Notification



Notification Issue Date:



Medicare Advantage Policy

Title:Fam-trastuzumab deruxtecan-nxki (Enhertu®)
Policy #:MA08.114

This policy is applicable to the Company’s Medicare Advantage products only. Policies that are applicable to the Company’s commercial products are accessible via a separate commercial policy database.


The Company makes decisions on coverage based on the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, benefit plan documents and contracts, and the member’s medical history and condition. If CMS does not have a position addressing a service, the Company makes decisions based on Company Policy Bulletins. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable. Although the Medicare Advantage Policy Bulletin is consistent with Medicare’s regulations and guidance, the Company’s payment methodology may differ from Medicare.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.


This Policy Bulletin document describes the status of CMS coverage, medical terminology, and/or benefit plan documents and contracts at the time the document was developed. This Policy Bulletin will be reviewed regularly and be updated as Medicare changes their regulations and guidance, scientific and medical literature becomes available, and/or the benefit plan documents and/or contracts are changed.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.

MEDICALLY NECESSARY

HER2 PROTEIN OVEREXPRESSION TESTING
Coverage of fam-trastuzumab deruxtecan-nxki requires that HER2 protein overexpression is verified as a positive result by one of the following FDA-approved diagnostic tests:
  • Immunohistochemical (IHC) assay with a result of 3+
  • Fluorescence in situ hybridization (FISH) test (ratio greater than 2.0)
  • Single-probe in situ hybridization (ISH) test with average HER2 copy number 6.0 signals/cell or greater
  • Dual-probe ISH test HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater or HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater

Confirmatory tests should be performed for borderline results as follows:
  • If IHC assay has a result of 2+, confirm with ISH test of the same sample or a new test with IHC or ISH (if new sample available).
  • If FISH test has a HER2 gene/chromosome 17 ratio of 1.8-2.0, confirm with FISH re-test; additional cell counting and recalculation of the ratio; or IHC assay.
  • If single-probe ISH assay has an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
  • If dual-probe ISH assay has a HER2/CEP17 ratio less than 2.0 and an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

FAM-TRASTUZUMAB DERUXTECAN-NXKI (ENHERTU®)
Fam-trastuzumab deruxtecan-nxki (Enhertu®) injection is considered medically necessary and, therefore, covered as monotherapy when the following criteria are met, including HER2 protein overexpression testing and dosing and frequency requirements:
  • Individual has unresectable or metastatic HER2-positive breast cancer
  • Individual has received two or more prior anti-HER2-based regimens (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, other anti-HER2 therapies ) in the metastatic setting
  • Dosing and frequency for fam-trastuzumab deruxtecan-nxki (Enhertu®): 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle)

CONTINUATION THERAPY
Fam-trastuzumab deruxtecan-nxki (Enhertu®) is considered medically necessary and, therefore, covered for continuation therapy until disease progression, drug intolerance or unacceptable toxicity.

NOT MEDICALLY NECESSARY

When FDA-approved diagnostic tests do not reveal HER2 protein overexpression, fam-trastuzumab deruxtecan-nxki (Enhertu®) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support their use in the treatment of those diseases.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of fam-trastuzumab deruxtecan-nxki (Enhertu ®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company's medical policy on off-label coverage for prescription drugs and biologics

DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this Policy to ensure consistency with the most recently published recommendations for the use of fam-trastuzumab deruxtecan-nxki (Enhertu ®). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA), Company-recognized authoritative pharmacology compendia, or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of fam-trastuzumab deruxtecan-nxki (Enhertu ®) outside of the Dosing and Frequency Requirements listed in this Policy. For a list of Company-recognized pharmacology compendia, view the policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the precertification process. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for fam-trastuzumab deruxtecan-nxki (Enhertu ®).

