Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2013014
Category:	Pharmacy
Initiated:	March 2013
Last Review:	April 2023

Ado-Trastuzumab Emtansine (e.g., Trastuzumab-DM1) for Treatment of HER-2 Positive Malignancies

Description:

Ado-trastuzumab emtansine, also known as trastuzumab-DM1 or T-DM1, is an antibody-drug conjugate comprising trastuzumab and emtansine (DM1). It is a HER2 antagonist that is intended as treatment for individuals with breast cancers that overexpress HER2, and it may also have applications for other HER-2 positive malignancies.

Background

Description of Disease. Breast cancer accounts for nearly 1 in 3 cancer diagnoses in women in the U.S. Among women, it is the most common cancer after non-melanoma skin cancer. After lung cancer, breast cancer ranks second for cancer mortality. In 2012, an estimated 229,000 new cases of invasive breast cancer will be diagnosed among women, and approximately 40,000 women are expected to die from breast cancer (Carlson, 2012).

Metastatic breast cancer has a poor prognosis. In a cohort of 3,524 women with de novo Stage IV or relapsed breast cancer diagnosed between 1992 and 2007, the median overall survival was 39.2 months among individuals with de novo Stage IV and 27.2 months among individuals with relapsed disease (estimates independent of HER2 status) (Dawood, 2010). Factors associated with reduced survival for individuals with metastatic breast cancer include age ≥50 years, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status (Chang, 2003).

Systemic treatment for metastatic breast cancer is mainly palliative. The goals of treatment are to prolong survival, alleviate symptoms, and maintain or improve quality of life. Treatment is primarily with chemotherapeutic and other anti-tumor drugs. The National Comprehensive Cancer Network (NCCN) guidelines on treatment of metastatic breast cancer include specific recommendations for first-line treatment of HER2-positive metastatic breast cancer (Carlson, 2012; NCNN, 2012). All of the recommended treatment regimens in the guidelines include trastuzumab. Recommended agents that are used singly or in combination with trastuzumab are paclitaxel, docetaxel, vinorelbine, capecitabine, and carboplatin.

HER2

HER2, previously called HER2/neu, or ErbB-2, (Hudis, 2007) is part of the HER tyrosine kinase receptor family that includes 4 transmembrane receptors (HER1 [EGFR], HER2, HER3, and HER4). These receptors mediate tumor cell growth, survival, and differentiation. The HER receptors, when activated by extracellular ligand binding, dimerize and activate cell signaling through the phosphatidyl inositol-3 (PI3)- kinase/AKT pathway, which regulates tumor cell survival, to and through the mitogen-activated protein kinase (MAPK) pathway, which regulates cellular proliferation. HER2 has no known ligand; it forms active heterodimers (particularly HER2:HER3) and, when overexpressed, homodimers (HER2:HER2) and that initiate tyrosine kinase signaling without ligand stimulation (Baselga, 2010).

Approximately 20-25% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein receptor with tyrosine kinase activity. Overexpression of this receptor is associated with reduced time to disease recurrence and poorer prognosis. Prior to the advent of HER2 targeted therapy, HER2 overexpression was associated with shorter disease-free and overall survival than women with either lymph node-negative or lymph node-positive breast cancers, with lack of responsiveness to tamoxifen therapy, and with altered responsiveness to cytotoxic chemotherapy (Press, 2005).

Before FDA approval of ado-trastuzumab emtansine, three anti-HER2 therapies were FDA-approved for HER2-positive cancers. These agents arrest tumor cell growth and promote apoptosis by blocking HER2-mediated intracellular signaling pathways that mediate cell growth, differentiation, and survival:

Trastuzumab (e.g., Herceptin®) is an intravenous monoclonal antibody to an extracellular domain of the HER2 receptor (Subdomain IV) that prevents activation of intracellular tyrosine kinase signaling cascades and also promotes antibody dependent cell mediated cytotoxicity (ADCC) (Hudis, 2007).

Lapatinib (e.g., Tykerb®) is an oral tyrosine kinase inhibitor that blocks the intracellular tyrosine kinase domain of HER2 and downstream cell signaling cascades (Drouet, 2008).

Pertuzumab (e.g., Perjeta™) is an oral monoclonal antibody to the extracellular dimerization domain of the HER2 receptor (Subdomain II) that, like trastuzumab, prevents activation of intracellular tyrosine kinase signaling cascades and also promotes ADCC (Perjeta Prescribing Information, 2012).

Trastuzumab is recommended for first-line treatment of individuals with HER2-positive metastatic breast cancer, either in combination with pertuzumab and a taxane (preferred); in combination with a taxane (e.g., paclitaxel with or without carboplatin, or docetaxel), vinorelbine, or capecitabine; or as monotherapy. Treatment with trastuzumab plus an anthracycline (i.e., doxorubicin or daunorubicin) is not recommended because of unacceptably high rates of cardiac toxicity. Most individuals who initially respond to trastuzumab will eventually progress.(10, 11) For second-line treatment of HER2-positive metastatic breast cancer that progresses after trastuzumab therapy (either in the adjuvant setting or as first-line treatment for metastatic disease), continuation of HER2 blockade is recommended. For individuals not previously exposed to pertuzumab, combination therapy with trastuzumab plus pertuzumab with or without cytotoxic chemotherapy (e.g., a taxane or vinorelbine) is recommended. Other treatment options are trastuzumab plus lapatinib or capecitabine and lapatinib plus capecitabine. In patients who obtain sustained disease control, the optimal duration of HER2-targeted therapy is unknown (NCCN, 2012).

Ado-trastuzumab emtansine

Ado-trastuzumab emtansine is an antibody-drug conjugate comprising trastuzumab and emtansine. Emtansine (previously called “DM1” for “derivative of maytansine 1”) is a sulfur-containing derivative of the potent microtubule inhibitor, maytansine. Emtansine is conjugated to trastuzumab by lysine side chains, forming a stable thioether linker (Verma, 2012). Ado-trastuzumab emtansine binds HER2 with an affinity comparable to that of trastuzumab (Burris, 2011). Once internalized, proteolytic degradation of the linker releases both trastuzumab and the active metabolite, maleimidomethyl cyclohexane-1-carboxylate (MCC)-emtansine. MCC-emtansine contains both positive and negative charges and therefore does not readily cross plasma membranes, maintaining intracellular concentrations (LoRusso, 2011). Ado-trastuzumab emtansine has been shown to preserve the antitumor activity of trastuzumab (described above) (Girish, 2012). Death of HER2-expressing cells therefore results from effects of both active moieties of ado-trastuzumab emtansine.

