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Ado-Trastuzumab Emtansine (Kadcyla®)
08.01.11i

Policy

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 US Food and Drug Administration (FDA)–approved diagnostic tests for the following indications:

BREAST CANCER 

Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered for individuals with HER2-positive​ breast cancer and the individual has a left ventricular ejection fraction of 50 percent or greater for any of the following indications:

Early Breast Cancer ​

  •  As adjuvant therapy​ for individuals with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
Metastatic breast cancer 
​
  •  As a single agent therapy for the treatment of individuals with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination, when any of the following criteria are met:
    • The individual received prior therapy for metastatic disease
    • The individual developed disease recurrence during or within 6 months of completing adjuvant therapy.  ​​​​
Inflammatory breast cancer

  • National Comprehensive Cancer Network (NCCN)-preferred adjuvant systemic therapy for individuals with inflammatory breast cancer​ who have residual disease following preoperative therapy for HER2-positive tumors 
  • ​As third-line and beyond (or ​second-line if not a candidate for fam-trastuzumab deruxtecan) as a single-agent therapy for individuals with no response to preoperative systemic therapy, or for recurrent unresectable (local or regional) or stage IV (M1) HER2-positive inflammatory breast cancer​ for one of the following:
      • Hormone receptor–negative 
      • Hormone receptor–positive with or without endocrine therapy​
  • Adjuvant systemic therapy for individuals who had a response to preoperative systemic therapy, followed by surgery, and need to complete planned chemotherapy, with HER2-positive tumors
​Invasive breast cancer

  • NCCN-preferred therapy for individuals with HER2-positive tumors and locally advanced clinical stage ≥T2 or cN+ and M0, or cT1c, cN0 invasive breast cancer and all of the following:   
    • ​The individual​ completed planned chemotherapy and following mastectomy or breast-conserving surgery (BCS) ​with surgical axillary staging for: 
      • ​ypT1-4N0 
      • ypN≥1 ​​​
  • ​Third line and beyond (or second-line if not a candidate for fam-trastuzumab deruxtecan) ​as a single-agent therapy for recurrent unresectable (local or regional) or stage IV (M1) HER2-positive invasive breast cancer​ for one of the following:
    • Hormone receptor–negative 
    • Hormone receptor–positive with or without endocrine therapy​​
  • Adjuvant systemic therapy for individuals with HER2-positive tumors and cT1c-3 and and pN0 or pN+ ​tumors disease 
CENTRAL NERVOUS SYSTEM (CNS)​ CANCERS 
Breast cancer with brain metastases 
 
Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered for individuals with HER2-positive​ breast cancer with brain metastases and the individual has a left ventricular ejection fraction of 50 percent or greater for any of the following indications criteria​:

  • As a single-agent treatment for limited brain metastases in individuals with HER2-positive breast cancer:
    • Initial treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
    • Treatment for recurrent brain metastases
    • Treatment for relapsed disease with either stable systemic disease or reasonable systemic treatment options​ 
  • As a single-agent treatment for extensive brain metastases in individuals with HER2-positive breast cancer:
    • Primary treatment in select individuals (e.g., individuals​​ with small asymptomatic brain metastases)
    • Treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options​
​HEAD AND NECK CANCERS - SALIVARY GLAND TUMORS 
Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered for individuals with HER2-positive recurrent disease and the individual has a left ventricular ejection fraction of 50 percent or greater for any of the following criteria: 
  • As a single-agent systemic therapy for recurrent disease with:
    • Distant metastases in individuals​ with a performance status (PS) of 0–3
    • Unresectable locoregional recurrence or second primary with prior radiation therapy
NON-SMALL CELL LUNG CANCER
Ado-trastuzumab emtansine (Kadcyla®) is considered medically necessary and, therefore, covered as a single-agent therapy for individuals with a left ventricular ejection fraction of 50 percent or greater for one of the following indications (except for locoregional recurrence or symptomatic local disease [excluding mediastinal lymph node recurrence with prior radiation therapy] with no evidence of disseminated disease):​
  • As subsequent therapy for ERBB2/(HER2) mutation–positive recurrent, advanced, or metastatic disease
  •  Advanced disease, previously treated, HER2 mutation–positive
​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, ado-trastuzumab 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.