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of fam-trastuzumab deruxtecan-nxki (Enhertu ®) is requested outside of the Dosing and Frequency Requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.
Policy Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

DRUG INFORMATION

In accordance with US Food and Drug Administration (FDA) prescribing information, fam-trastuzumab deruxtecan-nxki (Enhertu ®) is administered 5.4 mg/kg as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, fam-trastuzumab deruxtecan-nxki (Enhertu ®) is covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Fam-trastuzumab deruxtecan-nxki (Enhertu ®) was approved by the FDA on December 20, 2019 for the treatment of unresectable or metastatic HER2-positive breast cancer in individuals , who have received two or more prior anti HER2-based regimens in the metastatic setting . The safety and effectiveness have not been established in pediatric individuals.

Description

Fam-trastuzumab deruxtecan-nxki (Enhertu ®) is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult individuals with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Fam-trastuzumab deruxtecan-nxki is not indicated in breast cancer that does not overexpress the HER2 protein.

The monoclonal antibody is a humanized anti-HER2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor that is attached to the antibody by a cleavable linker. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death.

The HER2 gene is found on chromosome 17 and is involved in the process for making the HER2 protein. The HER2 protein is a receptor on the surface of the cell and sends messages to the cell to grow and divide more frequently. When cells have more than the normal number of copies of the HER2 gene, the gene is called amplified. Amplification of the HER2 gene results in HER2 protein overexpression, which occurs in approximately 25 percent of breast and gastric cancer cases.

HER2 gene amplification and HER2 protein overexpression are highly correlated with faster tumor growth, shortened disease-free survival time, and shortened overall survival for individuals with breast or gastric cancer.

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION
  1. HER2 protein overexpression is detected either by immunohistochemical (IHC) assay that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample or with a type of in situ hybridization (ISH) test for gene amplification (e.g., fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], dual in situ hybridization [DISH]). The FDA has approved several commercially available tests to aid in the selection of breast cancer individuals for fam-trastuzumab deruxtecan-nxki (Enhertu ®) therapy. The National Comprehensive Cancer Network (NCCN) and and American Society of Clinical Oncology (ASCO) guidelines (2019) further recommend that IHC assay and ISH testing should only be done at laboratories that are accredited to perform HER2 testing.
  • An IHC test result is reported as 0 or 1+ (negative), 2+ (borderline), or 3+ (positive).
  • A FISH test result is reported as a HER2 gene/chromosome 17 ratio less than 1.8 (negative), a ratio of 1.8 to less than 2.0 (borderline), or a ratio of 2.0 or greater (positive).
  • A single-probe ISH test result is reported as: average HER2 copy number less than 4.0 signals/cell (negative); 4.0 to less than 6.0 signals/cell (borderline); 6.0 or greater signals/cell (positive).
  • A dual-probe ISH test result is reported as HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater (positive); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number less than 4.0 signals/cell (negative); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 4.0 to less than 6.0 signals/cell (borderline); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater (positive).

The NCCN and ASCO both have issued guidelines for HER2 testing in invasive breast cancer that call for confirming a borderline or equivocal result:
  • IHC assay result of 2+: confirm with ISH test (if same sample), or with a new IHC or ISH test (if new sample available).
  • FISH assay: confirm with either a repeat FISH test or an additional cell counting and recalculation of the ratio. If a repeat FISH test remains equivocal, then an IHC assay is recommended for confirmation.
  • Single-probe ISH assay: confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
  • Dual-probe ISH assay: confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).
PEER-REVIEWED LITERATURE

SUMMARY
Fam-trastuzumab deruxtecan-nxki (Enhertu ®) was evaluated in two-part, open-label, single-group, multicenter, phase 2 trial DESTINY-Breast01. In a part 1 dose-evaluating study, trastuzumab deruxtecan (DS-8201a) was administered at 5.4, 6.4 or 7.4 mg/kg every 3 weeks. The efficacy and safety of the recommended dose was evaluated in the part 2 in adult individuals with pathologically documented HER2-positive metastatic breast cancer, who had received previous treatment with ado-trastuzumab emtansine. The primary end point was the objective response rate (ORR) (complete response plus partial response), assessed by independent central imaging facility review based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 of DS-8201a in HER2-positive, unresectable and/or metastatic breast cancer individuals, who are resistant or refractory to ado-trastuzumab emtansine. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.

