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 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).
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.
The NCCN and ASCO both have issued guidelines for HER2 testing in invasive breast cancer that call for confirming a borderline or equivocal result:
- 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).
- 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).