Notification



Notification Issue Date:



Medicare Advantage Policy

Title:Ado-Trastuzumab Emtansine (Kadcyla®)
Policy #:MA08.066c

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.

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.

MEDICALLY NECESSARY

Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered for the indication(s) identified below in individuals who meet the applicable criteria, and whose tumors have human epidermal growth factor receptor 2 (HER2) protein overexpression verified as a positive result by one of the following US Food and Drug Administration (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).

BREAST CANCER

ADJUVANT SYSTEMIC THERAPY
Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered when all of the following criteria are met:
  • For individuals with HER2-positive early breast cancer, who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
  • The individual has left ventricular ejection fraction of 50 percent or greater.

RECURRENT OR METASTATIC BREAST CANCER
Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered as a single agent for individuals with HER2 positive, recurrent or stage IV (M1) breast cancer (verified by one of the FDA-approved diagnostic tests listed above), who meet the following criteria:
  • The individual has a documented history of receiving trastuzumab (Herceptin®) and a taxane (separately or in combination)
  • The individual has received prior therapy for metastatic disease OR has developed disease recurrence during or within six months of completing adjuvant therapy
  • The individual has a left ventricular ejection fraction of 50% or greater
  • The individual is hormone receptor negative or hormone receptor positive

NON-SMALL CELL LUNG CANCER

Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered for individuals with adenocarcinoma (with mixed subtypes), Large cell carcinoma, Squamous cell carcinoma, who meet the following criteria:
  • The individual has a documented HER2 mutations
  • The individual has a left ventricular ejection fraction of 50 percent or greater

EXPERIMENTAL/INVESTIGATIONAL

All other uses for ado-trastuzumab emtansine (Kadcyla®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

NOT MEDICALLY NECESSARY
When FDA-approved diagnostic tests do not reveal HER2 protein overexpression, for the indication of breast cancer, Emtansine (Kadcyla®) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use in the treatment of those diseases.

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.
Policy Guidelines

There is no Medicare policy addressing this drug; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, ado-trastuzumab emtansine (Kadcyla®) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

Certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy benefit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when ado-trastuzumab emtansine (Kadcyla®) is covered under a member's medical benefit (Part B benefit). It does not address instances when ado-trastuzumab emtansine (Kadcyla®) is covered under a member’s pharmacy benefit (Part D benefit).

ADMINISTRATION

Ado-trastuzumab emtansine (Kadcyla®) is administered via intravenous (IV) infusion.

The US Food and Drug Administration (FDA) warns providers not to substitute ado-trastuzumab emtansine (Kadcyla®) for or with trastuzumab (Herceptin®).

BLACK BOX WARNINGS

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

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Ado-trastuzumab emtansine (Kadcyla®) was approved by the FDA on February 22, 2013 for use as a single agent in the treatment of HER2-positive metastatic breast cancer in individuals who have previously received trastuzumab (Herceptin®) and a taxane, separately or in combination. Individuals must have received prior therapy for metastatic disease OR developed disease recurrence during or within six months of completing adjuvant therapy.

Description

Ado-trastuzumab emtansine (Kadcyla®), formerly known as T-DM1, is an antibody-drug conjugate (ADC) that targets the human epidermal growth factor receptor 2 (HER2, previously called HER2/neu) protein, which is involved in normal cell growth. 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 that 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 20 percent of breast 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 cancer.

Ado-trastuzumab emtansine (Kadcyla®) is composed of the monoclonal antibody, trastuzumab (also known as Herceptin®), a chemotherapeutic agent called DM1, and a stable linker (MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) that holds the two agents together. (The prefix "ado" was added in order to avoid medication errors of mistaken identity from trastuzumab [Herceptin®]). Ado-trastuzumab emtansine (Kadcyla®) binds to the HER2-positive receptor on the tumor cells and becomes internalized. Once inside of the tumor cell, the stable linker breaks down via proteolytic degradation and releases DM1, which causes cell cycle arrest and cell death; the trastuzumab component interferes with the HER2 receptor signaling, so that tumors cannot survive or proliferate.

Ado-trastuzumab emtansine (Kadcyla®) is supplied as a sterile lyophilized powder in single-use vials and is administered by intravenous (IV) infusion.

METASTATIC BREAST CANCER TREATMENT

In February 2013, ado-trastuzumab emtansine (Kadcyla®) was approved by the US Food and Drug Administration (FDA) for use as a single agent in the treatment of HER2-positive metastatic breast cancer in individuals who have previously received trastuzumab (Herceptin®) and a taxane, separately or in combination. Individuals must have received prior therapy for metastatic disease OR developed disease recurrence during or within six months of completing adjuvant therapy.

The approval of ado-trastuzumab emtansine (Kadcyla®) is based on an international, randomized, multicenter, open-label, Phase III clinical trial of 991 individuals with HER2-positive unresectable locally advanced or metastatic breast cancer who were tested prior to treatment to determine whether the HER2 protein was increased. Individuals had previously received trastuzumab (Herceptin®) and a taxane. Individuals must have received prior therapy for metastatic disease OR developed disease recurrence during or within six months of completing adjuvant therapy. The inclusion criteria also required that individuals needed to have a left ventricular ejection fraction of 50% or greater, as well as an Eastern Co-Operative Oncology Group (ECOG) Performance Status of 0 or 1. Individuals were randomly assigned (1:1) to receive lapatinib plus capecitabine or ado-trastuzumab emtansine (Kadcyla®) until they experienced disease progression, unacceptable toxicity, or withdrew consent.