MANDATES 

 

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents" (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.


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.

Guidelines

BLACK BOX WARNINGS 

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

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2​ (HER2) PROTEIN OVEREXPRESSION TESTING
​
Coverage of ado-trastuzumab emtansine (Kadcyla®) requires that human epidermal growth factor receptor 2 (HER2) protein overexpression be 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 >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 the 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).
ADMINISTRATION

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

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

BENEFIT APPLICATION

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

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 6 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 known as amplified. Amplification of the HER2 gene results in HER2 protein overexpression, where the excess HER2 genes communicate to the breast cells to make more HER2 receptors. HER2 gene amplification and overexpression occur 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 6 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 6 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 individuals 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. 12/12/2023. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/4868969 [via subscription only]. Accessed February 03, 2024.

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. 08/2023. Available at: http://www.breastcancer.org/symptoms/diagnosis/her2#. Accessed February 03, 2024.

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). 07/13/23. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed February 03, 2024.

Genentech. Kadcyla (ado-trastuzumab emtansine), injection for intravenous use. Package labeling. 02/2022. Available at: http://www.gene.com/download/pdf/kadcyla_prescribing.pdf. Accessed February 03, 2024.

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):2078-2099.

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). 09/19/22. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/4177902. Accessed February 03, 2024.

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. 07/16/2020. Available at: http://emedicine.medscape.com/article/1689966-overview. Accessed February 03, 2024.

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations.. ado-trastuzumab emtansine. 12/07/2023. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. [via subscription only]. Accessed February 03, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Breast Cancer.V.1.2024. [NCCN Web site]. 01/25/2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
[via free subscription]. Accessed February 03, 2024.


National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Central Nervous System Cancers.V.1.2023. [NCCN Web site]. 03/24/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [via free subscription]. Accessed February 03, 2024. 


National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Head and Neck Cancers.V.2.2024. [NCCN Web site]. 12/08/2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [via free subscription]. Accessed February 03, 2024. 


National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Non-Small Cell Lung Cancer.V.1.2024. [NCCN Web site]. 12/21/2023​. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed February 03, 2024.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. ado-trastuzumab emtansine. [NCCN Web site]. 2024. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=399 [via subscription only].Accessed February 03, 2024.

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 February 03, 2024.

US Food and Drug Administration. Center for Drug Evaluation and Research. Kadcyla (ado-trastuzumab emtansine) Package labeling. 02/2022. Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed February 03, 2024​.​

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):1783-1791.

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

CPT Procedure Code Number(s)
N/A
ICD - 10 Procedure Code Number(s)
N/A
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

Policy History

Revisions From 08.01.11i:
03/11/2024This version of the policy will become effective 03/11/2024​​​​
  • This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.​
The following indication was revised, per NCCN:
  • Breast cancer

Revisions From 08.01.11h:
12/19/2022This version of the policy will become effective 12/19/2022​​
  • This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia. ​
The following indication was revised, per NCCN:
  • Breast cancer 
  • Head and neck tumors​
  • Non-small cell lung cancer

Revisions From 08.01.11g:
12/06/2021This version of the policy will become effective 12/06/2021​
  • 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 the indication of systemic therapy for breast cancer 
The following indications were added as Medically Necessary.
  • Central nervous system cancers
  • Head and neck tumors
The following indication was revised, per NCCN:
  • Breast cancer 
The following ICD-10 codes were added to the policy:
C06.9   Malignant neoplasm of mouth, unspecified
C07      Malignant neoplasm of parotid gland
C08.0   Malignant neoplasm of submandibular gland
C08.1   Malignant neoplasm of sublingual gland
C08.9   Malignant neoplasm of major salivary gland, unspecified
C33      Malignant neoplasm of trachea
C72.9   Malignant neoplasm of central nervous system, unspecified
C79.31 Secondary malignant neoplasm of brain​​

Revisions From 08.01.11f:
01/04/2020This version of the policy will become effective 01/04/2020​.
  • 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 the indication of adjuvant systemic therapy for breast cancer 

Revisions From 08.01.11e:
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 a 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
3/11/2024
3/11/2024
08.01.11
Medical Policy Bulletin
Commercial
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No