Comparable pharmacokinetic data suggest that toxicity associated with trastuzumab exposure is the same whether trastuzumab is administered as ado-trastuzumab emtansine or as trastuzumab. Both drugs carry Black Box Warnings for hepatotoxicity, cardiac toxicity and embryo-fetal toxicity.

Regulatory Status

Ado-trastuzumab emtansine (e.g., Kadcyla™) is FDA-approved for the treatment of individuals with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Individuals should have either received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

On May 3, 2019, the Food and Drug Administration expanded the indication to include adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

Safety Considerations

Although there are no absolute contraindications to ado-trastuzumab emtansine, there are a number of additional safety considerations:

Ado-trastuzumab emtansine is Pregnancy Category D, is associated with known gestational adverse effects, and should not be used in pregnant women. Effective contraception should be used during and for at least 6 months following treatment.
Increases in liver function enzymes are common. Dose modifications based on liver function tests are recommended.
Decreases in left ventricular ejection fraction have been noted. Inclusion criteria for the EMILIA trial included a LV ejection fraction of at least 50% or greater.
The safety and efficacy of ado-trastuzumab emtansine in pediatric individuals has not been established.
Other safety concerns, which generally do not warrant a change in management, include infusion reactions, pulmonary toxicity, GI symptoms, and fatigue.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.

Effective August 15, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ado-trastuzumab emtansine as a monotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for following indications:

Invasive Breast Cancer

Preferred adjuvant systemic therapy for individuals with human epidermal growth factor receptor 2 (HER2)-positive tumors and locally advanced c≥T2 or cN+ and M0 disease following completion of planned chemotherapy and following mastectomy or lumpectomy with surgical axillary staging if: ypT1-4N0 or ypN≥1 (NCCN 1)
Third-line and beyond (or second-line if not a candidate for fam-trastuzumab deruxtecan) single-agent therapy for recurrent unresectable (local or regional) or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive disease that is (NCCN 2A):

a. Hormone receptor-negative

b. Hormone receptor-positive with or without endocrine therapy

3. Adjuvant systemic therapy for individuals with HER2 positive tumors and cTc-3, cN0 or N+, M0 disease (NCCN 2A).

Inflammatory Breast Cancer

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 (NCCN 2A)

2. Third-line and beyond (or second-line if not a candidate for fam-trastuzumab deruxtecan) single-agent therapy for recurrent unresectable (local or regional) or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive disease that is (NCCN 2A):

a. Hormone receptor-negative

b. Hormone receptor-positive with or without endocrine therapy

3. Preferred adjuvant systemic therapy for individuals who have residual disease following preoperative therapy for HER2 positive tumors. (NCCN 1)

Head & Neck Cancers (Salivary Gland Tumors)

Useful in certain circumstances as single-agent systemic therapy for human epidermal growth factor receptor 2 (HER2)-positive recurrent disease with (NCCN 2A):

a. Distant metastases in individuals with a performance status (PS) of 0-3

b. Unresectable locoregional recurrence or second primary with prior radiation therapy

Non-Small Cell Lung Cancer

Activity against HER2 mutations in advanced lung cancer (NCCN 2A)

Central Nervous System Cancers

Limited Brain Metastases (NCCN 2A)

a. Used as a single-agent treatment for limited brain metastases in HER2 positive brain cancer:

i. May be considered as initial treatment in select cases (e.g., small asymptomatic brain metastases)

ii. As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options.

2. Extensive Brain Metastases (NCCN 2A)

a. Single agent treatment for extensive brain metastases in HER2 positive breast cancer:

i. May be considered as primary treatment in select cases (e.g., small asymptomatic brain metastases).

ii. As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options.

The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosage and administration

Dosing per FDA Guidelines

The recommended dose of Ado-trastuzumab emtansine is 3.6 mg/kg given IV every 3 weeks (21day cycle) until disease progression or unacceptable toxicity, or a total of 14 cycles for individuals with EBC.

The first infusion is administered over 90 minutes with slowing or interruptions for fever, chills, or other infusion-associated symptoms, followed by 90 minutes of observation and vital sign monitoring.

If the first infusion is well tolerated (i.e., with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Ado-trastuzumab is available as a lyophilized powder in single-dose vials containing 100 mg per vial or 160 mg per vial.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of Ado-trastuzumab emtansine for any indication or circumstance not described above, including but not limited to previously untreated progressive or recurrent locally advanced breast cancer, earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer does not meet member benefit certificate primary coverage criteria there be scientific evidence effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of Ado-trastuzumab emtansine for any indication or circumstance not described above, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer is considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective April 19, 2023 to August 14, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Invasive Breast Cancer

Preferred adjuvant systemic therapy for individuals with human epidermal growth factor receptor 2 (HER2)-positive tumors and locally advanced c≥T2 or cN+ and M0 disease following completion of planned chemotherapy and following mastectomy or lumpectomy with surgical axillary staging if: ypT1-4N0 or ypN≥1 (NCCN 1)
Preferred second-line single-agent therapy for recurrent unresectable (local or regional) or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive disease (NCCN 1) Used as a single-agent treatment for limited brain metastases in patients with HER2 positive breast cancer (NCCN 2A)

a. May be considered as initial treatment in select patients (e.g., patients with small asymptomatic brain metastases)

b. Consider as treatment for recurrent brain metastases.

c. Treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options

3. Adjuvant systemic therapy for individuals with HER2 positive tumors and cTc-3, cN0 or N+, M0 disease (NCCN 2A).

Inflammatory Breast Cancer

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 (NCCN 2A)
Preferred second-line single-agent therapy for individuals with no response to preoperative systemic therapy, or for recurrent unresectable (local or regional) or stage IV (M1) or no response to preoperative systemic therapy, human epidermal growth factor receptor 2 (HER2)-positive disease (NCCN 1)
Preferred adjuvant systemic therapy for individuals who have residual disease following preoperative therapy for HER2 positive tumors. (NCCN 1)

