorphisms - blood Medically necessary for genotyping for CYP2C19 Drug metabolism CYP2C19 polymorphisms in members who CPT 81225 are considering Plavix (clopidogrel)28

CYP2D6 Drug metabolism Medically necessary for genotyping for CYP2D6 polymorphisms in members who have been prescribed treatment with Xenazine (tetrabenazine)35 in doses of greater than 50 mg per day Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 11 of 19

Molecular Marker /Test Indication Coverage Criteria Cytochrome P450 (continued)

CYP2D6 Drug eligibility Medically necessary for genotyping for CPTs 81226, 0070U, CYP2D6 polymorphisms in members who +0071U, +0072U, are considering Cerdelga (eliglustat)18 for the +0073U, +0073U, treatment of Gaucher disease type 1 +0074U, +0075U, +0076U

*EGFR

EGFR T790 mutation, Drug eligibility Medically necessary for testing of members exon 19 deletion or exon who are considering a tyrosine kinase 21 (L858R) substitution inhibitor, eg, Iressa (gefitinib), Gilotrif mutations by cobas EGFR (afatinib), Keytruda (pembrolizumab), Mutation Test v2 – tissue Tagrisso (osimertinib), Tarceva (erlotinib) or or blood Vizimpro (dacomitinib) for the treatment of non-small cell lung cancer (NSCLC)

EGFR T790 mutation, Drug eligibility Medically necessary for testing of members exon 19 deletion or exon who are considering Gilotrif (afatinib), Iressa 21 (L858R) substitution (gefitinib), Tagrisso (osimertinib), Tarceva mutations by therascreen (erlotinib) or Vizimpro (dacomitinib) for the EGFR RGQ PCR Kit – treatment of non-small cell lung cancer tissue or blood (NSCLC)

EGFR T790 mutation, Drug eligibility Medically necessary for members who are exon 19 deletion or exon considering Erbitux (cetuximab) or Vectibix 21 (L858R) substitution (panitumumab) for the treatment of mutations by DAKO EGFR colorectal cancer pharmDX assay - tissue Medically necessary for testing of members EGFR mutation Drug eligibility who are considering Tecentriq (atezolizumab)34 for the treatment of non- small cell lung cancer (NSCLC)

Medically necessary for testing of members who are considering Opdivo (nivolumab)52 or 53 CPT 81235 Yervoy (ipilimumab) for the treatment of

non-small cell lung cancer (NSCLC) FDA CACDD *EZH2 Medically necessary for members who are cobas EZH2 Mutation Test Drug eligibility considering treatment with Tazverik – tissue (tazemetostat) for the treatment of follicular lymphoma CPT 81236

FDA CACDD Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 12 of 19

Molecular Marker /Test Indication Coverage Criteria Fecal Calprotectin Disease management Medically necessary for the management of inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis) and for distinguishing inflammatory bowel diseases CPT 83993 from irritable bowel syndrome 7,44,45,46 Fecal Lactoferrin Disease management Medically necessary for distinguishing inflammatory bowel diseases (Crohn's disease, ulcerative colitis) from irritable bowel syndrome.7 CPT 83630, 83631 FGFR2 and FGFR3

Oncology (urothelial Drug eligibility Indicated for use as an aid in identifying cancer), RNA, analysis by urothelial cancer (UC) patients who harbor real-time RT-PCR of the these alterations and are therefore eligible FGFR3 (fibroblast growth for treatment with Balversa (erdafitinib) factor receptor 3) gene analysis (ie, p.R248C [c.742C>T], p.S249C [c.746C>G], p.G370C [c.1108G>T], p.Y373C [c.1118A>G], FGFR3- TACC3v1, and FGFR3- TACC3v3) utilizing formalin-fixed paraffin- embedded urothelial cancer tumor tissue, reported as FGFR gene alteration status tissue by therascreen FGFR RGQ RT-PCR Kit, QIAGEN, QIAGEN GmbH tissue

CPT 0154U FDA CACDD *FLT3

FLT mutations by Drug eligibility Medically necessary for members who are LeukoStrat CDx to detect considering Rydapt (midostaurin) or Xospata internal tandem duplication (gilterinib) for the treatment of acute (ITD) mutations and the myelogenous/myeloid leukemia (AML) tyrosine kinase domain mutations D835 and I836 in the FLT3 gene - blood or bone marrow CPT 0023U

Molecular Marker /Test Indication Coverage Criteria *FLT3 (continued)

FLT mutations by ITD Monitoring Medically necessary for members who MRD (minimal residual receiving treatment for acute disease) - blood or bone myelogenous/myeloid leukemia (AML) marrow CPT 0046U

FLT mutations - blood or Prognostic, drug eligibility or Medically necessary for members who are bone marrow monitoring diagnosed with, considering treatment, or receiving treatment for acute myelogenous/ CPTs 81245, 81246 myeloid leukemia (AML)