Between October 2017 and September 2018, a total of 253 individuals were enrolled and received at least one dose of trastuzumab deruxtecan (DS-8201a). 184 individuals with HER2-positive, unresectable and/or metastatic breast cancer, who had received two or more prior anti-HER2 therapies, (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, other anti-HER2 therapies ) received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight every three weeks until disease progression, unacceptable toxicity or withdrawal of consent), and included (100 percent) of the individuals who were treated with ado-trastuzumab emtansine, (100 percent) with trastuzumab and (65.8 percent ) with pertuzumab. Primary reason for discontinuation was progression of the disease and the adverse events. The study treatment duration was up to 20.5 months.

Fam-trastuzumab deruxtecan-nxki (Enhertu ®) showed durable anti tumor activity in previously treated individuals with HER-2 positive metastatic breast cancer. Confirmed overall response rate was 60.9 percent; 95 percent confidence interval [CI], 53.4 to 68.0).The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95 percent CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95 percent CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7 percent of the individuals), anemia (in 8.7 percent), and nausea (in 7.6 percent).

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References

Daiichi Sankyo, Inc., Basking Ridge, NJ. Fam-trastuzumab deruxtecan-nxki (Enhertu ®) labeling.12/2019. Available at: https://dsi.com/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true Accessed January 22, 2020.

Eisenhauera E.A., Therasseb P, Bogaertsc J, et al., New Response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009 (45):228-247.

Elsevier’s Clinical Pharmacology Compendium .Fam-trastuzumab deruxtecan-nxki (Enhertu ®).[Clinical Key Web site]. 12/24/20. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed January 22, 2020.

Lexi-Drugs Compendium. Fam-trastuzumab deruxtecan-nxki. [Lexicomp Online Web site]. 12/23/2020. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 22, 2020.

Modi S, Saura C, Yamashita T, et al., Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. New Engl J Med. 2019. [Epub ahead of print].

Truven Health Analytics. Micromedex® DrugDex® Compendium. Fam-trastuzumab deruxtecan-nxki, Enhertu ®. Greenwood Village, CO. [Micromedex® Solutions Web site]. 12/30/2020. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 22, 2020.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Fam-trastuzumab deruxtecan-nxki (Enhertu ®). [FDA Web site]. Original: 12/20/20. Revised 11/29/18. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm . Accessed January 22, 2020.

US Food and Drug Administration (FDA). Devices @ FDA (HER2). Available at: http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm. Accessed January 22, 2020.

US Food and Drug Administration (FDA). Fam-trastuzumab deruxtecan-nxki (Enhertu ®) prescribing information & approval letter. [FDA Web site]. 12/2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761106Orig1s000lbl.pdf. Accessed January 22, 2020.

Wolff AC, Hammond EH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer. [ASCO.] 05/30/18. Available at: https://www.asco.org/research-guidelines/quality-guidelines/guidelines/breast-cancer#/9751. Accessed January 22, 2020.



Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)