Head & Neck Cancers (Salivary Gland Tumors)

Useful in certain circumstances as single-agent systemic therapy for human epidermal growth factor receptor 2 (HER2)-positive recurrent disease with (NCCN 2A):

a. Distant metastases in individuals with a performance status (PS) of 0-3

b. Unresectable locoregional recurrence or second primary with prior radiation therapy

Non-Small Cell Lung Cancer

Activity against HER2 mutations in advanced lung cancer (NCCN 2A)

Central Nervous System Cancers

Limited Brain Metastases (NCCN 2A)

a. Used as a single-agent treatment for limited brain metastases in HER2 positive brain cancer:

i. May be considered as initial treatment in select cases (e.g., small asymptomatic brain metastases)

ii. As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options.

2. Extensive Brain Metastases (NCCN 2A)

a. Single agent treatment for extensive brain metastases in HER2 positive breast cancer:

i. May be considered as primary treatment in select cases (e.g., small asymptomatic brain metastases).

ii. As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options.

Dosage and administration

Dosing per FDA Guidelines

If the first infusion is well tolerated (i.e., with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Ado-trastuzumab is available as a lyophilized powder in single-dose vials containing 100 mg per vial or 160 mg per vial.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 1, 2022 to April 18, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ado-trastuzumab emtansine as a monotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for following indications:

Invasive Breast Cancer

Preferred adjuvant systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive tumors and locally advanced c≥T2 or cN+ and M0 disease following completion of planned chemotherapy and following mastectomy or lumpectomy with surgical axillary staging if: ypT1-4N0 or ypN≥1 (NCCN 1)
Preferred second-line single-agent therapy for recurrent unresectable (local or regional) or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive disease (NCCN 1)
Used as a single-agent treatment for limited brain metastases in patients with HER2 positive breast cancer (NCCN 2A)

May be considered as initial treatment in select patients (eg, patients with small asymptomatic brain metastases)
Consider as treatment for recurrent brain metastases
Treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options

Single agent treatment for extensive brain metastases in patients with HER2 positive breast cancer (NCCN 2A)

May be considered as primary treatment in select patients (eg, patients with small asymptomatic brain metastases)
As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options

Inflammatory Breast Cancer

Preferred adjuvant systemic therapy for patients who had a response to preoperative systemic therapy, followed by surgery, and need to complete planned chemotherapy, with human epidermal growth factor receptor 2 (HER2)-positive tumors (NCCN 1)
Preferred second-line single-agent therapy for patients with no response to preoperative systemic therapy, or for recurrent unresectable (local or regional) or stage IV (M1) or no response to preoperative systemic therapy, human epidermal growth factor receptor 2 (HER2)-positive disease (NCCN 1)

Head & Neck Cancers (Salivary Gland Tumors)

Useful in certain circumstances as single-agent systemic therapy for human epidermal growth factor receptor 2 (HER2)-positive recurrent disease with (NCCN 2A):

Distant metastases in patients with a performance status (PS) of 0-3
Unresectable locoregional recurrence or second primary with prior radiation therapy

Non-Small Cell Lung Cancer

Activity against HER2 mutations in advanced lung cancer (NCCN 2A)

Dosage and administration

The recommended dose of Ado-trastuzumab emtansine (Kadcyla®) is 3.6 mg/kg given IV every 3 weeks (21day cycle) until disease progression or unacceptable toxicity, or a total of 14 cycles for patients with EBC.

If the first infusion is well tolerated (ie, with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of Ado-trastuzumab emtansine (Kadcyla®) in all other situations, including but not limited to previously untreated progressive or recurrent locally advanced breast cancer, earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer does not meet member benefit certificate primary coverage criteria there be scientific evidence effectiveness.

For members with contracts without primary coverage criteria, the use of Ado-trastuzumab emtansine is considered investigational in all other situations, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective November 1, 2021 to December 31, 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ado-trastuzumab emtansine (Kadcyla®) as a monotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for following indications:

For treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

Received prior therapy for metastatic disease, OR
Developed disease recurrence during or within six months of completing adjuvant therapy

The adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

Dosage and administration

If the first infusion is well tolerated (ie, with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective July 2019 to October 31, 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ado-trastuzumab emtansine (Kadcyla®) as a monotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for following indications:

For treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

Received prior therapy for metastatic disease, OR
Developed disease recurrence during or within six months of completing adjuvant therapy

The adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

NCCN 1, 2A and 2B recommendations in accordance with Coverage Policy #2000030.

Dosage and administration

If the first infusion is well tolerated (ie, with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective April 2019 to June 2019

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ado-trastuzumab emtansine (Kadcyla®) as a monotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for following indications:

Patient has human epidermal growth factor receptor 2−positive, metastatic breast cancer,
Patient has received prior treatment for metastatic disease or has developed recurrent disease within 6 months of completing adjuvant therapy, and
Patient has received prior treatment with trastuzumab and a taxane.

NCCN 2A and 2B recommendations in accordance with Coverage Policy #2000030.

Dosage and administration

The recommended dose of Ado-trastuzumab emtansine (Kadcyla®) is 3.6 mg/kg given IV every 3 weeks (21 day cycle) until disease progression or unacceptable toxicity. The first infusion is administered over 90 minutes with slowing or interruptions for fever, chills, or other infusion-associated symptoms, followed by 90 minutes of observation and vital sign monitoring.

If the first infusion is well tolerated (ie, with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, the use of Ado-trastuzumab emtansine is considered investigational in all other situations, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective July 2018 - March 2019

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ado-trastuzumab emtansine (Kadcyla®) as a monotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for following indications:

Patient has human epidermal growth factor receptor 2−positive, metastatic breast cancer,
Patient has received prior treatment for metastatic disease or has developed recurrent disease within 6 months of completing adjuvant therapy, and
Patient has received prior treatment with trastuzumab and a taxane.
NCCN 2A and 2B Recommendations in accordance with Coverage Policy #2000030

Dosage and administration

The recommended dose of Ado-trastuzumab emtansine (Kadcyla®) is 3.6 mg/kg given IV every 3 weeks (21 day cycle) until disease progression of unacceptable toxicity. The first infusion is administered over 90 minutes with slowing or interruptions for fever, chills, or other infusion-associated symptoms, followed by 90 minutes of observation and vital sign monitoring.