FDA CACDD *FIP1L1-PDGFRα fusion Drug eligibility Medically necessary for members who are kinase/ CHIC2 allele considering Gleevec (imatinib)20 for the deletion - blood treatment of hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia CPT 81401 (CEL)

*FoundationOne CDx by Drug eligibility Medically necessary for members who are Foundation Medicine for considering the following drugs for the detection of substitutions, corresponding cancer conditions insertion and deletion Breast cancer alterations (indels), and • Herceptin (trastuzumab) copy number alterations • Kadcyla (ado-trastuzumab) (CNAs) in 324 genes and • Perjeta (pertuzumab) select gene • Piqray (alpelisib) rearrangements, as well Cholangiocarcinoma as genomic signatures • Pemazyre (pemigatinib) including microsatellite • Truseltiq (infigratinib) instability (MSI) and tumor Colorectal cancer mutational burden (TMB) - • Erbitux (cetuximab) tissue • Vectibix (panitumumab)

Melanoma CPT 0037U • Cotellic (cobimetinib)

• Mekinist (trametinib) • Tafinlar (dabrafenib) • Zelboraf (vemurafenib) Non-small cell lung cancer (NSCLC) • Alecensa (alectinib) • Gilotrif (afatinib) • Iressa (gefinitnib) • Opdivo (nivolumab)52 • Tafinlar (dabrafenib) in combination with Mekinist (trametinib) • Tagrisso (osimertinib) • Tarceva (erlotinib) • Tecentriq (atezolizumab)30 Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 14 of 19

Molecular Marker /Test Indication Coverage Criteria *FoundationOne CDx • Trabecta (capmatinib) (continued) • Xalkori (crizotinib) • Yervoy (ipilimumab)53 CPT 0037U • Zykadia (ceritinib) Ovarian cancer • Lynparza (olaparib) • Rubraca (rucaparib) Primary peritoneal cancer • Rubraca (rucaparib) Prostate cancer, metastatic castration resistant

• Lynparza (olaparib)

• Rubraca (rucaparib)

Solid tumors (TMB≥ 10 mutations per

megabase)

• Keytruda (pembrolizumab) FDA CACDD Solid tumors (NTRK1/2/3 fusions) • Vitrakvi (larotrectinib) *FoundationOne Liquid Drug eligibility Medically necessary for members who are CDx by Foundation considering the following drugs for the Medicine – blood corresponding cancer conditions Breast cancer Utilizes circulating cell-free • Piqray (alpelisib) DNA (cfDNA) Non-small cell lung cancer (NSCLC)

• Alecensa (alectinib) • Iressa (gefitinib) • Tagrisso (osimertinib) or

• Tarceva (erlotinib)

• Trabecta (capmatinib)

Ovarian cancer • Rubraca (rucaparib)

Prostate cancer, metastatic castrate CPT 0239U resistant (mCRPC)

• Lynparza (olaparib) • Rubraca (rucaparib) FDA CACDD

*Guardant360 CDx Drug eligibility Medically necessary for members who are (Guardant Health) – blood considering Lumakras (sotorasib), Rybrevant (amivantamab-vmjw) or Tagrisso CPT 0242U (osimertinib) for the treatment of non-small FDA CACDD cell lung cancer (NSCLC)

HER-2/NEU Prognostication, drug Indicated as an aid in the assessment of eligibility patients for whom treatment is being considered for the cancer conditions listed Breast cancer • Herceptin (trastuzumab) Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 15 of 19

Molecular Marker /Test Indication Coverage Criteria HER-2/NEU (continued) • Kadcyla (ado-trastuzumab emtansine) CPTs 83950, 0009U • Perjeta (pertuzumab) Gastric and gastroesophageal cancer FDA CACDD • Herceptin (trastuzumab) HLA HLA-B*1502 Drug eligibility Indicated for persons of Asian ancestry before initiating treatment with Tegretol (carbamazepine)37

HLA-B*5701 Drug eligibility Indicated for persons with HIV-1 before initiating treatment with Ziagen (abacavir)42

HLA-B*58:01 Drug eligibility Indicated in Asian persons prior to 6 commencing allopurinol therapy CPTs 81370-81383 *IDH1 by Abbott RealTime Drug eligibility Medically necessary for members who are IDH1 R132 mutations considering Tibsovo (ivosidenib) for the (R132C, R132H, R132G, treatment of acute myeloid leukemia (AML) R132S, and R132L) - blood or bone marrow

CPT 81120

FDA CACDD *IDH2 by Abbott RealTime Drug eligibility Medically necessary for members who are for IDH2 mutations considering Idhifa (enasidenib) for the (R140Q, R140L, R140G, treatment of acute myeloid leukemia (AML) R140W, R172K, R172M, R172G, R172S, and R172W) - blood or bone marrow

