Coverage Policy Manual
Policy #: 2021025
Category: Pharmacy
Initiated: June 2021
Last Review: March 2025
  Margetuximab-cmkb (e.g., MARGENZA)
Description:
Margetuximab-cmkb, a human epidermal growth factor receptor 2 protein (HER2)/ neu receptor antagonist, is a monoclonal antibody. Margetuximab-cmkb binds to the extracellular domain of the HER2. Upon binding to HER2-expressing tumor cells, margetuximab-cmkb inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain and mediates antibody-dependent cellular cytotoxicity (ADCC). (Margenza, 2020)
 
Regulatory Status
 
Margetuximab-cmkb (e.g., Margenza) was approved by the U.S. Food and Drug Administration (FDA) on December 16, 2020, in combination with chemotherapy, for the treatment of adult individuals with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
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 March 5, 2025
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of margetuximab-cmkb, in combination with chemotherapy, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of HER2-positive breast cancer when ALL the following criteria are met:
 
FDA Labeled Indications:
 
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”)].
 
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Individual is 18 years of age or older (Margenza, 2023); AND
2. Individual has a diagnosis of metastatic HER2-positive breast cancer(Margenza, 2023); AND
3. Individual has received two or more prior anti-HER2 regimens with at least one of which was for metastatic disease (Margenza, 2023); AND
4. Individual has no evidence of significantly reduced left ventricular ejection fraction (less than 40%) or diagnosis of congestive heart failure (CHF) at the time of initiation (Margenza, 2023); AND
5. Individual has a current ECOG performance status of 2 or lower (Margenza, 2023).
 
CONTINUED APPROVAL for 1 year:
 
1. No evidence of disease progression; AND
2. No unacceptable toxicity while on the current regimen.
 
Off-label Indications:
 
The use of this drug for off-label indications not listed below is subject to policy 2000030.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
The following indications are covered when the individual meets the related NCCN category 1 or 2A recommendations specific to the indications below (e.g., histology, cancer staging, surgical status, mono- or combination therapy, and previous lines of therapy):
 
1. Breast Cancer:
a. Invasive Breast Cancer (NCCN 2A):
i. Fourth-line therapy and beyond in combination with either capecitabine, eribulin, gemcitabine or vinorelbine for recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is:
1. Hormone receptor-negative; OR
2. Hormone receptor-positive with or without endocrine therapy; OR
b. Inflammatory Breast Cancer (NCCN 2A):
i. Fourth-line therapy and beyond in combination with either capecitabine, eribulin, gemcitabine or vinorelbine for individuals with no response to preoperative systemic therapy, or recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is:
1. Hormone receptor-negative; OR
2. Hormone receptor-positive with or without endocrine therapy.
 
CONTINUED APPROVAL for 1 year:
 
      1. No evidence of disease progression AND
      2. No unacceptable toxicity while on the current regimen.
 
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications.
 
Policy Guidelines:
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale (ECOG -ACRIN Cancer Research Group, 2022):
    •  0 = Fully active, able to carry on all pre-disease performance without restriction
    •  1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    •  2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    •  3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    •  4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    •  5 = Dead
 
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
 
The recommended dose of margetuximab-cmkb is 15mg/kg for the initial dose, every three weeks until disease progression or unacceptable toxicity.
 
Margetuximab-cmkb (e.g., Margenza) is available as a 250mg/10ml vial.
 
Margetuximab-cmkb (e.g., Margenza) should be administered as an intravenous infusion by a healthcare professional.
 
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
 
Margetuximab-cmkb (e.g., Margenza), for any indicaiton or circumstance other than those outlined above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, margetuximab-cmkb (e.g., Margenza) for any indication or circumstance other than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective April 2024 to March 4, 2025
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of margetuximab-cmkb, in combination with chemotherapy, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of HER2-positive breast cancer when ALL the following criteria are met:
 
Invasive Breast Cancer
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
1. Individual is 18 years of age or older (FDA Margenza, 2020); AND
2. For third-line therapy and beyond, in combination with either capecitabine, eribulin, gemcitabine or vinorelbine 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; or
b. Hormone receptor-positive with or without endocrine therapy; AND
3. Individual has no evidence of significantly reduced left ventricular ejection fraction (<40%) or diagnosis of congestive heart failure (CHF) at the time of initiation (FDA Margenza 2020); AND
4. Individual has a current ECOG* performance status of 2 or lower (FDA Margenza, 2020).
5. Must be dosed in accordance with the FDA label.
 