If the first infusion is well tolerated (ie, with no signs or symptoms of infusion reaction), subsequent infusions may be administered over 30 minutes followed by 30 minutes of observation.

Management of adverse events may require temporary interruption, dose reduction, or treatment discontinuation.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective Prior to July 2018

The use of ado-trastuzumab emtansine as monotherapy meets member benefit certificate primary coverage criteria when all of the following conditions have been met:

Patient has HER2-positive, metastatic breast cancer
Patient has received prior treatment for metastatic disease, or has developed recurrent disease within 6 months of completing adjuvant therapy.
Patient has received prior treatment with trastuzumab and a taxane

The use of ado-trastuzumab emtansine in all other situations, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer does not meet member benefit certificate primary coverage criteria because there is a lack of scientific evidence regarding the safety and effectiveness of these indications.

For members with contracts without primary coverage criteria, the use of ado-trastuzumab emtansine is considered investigational in all other situations, including but not limited to earlier stages of breast cancer, combination treatment with different agents, and treatment of gastric cancer. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Efficacy

Randomized, controlled trial. The Phase III EMILIA trial (N=991) was a randomized, stratified, active-controlled, open-label trial conducted in 26 countries (27% US) (Verma, 2011). Patients had unresectable, locally advanced or metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane. Median age was 53 years, approximately 37% of patients had three or more metastatic sites, and 68% had visceral disease involvement. Patients were stratified (by world region, number of prior chemotherapy regimens for advanced disease, and visceral disease involvement) and randomized to one of two treatment groups: intravenous infusions of ado-trastuzumab emtansine 3.6 mg/kg every 21 days or self-administered oral lapatinib 1250 mg daily plus oral capecitabine 1000 mg/m2 every 12 hours for the first 14 days of each 21-day treatment cycle.

The Phase III EMILIA trial was rated good quality, with no areas of major bias identified. Potential bias introduced by the open-label trial design was minimized by assessor blinding of PFS and tumor response endpoints and by the use of an easily measured endpoint, OS.

Primary efficacy outcomes were PFS by independent review committee and overall survival (OS). PFS was 9.6 months in the ado-trastuzumab emtansine group and 6.4 months in the lapatinib+capecitabine group (hazard ratio [HR] 0.65 [95% CI: 0.55, 0.77]). Statistically nonsignificant differences in PFS were found in patients without visceral involvement and in patients from Asia and other parts of the world (stratified subgroups) and in patients 65 to 74 years of age and patients without measurable disease at baseline (prespecified subgroups). At a median follow-up of approximately19 months, an interim analysis of OS crossed the pre-determined stopping boundary, and the trial was discontinued. OS was 30.9 months in the ado-trastuzumab emtansine group and 25.1 in the lapatinib+capecitabine group (HR 0.68 [95% CI: 0.55, 0.85]).

Uncontrolled trials. Two single-arm, open-label, Phase II studies conducted in the US enrolled patients with HER2 positive metastatic breast cancer and measurable disease. In TDM4374g (N=110), patients were previously treated with trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine (Krop, 2012). Ninety-eight percent of patients were female, median age was 53 years, 74% of patients had three or more metastatic sites, and patients had received a median of 7 systemic treatments for metastatic disease. In TDM4258g (n=112), patients were previously treated with HER2-directed therapy (trastuzumab or lapatinib) (Burris, 2011). Median age was 55 years, 75% of patients had three or more metastatic sites, and patients had received a median of 5 systemic treatments for metastatic disease. All patients in both studies received ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks with dose modifications for adverse events.

Objective response rate (ORR, defined as complete responses plus partial responses) by independent radiologic facility (IRF) was the primary efficacy outcome in both studies. In TDM4374g (more pre-treatment), ORR was 35% (95% confidence interval [CI]: 26, 44). In TDM4258g (less pre-treatment), ORR was 26% (95% CI: 18, 34). There were no complete responses. Median progression-free survival (PFS), a secondary outcome, was 6.9 months (95% CI: 4.2, 8.4) in TDM4374g and 4.6 months (95% CI: 3.9, 8.6) in TDM4258g.

Adverse events

Adverse events were commonly reported in patients receiving ado-trastuzumab emtansine. In the ado-trastuzumab emtansine group of the EMILIA trial, 96% of patients experienced an adverse event. In the two Phase II studies, the most common adverse events were fatigue (63%), nausea (44%), thrombocytopenia (38%), and headache (31%). The most common Grade 3 or 4 adverse event in all three studies was thrombocytopenia.

Thrombocytopenia

In the EMILIA trial, any Grade and Grade 3 or 4 thrombocytopenia occurred in 28% and 13% of patients in the ado-trastuzumab emtansine group, respectively, and in 2.5% and 0.2% of patients in the lapatinib+capecitabine group, respectively.

The association between thrombocytopenia and severe hemorrhagic events is unclear. In the two Phase II studies, three patients (1.3%) experienced Grade 3 epistaxis. Two of these patients had concurrent Grade 2 or 3 thrombocytopenia. Eight patients in these studies (3.6%) received a platelet transfusion. The incidence of bleeding events in the EMILIA trial was higher in the ado-trastuzumab emtansine group than in the lapatinib+capecitabine group (any Grade: 29.8% and 15.8%, respectively; Grade 3 or 4: 1.4% and 0.8%, respectively).

Elevated Liver Enzymes

In the EMILIA trial, elevated serum transaminases of any Grade occurred in approximately 20% of patients in the ado-trastuzumab emtansine -group and 9% of patients in the lapatinib+capecitabine group. With ado-trastuzumab emtansine dose modification, most patients (80%) with Grade 3 or 4 elevated serum transaminases continued treatment. Increases were commonly observed by Day 8 of each treatment cycle and generally returned to baseline before the next cycle. AST elevations occurred more commonly than ALT elevations. The incidence of Grade 1 or 2 serum transaminase elevations, but not the proportion of Grade 3 or 4 events, increased with successive cycles.