CPT 81121 FDA CACDD LSI TP53 by Vysis CLL Drug eligibility Medically necessary for members who are FISH PROBE kit for considering Venclexta (venetoclax) for the detecting deletion of the treatment of B-cell chronic lymphocytic LSI TP53 probe target leukemia (CLL) (17p-) - blood

No specific CPT code FDA CACDD *KIT by D816V assay for Drug eligibility Medically necessary for members who are the kit d816v mutation - considering Gleevec (imatinib mesylate) for bone marrow the treatment of aggressive systemic CPT 81273 mastocytosis (ASM)

Molecular Marker /Test Indication Coverage Criteria *KRAS/NRAS codons 12 Drug eligibility Medically necessary for members who are and 13 mutations by cobas considering Erbitux (cetuximab) or Vectibix KRAS mutation test or (panitumumab) for the treatment of therascreen KRAS RGQ colorectal cancer PCR kit - tissue Medically necessary for members who are considering Lumakras (sotorasib) for the CPT 81275, 81311 treatment of NSCLC

FDA CACDD MGMT (O(6)- Drug metabolism Medically necessary for predicting response methylguanine-DNA to Temodar (temozolomide) for the methyltransferase) gene treatment of glioblastoma14 methylation assay- blood

CPT 81287

NCCN *Microsatellite Drug eligibility Medically necessary for members who are instability-high (MSH-H) considering Keytruda (pembrolizumab)23, for or mismatch repair (MMR) the treatment of solid tumors or colorectal genes - tissue cancer

Medically necessary for members who are considering Opdivo (nivolumab)52 or Yervoy (ipilimumab)53 for the treatment of colorectal CPT 81301 cancer

*Mismatch repair genes Drug eligibility Medically necessary for members who are MLH-1, PMS2, MSH2, considering Jemperli (dostarlimab-gxly) for MSH6, BRAF V600E the treatment of endometrial carcinoma Ventana MMR RxDx panel - tissue

CPT 81301

CACDD NUDT15 (nudix hydrolase Drug monitoring Medically necessary to identify member at 15) risk of thiopurine-induced toxicity prior to initiation of thiopurine therapy (i.e. azathioprine, mercaptopurine, or thioguanine)7

CPTs 0034U, 0169U

Molecular Marker /Test Indication Coverage Criteria *ONCO/Reveal DX Lung Drug eligibility Medically necessary for members who are & Colon Cancer Assay considering Erbitux (cetuximab) or Vectibix KRAS KRAS wild-type (panitumumab) for the treatment of (absence of mutations in colorectal cancer codons 12 and 13) EGFR Exon 19 deletions Medically necessary for members who are and Exon 21 L858R considering an EGFR Tyrosine Kinase substitution mutations – Inhibitor that is approved by the FDA for tissue NSCLC, such as but not limited to • Gilotrif (afatinib) • Iressa (gefitinib) • Tagrisso (osimertinib) No specific CPT • Tarceva (erlotinib)

• Vizimpro (dacomitinib FDA CACDD *Oncomine DX Target Drug eligibility Medically necessary for members who are Test considering Gavreto (pralsetinib), Iressa Single nucleotide variants (gefitinib), Tafinlar (dabrafenib) in (SNVs) and deletions in 23 combination with Mekinist (trametinib), or genes from DNA and Xalkori (crizotinib) for the treatment of non- fusions in ROS1, BRAF small cell lung cancer (NSCLC) V600E, ROS1 fusions and EGFR

L858R, Exon 19 deletions - tissue

CPT 0022U

FDA CACDD PD-L1

PD-L1 by IHC 22C3 Drug eligibility Medically necessary for members who are pharmDX - tissue considering Keytruda (pembrolizumab)23 or Libtayo (cemiplimab-rwlc) for the treatment of cervical cancer, esophageal squamous cell carcinoma (ESCC), gastric/ gastroesophageal junction (GEJ) adenocarcinoma, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC) or urothelial carcinoma

PD-L1 IHC 28-8 Drug eligibility Medically necessary for members who are pharmDX - tissue considering Opdivo (nivolumab)52 in combination with Yervoy (ipilimumab)53 for the treatment of non-small cell lung cancer (NSCLC) Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 18 of 19

Molecular Marker /Test Indication Coverage Criteria PD-LI (continued) Drug eligibility Medically necessary for members who are PD-L1 by Ventana SP142 considering Tecentriq (atezolizumab) for the CDx assay - tissue treatment of triple negative breast cancer, non-small cell lung cancer (NSCLC) or urothelial carcinoma

PD-L1 by Ventana SP263 Drug eligibility Medically necessary for members who are CDx assay - tissue considering Imfinzi (durvalumab)for the treatment of urothelial carcinoma54 No specific CPT