C50.011 Malignant neoplasm of nipple and areola, right female breast

C50.012 Malignant neoplasm of nipple and areola, left female breast

C50.019 Malignant neoplasm of nipple and areola, unspecified female breast

C50.021 Malignant neoplasm of nipple and areola, right male breast

C50.022 Malignant neoplasm of nipple and areola, left male breast

C50.029 Malignant neoplasm of nipple and areola, unspecified male breast

C50.111 Malignant neoplasm of central portion of right female breast

C50.112 Malignant neoplasm of central portion of left female breast

C50.119 Malignant neoplasm of central portion of unspecified female breast

C50.121 Malignant neoplasm of central portion of right male breast

C50.122 Malignant neoplasm of central portion of left male breast

C50.129 Malignant neoplasm of central portion of unspecified male breast

C50.211 Malignant neoplasm of upper-inner quadrant of right female breast

C50.212 Malignant neoplasm of upper-inner quadrant of left female breast

C50.219 Malignant neoplasm of upper-inner quadrant of unspecified female breast

C50.221 Malignant neoplasm of upper-inner quadrant of right male breast

C50.222 Malignant neoplasm of upper-inner quadrant of left male breast

C50.229 Malignant neoplasm of upper-inner quadrant of unspecified male breast

C50.311 Malignant neoplasm of lower-inner quadrant of right female breast

C50.312 Malignant neoplasm of lower-inner quadrant of left female breast

C50.319 Malignant neoplasm of lower-inner quadrant of unspecified female breast

C50.321 Malignant neoplasm of lower-inner quadrant of right male breast

C50.322 Malignant neoplasm of lower-inner quadrant of left male breast

C50.329 Malignant neoplasm of lower-inner quadrant of unspecified male breast

C50.411 Malignant neoplasm of upper-outer quadrant of right female breast

C50.412 Malignant neoplasm of upper-outer quadrant of left female breast

C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast

C50.421 Malignant neoplasm of upper-outer quadrant of right male breast

C50.422 Malignant neoplasm of upper-outer quadrant of left male breast

C50.429 Malignant neoplasm of upper-outer quadrant of unspecified male breast

C50.511 Malignant neoplasm of lower-outer quadrant of right female breast

C50.512 Malignant neoplasm of lower-outer quadrant of left female breast

C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast

C50.521 Malignant neoplasm of lower-outer quadrant of right male breast

C50.522 Malignant neoplasm of lower-outer quadrant of left male breast

C50.529 Malignant neoplasm of lower-outer quadrant of unspecified male breast

C50.611 Malignant neoplasm of axillary tail of right female breast

C50.612 Malignant neoplasm of axillary tail of left female breast

C50.619 Malignant neoplasm of axillary tail of unspecified female breast

C50.621 Malignant neoplasm of axillary tail of right male breast

C50.622 Malignant neoplasm of axillary tail of left male breast

C50.629 Malignant neoplasm of axillary tail of unspecified male breast

C50.811 Malignant neoplasm of overlapping sites of right female breast

C50.812 Malignant neoplasm of overlapping sites of left female breast

C50.819 Malignant neoplasm of overlapping sites of unspecified female breast

C50.821 Malignant neoplasm of overlapping sites of right male breast

C50.822 Malignant neoplasm of overlapping sites of left male breast

C50.829 Malignant neoplasm of overlapping sites of unspecified male breast

C50.911 Malignant neoplasm of unspecified site of right female breast

C50.912 Malignant neoplasm of unspecified site of left female breast

C50.919 Malignant neoplasm of unspecified site of unspecified female breast

C50.921 Malignant neoplasm of unspecified site of right male breast

C50.922 Malignant neoplasm of unspecified site of left male breast

C50.929 Malignant neoplasm of unspecified site of unspecified male breast

C79.81 Secondary malignant neoplasm of breast

Do you agree with the current version of this coding?



HCPCS Level II Code Number(s)



THE FOLLOWING CODES ARE USED TO REPORT
Fam-trastuzumab deruxtecan-nxki (Enhertu®)


C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics


Revenue Code Number(s)



N/A



Misc Code

N/A:

N/A


Coding and Billing Requirements


Cross References




Policy History

MA08.114
03/09/2020This version of the policy will become effective 03/09/2020.
This new policy has been issued to communicate the Company’s coverage position and criteria for Fam-trastuzumab deruxtecan-nxki (Enhertu®).




Version Effective Date: 03/09/2020
Version Issued Date: 03/09/2020
Version Reissued Date: N/A