Heart Failure

An LVEF of 50% or more was an entry criterion for the EMILIA trial and the Phase II studies. In a Phase II safety population of 273 patients (including TDM4258g and TDM4374g), eight patients (3%) developed an asymptomatic decrease from baseline LVEF of 10 percentage points or more to an absolute LVEF less than 50%. In the EMILIA trial, 1.7% (eight patients) in the ado-trastuzumab emtansine group and 1.6% (7 patients) in the lapatinib+capecitabine group had an LVEF less than 50% and a decrease from baseline of 15 percentage points. At the time of final data cut-off, Grade 3 left ventricular systolic dysfunction developed in only one ado-trastuzumab emtansine -treated patient.

Infusion Reactions

In the Phase II TDM4258g study, infusion-related reactions occurred in 13.6% of patients; all were Grade 1 or 2.

Off-Label Use

Conference abstracts have presented results of several Phase I and Phase II studies of ado-trastuzumab emtansine for off-label uses. The main categories for off-label uses are for breast cancer at earlier stages or in various combination therapies for breast cancer, and for use in non-breast cancers.

Earlier Stages of Breast Cancer. The MARIANNE trial, currently in progress, is a Phase III, three-arm trial comparing ado-trastuzumab emtansine, ado-trastuzumab emtansine plus pertuzumab, and trastuzumab plus a taxane for first-line treatment of metastatic breast cancer. GDC-0941 is an oral inhibitor of a downstream intracellular pathway regulated by HER2. Constitutive activation of this pathway is thought to contribute to trastuzumab insensitivity in HER2-positive breast cancer. A Phase Ib dose escalation study of this combination in patients with HER2-positive breast cancer who progressed on prior trastuzumab therapy is currently in progress.

Additional indications being studied include initial treatment of metastatic breast cancer, in combination with pertuzumab and/or paclitaxel for previously treated metastatic disease, or in patients previously treated with systemic chemotherapy.

Other cancer types. In preclinical studies of gastric cancer, ado-trastuzumab emtansine has shown efficacy. An ongoing Phase I study is assessing the combination of ado-trastuzumab emtansine plus capecitabine in patients with metastatic HER2-positive gastric cancer. A Phase III trial (N=412) comparing two different doses of ado-trastuzumab emtansine (3.6 mg/kg every three weeks or 2.4 mg/kg weekly) to standard taxane therapy in patients with HER2- positive advanced gastric cancer who experienced disease progression during or after first-line therapy is currently in progress.

Ongoing clinical trials

A search of ClinicalTrials.Gov returned numerous trials of ado-trastuzumab emtansine for various stages of breast cancer, in different combinations with other agents, and a smaller number of trials on treatment of gastric cancer. The following is a summary of the ongoing studies.

Breast Cancer

NCT01120184- A Phase III Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE). Study population is adults with HER2-positive progressive or recurrent locally advanced breast cancer or with previously untreated metastatic breast cancer.

NCT01419197- A Phase III study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-Positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-Directed Therapy (TH3RESA). This study will be conducted in adults with HER2 positive metastatic breast cancer who have received at least two prior regimens of HER2-directed therapy.

NCT0170257- A Phase III study of Trastuzumab Emtansine in adults with HER2-positive locally advanced or metastatic breast cancer who have received prior anti-HER2 and chemotherapy-based Treatment.

NCT01745965- A Prospective, Randomized Multicenter, Open-label Comparison of Preoperative Trastuzumab Emtansine (T-DM1) With or Without Standard Endocrine Therapy vs. Trastuzumab With Standard Endocrine Therapy Given for Twelve Weeks in Patients With Operable HER2+/HR + breast cancer within the ADAPT protocol. Phase II.

NCT00934856- A Study of Trastuzumab Emtansine (T-DM1) in Combination With Docetaxel, and Potentially Pertuzumab, in Patients With Advanced Breast Cancer , Phase I.

Gastric Cancer

NCT01641939- A Study of Trastuzumab Emtansine Versus Taxane in Patients With Advanced Gastric Cancer. Studied in adults with HER2-positive advanced gastric cancer who have experienced disease progression during or after first-line therapy. Phase III.

NCT01702558- A Combination Study of Trastuzumab Emtansine And Capecitabine in Patients With Breast Cancer Or Gastric Cancer. Studied in adults with HER2-positive metastatic breast cancer or locally advanced or metastatic gastric cancer. Phase II.

Summary

Trastuzumab emtansine (ado-trastuzumab emtansine) is an antibody-drug conjugate that links the HER2 antagonist activity of trastuzumab to the cytotoxic activity of emtansine (DM1). Based on results of the pivotal EMILIA trial, ado-trastuzumab emtansine is FDA-approved for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab and a taxane. The EMILIA trial reported an improvement in PFS of 3.2 months, and an absolute improvement in overall survival of 5.8 months for patients treated with ado-trastuzumab emtansine compared with lapatinib plus capecitabine. Uncontrolled studies corroborate the efficacy of ado-trastuzumab emtansine with objective response rates reported for 26% and 35% of patients in two phase II studies. Adverse events from ado-trastuzumab emtansine treatment are common. Thrombocytopenia is the most common dose-limiting side effect, with 13% of ado-trastuzumab emtansine -treated patients in EMILIA experiencing grade 3 or 4 thrombocytopenia. Increases in liver enzymes are also common. Decreases in left ventricular ejection fraction have been observed; ado-trastuzumab emtansine has not been studied in patients with a LVEF of less than 50% before initiation of treatment.

Practice Guidelines and Position Statements

Trastuzumab emtansine is not currently included in any identified guidelines.

In June 2012, the UK’s National Institute for Health Research (NIHR) Horizon Scanning Centre identified T-DM1 in combination with pertuzumab (Perjeta®) for first-line treatment of HER2-positive metastatic breast cancer as an emerging health technology that may “significantly impact patients or the provision of health services” (Llau, 2008).