FDA CACDD *PDGFRα exon 18 Drug eligibility Medically necessary to determine eligibility mutation, including for Ayvakit (avapritinib)40 for gastrointestinal PDGFRA D842V stromal tumor (GIST) tissue

CPT 81314

PDGFRβ gene Drug eligibility Medically necessary for members who are rearrangement by considering Gleevec (imatinib) for the PDGFRβ FISH assay treatment of chronic myelomonocytic bone marrow leukemia of myelodysplastic syndrome/myeloproliferative disease No specific CPT (MDS/MPD)

FDA CACDD *PIK3CA

PIK3CA RGQ PCR Kit by Drug eligibility Medically necessary to detect the presence therascreen - tissue of one or more PIK3CA mutations in CPT 0155U members with breast cancer to determine if they are eligible for treatment with Piqray PIK3CA RGQ PCR Kit by (alpelisib) therascreen gene analysis of 11 gene variants - blood

CPT 0177U FDA CACDD *RAS detection of 56 Drug eligibility Medically necessary for members specific mutations in RAS considering Vectibix (panitumumab) for the genes [KRAS (exons 2, 3, treatment of colorectal cancer and 4) and NRAS (exons 2, 3, and 4)] by Praxis Extended RAS panel - tissue

CPT 0111U FDA CACDD Department of Origin: Effective Date: Integrated Healthcare Services 09/14/21 Approved by: Date Approved: Chief Medical Officer 09/03/21 Clinical Policy Document: Replaces Effective Clinical Policy Dated: Pharmacogenetic / Pharmacogenomic Testing and 09/03/21 Serologic Testing for Inflammatory Conditions Reference #: Page: MP/P013 19 of 19

Molecular Marker /Test Indication Coverage Criteria 6-MMPN13 Drug compliance and/or Medically necessary to monitor compliance 6-thioguanine nucleotide toxicity in those not responding to 6-mercaptopurine (6-TGN) & and azathioprine therapy and to assess 6-methylmercaptopurine suspected toxicity7 nucleotide metabolite measurements (eg, Prometheus Thiopurine Metabolites)

No specific CPT code

SMN 1 and 2 Drug eligibility Medically necessary for members deletions/mutations considering Spinraza (nusinersen)38 or Zolgensma (onasemnogene abeparvovec- CPTs 81329, 81336, xioi)39 for the treatment of spinal muscular 81337 atrophy

TPMT gene mutation or Drug eligibility Medically necessary prior to initiation of phenotypic assays (eg, 6-mercaptopurine or azathioprine therapy. Prometheus TPMT Genetics, Repeat genotypic or phenotypic assay of Prometheus TPMT Enzyme) TPMT activity has no proven value13

CPTs 81335, 0034U, 0169U Tumor Necrosis Factor Medically necessary for members with alpha (TNFα) antagonist Ulcerative Colitis who have experienced an serum drug concentration inadequate primary response or secondary loss of response to TNFa antagonist CPT 80230 therapy45 U.S. Food and Drug Administration (FDA) FDA List of Cleared or Approved Companion Diagnostic Devices (CACDD) NCCN: National Comprehensive Cancer Network Nondiscrimination & Language Access Policy

Aspirus Health Plan, Inc. complies with applicable Federal civil rights laws and does not discriminate on the basis of race, color, national origin, age, disability, or sex. We do not exclude people or treat them differently because of race, color, national origin, age, disability, or sex. We will: • Provide free aids and services to people with disabilities to communicate effectively with us, such as: - Qualified sign language interpreters - Written information in other formats (large print, audio, accessible electronic formats, other formats) • Provide free language services to people whose primary language is not English, such as: - Qualified interpreters - Information written in other languages If you need these services, contact us at the phone number shown on the inside cover of this COC, your id card, or aspirushealthplan.com. If you believe that we have failed to provide these services or discriminated in another way on the basis of race, color, national origin, age, disability, or sex, you can file a grievance with: Nondiscrimination Grievance Coordinator Aspirus Health Plan, Inc. PO Box 1062 Minneapolis, MN 55440 Phone: 1. 866.631.5404 (TTY: 1.866.631.8597) Fax: 763.847.4010 Email: [email protected] You can file a grievance in person or by mail, fax, or email. If you need help filing a grievance, the Nondiscrimination Grievance Coordinator is available to help you. You can also file a civil rights complaint with the U.S. Department of Health and Human Services, Office for Civil Rights, electronically through the Office for Civil Rights Complaint Portal, available at https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at: U.S. Department of Health and Human Services 200 Independence Avenue, SW Room 509F, HHH Building Washington, D.C. 20201 1-800-368-1019, 800-537-7697 (TDD) Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html.

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