The primary outcomes of this study were overall survival (OS) and progression-free survival (PFS). The trial resulted in a significant increase in the median OS of 5.8 months (30.9 months in ado-trastuzumab emtansine [Kadcyla®] group vs. 25.1 months in the lapatinib plus capecitabine group). There was also a significant increase in the median PFS of 3.2 months (9.6 months in ado-trastuzumab emtansine [Kadcyla®] group vs. 6.4 months in the lapatinib plus capecitabine group).

OTHER INDICATIONS

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.

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION

HER2 protein overexpression is detected either by immunohistochemical (IHC) assay 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]. Each technique has its own advantages and disadvantages, such as accuracy of results, timeliness of results, and whether the sample will fade over time. The FDA has approved several commercially available tests to aid in the selection of breast cancer patients for ado-trastuzumab emtansine (Kadcyla®) therapy. The NCCN and American Society of Clinical Oncology (ASCO) guidelines 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).

References

American Hospital Formulary Service (AHFS). Ado-trastuzumab emtansine (Kadcyla). Drug Information 2017. 02/22/2019. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/4868969 [via subscription only]. Accessed April 23, 2019.

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Trastuzumab emtansine. (T-DM1). TEC Specialty Pharmacy Reports 2013; #03-2013.

Breastcancer.org WebSite. HER2 status. 03/2019. Available at: http://www.breastcancer.org/symptoms/diagnosis/her2#. Accessed April 23, 2019.

Carlson B. New automated HER2 test promises faster, more accurate testing. Biotechnol Healthc. 2011;8(4): 32–33.

Elsevier’s Clinical Pharmacology Compendium. ado-trastuzumab emtansine (Kadcyla). 12/20/18. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed April 23, 2019.

Genentech. Kadcyla (ado-trastuzumab emtansine), injection for intravenous use. Package labeling. 12/2018. Available at: http://www.gene.com/download/pdf/kadcyla_prescribing.pdf . Accessed April 23, 2019.

Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol.2014;32(19):2078-99.

Hammond MEH, Hayes DF, Dowsett M, et al. ASCO-CAP Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. J Clin Oncol. 2010;28(16):2784-2795.

Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007;25(33):5287-5312.

Lexi-Drugs Compendium. ado-trastuzumab emtansine (Kadcyla). 04/17/19. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/4177902. Accessed April 23, 2019.

Li BT, Ross DS, Aisner DL et al. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thoracic Oncol. 2016;11:(3): 414-419.

Markman, M. Breast Cancer and HER2 Overview of HER2 Breast Cancer. 03/14/2019. Available at: http://emedicine.medscape.com/article/1689966-overview. Accessed April 23, 2019.

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations.. ado-trastuzumab emtansine. 02/28/2019. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. [via subscription only]. Accessed April 23, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Breast Cancer.V.1.2019. [NCCN Web site]. 03/14/2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
[via free subscription]. Accessed April 23, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Non-Small Cell Lung Cancer.V.3.2019. [NCCN Web site]. 01/18/2019. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed April 23, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. ado-trastuzumab emtansine. [NCCN Web site]. 2019. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=399 [via subscription only].Accessed April 23, 2019.

Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene. Science.1987;235(4785):177-182.

Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Kadcyla (ado-trastuzumab emtansine). Approval letter. [FDA Web site]. 02/22/13. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/125427Orig1s000Approv.pdf. Accessed April 23, 2019.

US Food and Drug Administration. Center for Drug Evaluation and Research. Kadcyla (ado-trastuzumab emtansine) Package labeling. 12/2018. Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm . Accessed April 23, 2019.

Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91.

Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol.2013;31(31):3997-4013.



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)

See attachment A


HCPCS Level II Code Number(s)

J9354: Injection, ado-trastuzumab emtansine, 1 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References

Attachment A: Ado-Trastuzumab Emtansine (Kadcyla®)
Description: ICD-10 CODES AND NARRATIVES






Policy History

MA08.066c
07/01/2019This version of the policy will become effective 07/01/2019.
  • This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.
  • Policy criteria were updated for NCCN guidelines for new indication of Non-Small Cell Lung Cancer and Adjuvant systemic therapy for Breast cancer
  • Not medically necessary statement was added for testing results that do not show HER2 protein overexpression

MA08.066b
10/18/2017This version of the policy will become effective 10/18/2017.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria was updated to include new recommendations from NCCN:
  • Individual has symptomatic visceral disease or visceral crisis
  • Individual is hormone receptor negative or hormone receptor positive and endocrine therapy refractory

MA08.066a
11/06/2015This version of the policy will become effective 11/06/2015.

The testing for human epidermal growth factor receptor 2 (HER2) protein status has been updated.

MA08.066
01/01/2015This is a new policy.






Version Effective Date: 07/01/2019
Version Issued Date: 07/01/2019
Version Reissued Date: N/A