In September 2012, the UK’s National Institute for Health and Clinical Excellence (NICE) published the draft scope for a proposed Health Technology Appraisal entitled, “Trastuzumab emtansine for the treatment of locally advanced or metastatic HER2-positive breast cancer after treatment with trastuzumab and a taxane” (Granero, 2008). A completion date for the Appraisal was not provided.

2014 Update

A literature search conducted through February 2014 did not identify any new information that would prompt a change in the coverage statement.

2015 Update

A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Two exploratory analyses of the EMILIA trial have been published subsequently. Krop and colleagues examined outcomes in patients with central nervous system (CNS) metastases (Krop, 2015). Patients with untreated and/or symptomatic CNS metastases or with CNS-only disease were excluded from the EMILIA trial. For the post-hoc analyses, patients with treated, asymptomatic CNS metastases at baseline (n=45 in the ado-trastuzumab emtansine group; n=50 in the control group) were reviewed. At median follow-up of 19 months, median PFS was similar between treatment groups (5.9 months ado-trastuzumab emtansine vs 5.7 months controls; HR, 1.00 [95% CI, 0.54 to 1.84]; stratified [by world region, prior chemotherapy regimen for advanced or metastatic disease, and presence of visceral metastases], log-rank test, p=1.00), but median OS was longer in the ado-trastuzumab emtansine group (26.8 months vs 12.9 months; HR, 0.38 [95% CI, 0.18 to 0.80]; stratified log-rank test, p=0.008). No new safety signals were identified. Welslau and colleagues reported greater improvements in patient-reported outcomes (time to symptom worsening and increase in diarrhea symptoms) with ado-trastuzumab emtansine compared with capecitabine-lapatinib (control) (Welslau, 2014). The proportion of patients experiencing a clinically significant improvement in symptoms was similar between groups.

In 2014, Krop et al published results of the TH3RESA trial in patients with progressive disease after 2 or more HER2-targeted treatment regimens for recurrent or metastatic breast cancer (Krop, 2015). TH3RESA was an international, phase 3, open-label randomized controlled trial (RCT) that compared ado-trastuzumab emtansine with treatment of physician’s choice (chemotherapy, hormone therapy, and/or HER2-targeted therapy). Eligible patients had been treated with both trastuzumab and lapatinib in the advanced setting and a taxane in any setting. Patients were randomized 2:1 to trastuzumab emtansine (n=404) or physician’s choice treatment (n=198), stratified by world region (U.S. vs Western Europe vs other), number of previous regimens for advanced disease (2-3 vs >3), and presence of visceral disease (any vs none). Co-primary end points were investigator-assessed PFS and OS. Analysis was intention to treat. Most patients (83%) in the physician’s choice group received HER2-targeted therapy plus chemotherapy (most commonly vinorelbine); 80% of patients in this group received trastuzumab. Median treatment duration was 2.7 months in the physician’s choice group versus 4.2 months in the ado-trastuzumab emtansine group. At median follow-up of approximately 7 months, median PFS was almost twice as long in the ado-trastuzumab group compared with the physicians’ choice group (6.2 months vs 3.3 months; stratified HR, 0.53 [95% CI, 0.42 to 0.66]; log-rank test, p<0.001). This finding was replicated in subgroup analyses of patients who did (n=149) or did not (n=49) receive trastuzumab in the physician’s choice group, and in several other subgroup analyses. For U.S. patients (n=99 in the ado-trastuzumab group; n=48 in the physician’s choice group), median PFS did not differ statistically between groups (HR, 0.71 [95% CI, 0.44 to 1.14]). In interim OS analysis, 15% of patients in the ado-trastuzumab emtansine group versus 22% in the physician’s choice group died a statistically nonsignificant result due to statistical correction (O’Brien-Fleming stopping boundary). Incidence of grade 3 or greater adverse events was lower in the ado-trastuzumab emtansine group compared with the physician’s choice group (32% vs 43%, respectively). Of several hematologic adverse events (neutropenia, febrile neutropenia, anemia, leukopenia, thrombocytopenia), only thrombocytopenia occurred more commonly in the ado-trastuzumab emtansine group (15% vs 3%). Nine patients (2%) who received ado-trastuzumab emtansine had grade 3 or worse hemorrhage compared with 1 patient (<1%) who received physician’s choice treatment.

In 2014, Genentech published an integrated safety analysis from 6 industry-funded studies of single-agent ado-trastuzumab emtansine (total N=884) (Dieras, 2014).

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov returned numerous trials of ado-trastuzumab emtansine for various stages of breast cancer, in various combinations with other agents, and a smaller number of trials of treatment of gastric cancer.

Breast Cancer

[NCT02131064] A Study Comparing Kadcyla Plus Perjeta Treatment to Chemotherapy Combined With Herceptin Plus Perjeta in Patients With HER2-Positive Breast Cancer; Phase 3 (432); population is neoadjuvant treatment of operable HER2-positive breast cancer.

[NCT01853748] A Randomized Phase II Study of Trastuzumab Emtansine (T-DM1) vs. Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT Trial); Phase 2 (500); population is adjuvant treatment of adults with HER2-positive, stage 1 invasive breast cancer.

[NCT01966471] A Study of Kadcyla (Trastuzumab Emtansine) Plus Perjeta (Pertuzumab) Following Anthracyclines in Comparison With Herceptin (Trastuzumab) Plus Perjeta and a Taxane Following Anthracyclines as Adjuvant Therapy in Patients With Operable HER2-positive Primary Breast Cancer; Phase 3 (2500); population is adults with HER2-positive, primary invasive, operable (nonmetastatic), node-positive brease cancer who have not received previous anthracycline therap or systemic therapy for currently diagnosed breast cancer.

[NCT01702571] A Study of Trastuzumab Emtansine in Patients With HER2-Positive Breast Cancer Who Have Received Prior Anti-HER2 And Chemotherapy-based Treatment; Phase 3 (1000); population is Adults with HER2-positive locally advanced or metastatic breast cancer who have received prior anti-HER2 and chemotherapy-based treatment

[NCT01772472] A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2- Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE); Phase 3 (1484); population is Adults with HER2-positive breast cancer who have residual tumor present in breast or axillary lymph nodes following preoperative therapy

[NCT01042379] I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer ; Phase 2 (800); population is Previously untreated women with operable (nonmetastatic) invasive breast cancer.

