Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Ado-Trastuzumab Emtansine (Kadcyla®)

Policy #:08.01.11d

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


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. 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.

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 Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

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

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).

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 metastatic breast cancer* (verified by one of the FDA-approved diagnostic tests listed above), who meet the following criteria:
  • Individual has a documented history of receiving trastuzumab (Herceptin®) and a taxane (separately or in combination)
  • Individual has received prior therapy for metastatic disease OR has developed disease recurrence during or within six months of completing adjuvant therapy
  • Individual has a left ventricular ejection fraction of 50% or greater
  • Individual has symptomatic visceral disease or visceral crisis
  • Individual is hormone receptor negative or hormone receptor positive and endocrine therapy refractory

*The National Comprehensive Cancer Network (NCCN) Panel on Breast Cancer recommends ado-trastuzumab emtansine (Kadcyla®) as the preferred agent for individuals with HER2-positive recurrent or metastatic breast cancer who have previously received a trastuzumab-based regimen.

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.

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

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.

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 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 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.
Note: Ado-trastuzumab emtansine (Kadcyla®) is not indicated for breast cancer that does not overexpress the HER2 protein.

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. 03/08/2017. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/4868969 [via subscription only]. Accessed August 29, 2017.


    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. 03/2015. Available at: http://www.breastcancer.org/symptoms/diagnosis/her2#. Accessed August 29, 2017.

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

    Elsevier Gold Standard’s Clinical Pharmacology Compendium. ado-trastuzumab emtansine (Kadcyla). 05/23/16. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed August 29, 2017.

    Genentech. Kadcyla (ado-trastuzumab emtansine), injection for intravenous use. Package labeling. 07/2016. Available at: http://www.gene.com/download/pdf/kadcyla_prescribing.pdf . Accessed August 23, 2017.

    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). 08/23/17. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/4177902. Accessed August 29, 2017.

    Markman, M. Breast Cancer and HER2 Overview of HER2 Breast Cancer. 08/08/2017. Available at: http://emedicine.medscape.com/article/1689966-overview. Accessed August 28, 2017.

    Micromedex® 2.0. DrugDex® Evaluations.[Micromedex Web site]. ado-trastuzumab emtansine. 06/13/2017. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. [via subscription only]. Accessed August 29, 2017.

    National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Breast Cancer.V.2.2017. [NCCN Web site]. 04/06/2017. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed August 23, 2017.

    National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. ado-trastuzumab emtansine. [NCCN Web site]. 2017. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=399 [via subscription only]. Accessed August 23, 2017.

    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 August 30, 2017.

    US Food and Drug Administration. Center for Drug Evaluation and Research. Kadcyla (ado-trastuzumab emtansine) Package labeling. 07/2016. Available at:http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm . Accessed August 22, 2017.

    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-CM Codes and Narratives




Policy History

Version Effective Date: 10/18/2017
Version Issued Date: 10/18/2017
Version Reissued Date: N/A

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