[NCT01745965] A Prospective, Randomized Multicenter, Open-label Comparison of Preoperative Trastuzumab Emtansine (T-DM1) With or Without Standard Endocrine Therapy vs Trastuzumab With Standard Endocrine Therapy Given for Twelve Weeks in Patients With Operable HER2+/HR+ Breast Cancer Within the ADAPT Protocol; Phase 2 (380); population is Women age 18-75 y with operable HER2+/HR+ breast cancer within the ADAPT protocol.

Gastric cancer

[NCT01641939] A Study of Trastuzumab Emtansine Versus Taxane in Patients With Advanced Gastric Cancer; Phase 3 (412); population is Adults with HER2-positive advanced gastric cancer who experienced disease progression during or after first-line therapy

[NCT01702558] A Combination Study of Trastuzumab Emtansine and Capecitabine in Patients With Breast Cancer or Gastric Cancer; Phase 2 (130); population is Adults with HER2-positive metastatic breast cancer or locally advanced or metastatic gastric cancer.

Practice Guidelines and Position Statements

American Society of Clinical Oncology

In 2014, ASCO published evidence-based guidelines on systemic therapy for patients with advanced HER2-positive breast cancer (Giordano, 2014). Ado-trastuzumab emtansine is recommended as second-line treatment for patients whose cancer progresses during or after first-line HER2-targeted therapy (eg, with trastuzumab, pertuzumab, and a taxane). Ado-trastuzumab emtansine is also recommended in subsequent lines unless previously tried. (Strength of both recommendations: strong, based on high quality evidence).

2016 Update

A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement.

2019 Update

In this study, T-DM1 and T-DM1 plus pertuzumab demonstrated noninferior PFS compared with trastuzumab plus taxane. Whereas the median PFS observed with T-DM1 (14.1 months) was similar to that observed in a previous phase II study, median PFS of 13.7 months in the trastuzumab plus taxane arm was somewhat longer than expected on the basis of reports of this regimen that were available at the time of study design (median PFS of approximately 9.5 months to 12.5 months). However, the median PFS of control arm is consistent with results from more recent studies. Addition of pertuzumab to T-DM1 did not improve PFS. Although preclinical data showed synergistic activity for the combination of T-DM1 and pertuzumab, such activity was not substantiated in this trial. Thus, further study that includes ongoing biomarker research may help to better explain this unexpected result (Perez, E.A., Barrios, C., Eiermann, W., et. al., 2019).

Whereas T-DM1–containing treatments did not show a statistically significant improvement overall in PFS, data presented here suggest that some patients may derive more relative benefit from T-DM1 than do others. Subgroup analyses showed a numerical trend for an increased relative treatment effect with T-DM1 in patients who had received HER2-directed therapy or taxanes in the early breast cancer setting. This finding is consistent with prior trials in which T-DM1 improved clinical outcomes in patients who previously received treatment with trastuzumab and taxane. Moreover, in patients who achieved response, duration of response was numerically longer in T-DM1−treated patients compared with trastuzumab plus taxane−treated patients. Further investigation is necessary to determine whether specific characteristics can define a subgroup of patients with a greater response to T-DM1 in this treatment setting (Perez, E.A., Barrios, C., Eiermann, W., et. al., 2019).

Safety profiles of T-DM1 and pertuzumab in this study were consistent with previous reports. Treatment with T-DM1 seemed to be more tolerable than that of the control regimen, as there were numerically fewer grade ≥ 3 AEs and fewer treatment discontinuations as a result of AEs observed with T-DM1 versus trastuzumab plus taxane. Of note, incidence of grade ≥ 3 AEs in the control arm (54.1%) was lower than that observed in other trials that used trastuzumab plus docetaxel in the first-line setting (63% to 91%).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455677/#B17 This may be explained, at least in part, by the observation that 27% of patients received paclitaxel instead of docetaxel in the control arm of this study. Nevertheless, T-DM1 also seemd to be more tolerable on the basis of a numerically lower incidence of certain clinically important AEs (febrile neutropenia, neuropathy, diarrhea, and alopecia) versus trastuzumab plus taxane. The most commonly reported high-grade AEs with T-DM1 were laboratory abnormalities, such as transaminase elevation and thrombocytopenia, as previously observed in other T-DM1 studies. T-DM1−treated patients also had a longer time to a clinically meaningful decrease according to the FACT-B TOI-PFB scale, which indicated that they maintained baseline HRQOL longer than did trastuzumab plus taxane−treated patients (Perez, E.A., Barrios, C., Eiermann, W., et. al., 2019).

In conclusion, T-DM1−containing regimens demonstrated noninferior—but not superior—PFS compared with treatment with trastuzumab plus taxane. On the basis of the improved tolerability and noninferior PFS observed with T-DM1, it may provide an alternate treatment option to trastuzumab plus taxane in patients HER2-positive MBC. Indeed, the National Comprehensive Cancer Network has included T-DM1 in its breast cancer guidelines as a first-line treatment option for patients with HER2-positive MBC who are considered not suitable for treatment with the preferred regimen, pertuzumab, trastuzumab, and a taxane (Perez, E.A., Barrios, C., Eiermann, W., et. al., 2019).

Update July 2019

KATHERINE (NCT01772472) was a randomized, multicenter, open-label trial of 1486 patients

with HER2-positive, early breast cancer. Patients were required to have had neoadjuvant taxane

and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph

nodes. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment

as per local guidelines. Breast tumor samples were required to show HER2 overexpression

defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory using

Ventana’s PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or

INFORM HER2 Dual ISH DNA Probe Cocktail assays. Patients were randomized (1:1) to

receive KADCYLA or trastuzumab. Randomization was stratified by clinical stage at

presentation, hormone receptor status, preoperative HER2-directed therapy (trastuzumab,

trastuzumab plus additional HER2-directed agent[s]), and pathological nodal status evaluation

after preoperative therapy.

KADCYLA was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Trastuzumab was

given intravenously at 6 mg/kg on Day 1 of a 21-day cycle. Patients were treated with KADCYLA

or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of

consent, or unacceptable toxicity. At the time of the major efficacy outcome analysis, median

treatment duration was 10 months for both KADCYLA- and trastuzumab-treated patients. Patients

who discontinued KADCYLA for reasons other than disease recurrence could complete the

remainder of the planned HER2-directed therapy with trastuzumab if appropriate based on toxicity

considerations and investigator discretion.

The major efficacy outcome of the study was invasive disease-free survival (IDFS). IDFS was

defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast

tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence,

contralateral invasive breast cancer, or death from any cause. Additional efficacy outcomes

included IDFS including second primary non-breast cancer, disease free survival (DFS), and

overall survival (OS).

After a median follow-up of 40 months, a statistically significant improvement in IDFS was

observed in patients who received KADCYLA compared with trastuzumab.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through April 2020. No new literature was identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

A phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab was conducted. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).

At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.

Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (von Minckwitz G, Huang CS, Mano MS, 2019)

CPT/HCPCS:

References:

Baselga J, Swain SM.(2010) CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010; 10(6):489-91.

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

Burris HA, 3rd, Rugo HS, Vukelja SJ et al.(2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011; 29(4):398-405.

Burris HA, 3rd, Tibbitts J, Holden SN et al.(2011) Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer. Clin Breast Cancer 2011; 11(5):275-82.

Burris HA.(2011) Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Expert Opin Biol Ther 2011; 11(6):807-19.

Carlson RW, Allred DC, Anderson BO et al.(2012) Metastatic Breast Cancer, Version 1.2012: Featured Updates to the NCCN Guidelines. J Natl Comp Cancer Netw 2012; 10(7):821-29.

Chang J, Clark GM, Allred DC et al.(2003) Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 2003; 97(3):545-53.

Dawood S, Broglio K, Ensor J et al.(2010) Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol 2010; 21(11):2169-74.

Dieras V, Harbeck N, Budd GT, et al.(2014) Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. J Clin Oncol. Sep 1 2014;32(25):2750-2757. PMID 25024070

Dieras V, Miles D, Verma S, et al.(2017) Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. Jun 2017;18(6):732-742. PMID 28526536

Drouet L. [Rivaroxaban: mode of action]. Ann Fr Anesth Reanim 2008; 27 Suppl 3:S9-15.

Giordano SH, Temin S, Kirshner JJ, et al.(2014) 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. Jul 1 2014;32(19):2078-2099. PMID 24799465

Girish S, Gupta M, Wang B et al.(2012) Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 2012; 69(5):1229-40.

Granero Xiberta J, Soler Minoves JM, Garcia Nuno L.(2008) [Anaesthesia and thromboembolic disease]. Med Clin (Barc) 2008; 131 Suppl 2:18-24.

Gunter von Minckwitz, M.D., Chiun-Sheng Huang, M.D., Ph.D., Max S. Mano, M.D., Ph.D., et. al.(2019) Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019; 380:617-628. DOI: 10.1056/NEJMoa1814017

Hudis CA.(2007) Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357(1):39-51.

Hurvitz SA, Martin M, Symmans WF, et al.(2018) Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Jan 2018;19(1):115-126. PMID 29175149

Krop IE, Kim SB, Gonzalez-Martin A, et al.(2014) Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. Jun 2014;15(7):689-699. PMID 24793816

Krop IE, Kim SB, Martin AG, et al.(2018) Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. Jun 2017;18(6):743-754. PMID 28526538

Krop IE, Lin NU, Blackwell K, et al.(2015) Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol. Jan 2015;26(1):113-119. PMID 25355722

Krop IE, LoRusso P, Miller KD et al.(2012) A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30(26):3234-41.

Lippi G, Franchini M, Targher G.(2008) Rivaroxaban for thromboprophylaxis. N Engl J Med 2008; 359(20):2174; author reply 75-6.

LoRusso PM, Weiss D, Guardino E et al.(2011) Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res 2011; 17(20):6437-47.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Breast Cancer v.4.2023. Available at https://www.nccn.org. Accessed April 12, 2023.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Breast Cancer v.4.2023. Available at https://www.nccn.org. Accessed April 12, 2023.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Central Nervous System Cancers v.1.2023. Available at https://www.nccn.org. Accessed April 12, 2023.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Head and Neck Cancers v.1.2023. Available at https://www.nccn.org. Accessed April 12, 2023.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Non-Small Cell Lung Cancer v.2.2023. Available at https://www.nccn.org. Accessed April 12, 2023.

National Comprehensive Cancer Network (NCCN).(2018) NCCN Clinical Practice Guidelines in Oncology: breast cancer. Version 1.2018. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed June 27, 2018.

National Comprehensive Care Network. Breast Cancer.(2012) NCCN Clinical Practice Guidelines in Oncology 2012; version 1.2012. Available online at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Last accessed June, 2012.

Perez EA, Barrios C, Eiermann W, et al.(2017) Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol. Jan 10 2017;35(2):141-148. PMID 28056202

Perez EA, Barrios C, Eiermann W, et al.(2019) Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study J Clin Oncol. 2019 Feb 1;37(4):358]. J Clin Oncol. 2016;35(2):141–148. doi:10.1200/JCO.2016.67.4887

PerjetaTM (pertuzumab) injection for intravenous use prescribing information, June 2012. Genentech, Inc. http://www.perjeta.com/. Accessed February 2013.

Press MF, Sauter G, Bernstein L et al.(2005) Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 2005; 11(18):6598-607.

Verma S, Dieras V, Gianni L et al. EMILIA: A phase III, randomized, multicenter study of trastuzumab-DM1 (T-DM1)(2011) Compared with lapatinib (L) plus capecitabine (X) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC) and previously treated with a trastuzumab-based regimen. J Clin Oncol 2011; 29(15 suppl 1)abstract.

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

von Minckwitz G, Huang CS, Mano MS, et.al.,(2019) Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. doi: 10.1056/NEJMoa1814017. Epub 2018 Dec 5. PMID: 30516102.

Welslau M, Dieras V, Sohn JH, et al.(2014) Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer. Mar 1 2014;120(5):642-651. PMID 24222194

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.