Inflammatory Breast Cancer
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
1. Individual is 18 years of age or older (FDA Margenza, 2020); AND
2. Third-line therapy and beyond in combination with either capecitabine, eribulin, gemcitabine or vinorelbine for patients with no response to preoperative systemic therapy, or 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; or
b.  Hormone receptor-positive with or without endocrine therapy; AND
3. Individual has no evidence of significantly reduced left ventricular ejection fraction (<40%) or diagnosis of congestive heart failure (CHF) at the time of initiation (FDA Margenza 2020); AND
4. Individual has a current ECOG* performance status of 2 or lower (FDA Margenza, 2020)
5. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
1. No evidence of disease progression AND
2. No unacceptable toxicity while on the current regimen.
 
Policy Guidelines:
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
0 = Fully active, able to carry on all pre-disease performance without restriction
 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 = Dead
 
The use of this drug is covered if an 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 all of specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of margetuximab-cmkb is 15mg/kg for the initial dose, every three weeks until disease progression or unacceptable toxicity.
 
Margetuximab-cmkb (e.g., Margenza) is available as a 250mg/10ml vial.
 
Margetuximab-cmkb (e.g., Margenza) should be administered as an intravenous infusion by a healthcare professional.
 
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
 
Margetuximab-cmkb does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of margetuximab-cmkb for any indication or circumstance other than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 2022 - March 2024
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of margetuximab-cmkb, in combination with chemotherapy, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of HER2-positive breast cancer for the following indications when ALL the following criteria are met:
 
Invasive Breast Cancer  
    1.  Individual is 18 years of age or older (FDA Margenza, 2020); AND
    2.  For third-line therapy and beyond, in combination with either capecitabine, eribulin, gemcitabine or vinorelbine 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; or
b.  Hormone receptor-positive with or without endocrine therapy; AND
3.  Individual has no evidence of significantly reduced left ventricular ejection fraction (<40%) or diagnosis of congestive heart failure (CHF) at the time of initiation (FDA Margenza 2020); AND
4.  Individual has a current ECOG* performance status of 2 or lower (FDA Margenza, 2020).
5.  Must be dosed in accordance with the FDA label.
 
Inflammatory Breast Cancer    
    1.  Individual is 18 years of age or older (FDA Margenza, 2020); AND
    2.  Third-line therapy and beyond in combination with either capecitabine, eribulin, gemcitabine or vinorelbine for patients with no response to preoperative systemic therapy, or 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; or
b.  Hormone receptor-positive with or without endocrine therapy; AND
3.  Individual has no evidence of significantly reduced left ventricular ejection fraction (<40%) or diagnosis of congestive heart failure (CHF) at the time of initiation (FDA Margenza 2020); AND
4.  Individual has a current ECOG* performance status of 2 or lower (FDA Margenza, 2020)
5.  Must be dosed in accordance with the FDA label.
 
Policy Guidelines
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    •  0 = Fully active, able to carry on all pre-disease performance without restriction
    •  1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    •  2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    •  3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    •  4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    •  5 = Dead
 
The use of this drug is covered if an 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 all of specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of margetuximab-cmkb is 15mg/kg for the initial dose, every three weeks until disease progression or unacceptable toxicity.
 
Margetuximab-cmkb (e.g., Margenza™)  is available as a 250mg/10ml vial.
 
Margetuximab-cmkb (e.g., Margenza™) should be administered as an intravenous infusion by a healthcare professional.
 
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
 
Margetuximab-cmkb does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of margetuximab-cmkb for any indication or circumstance other than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2022
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of margetuximab-cmkb, in combination with chemotherapy, meets primary coverage criteria for the treatment of adult patients with metastatic HER2-positive breast cancer when dosed in accordance with FDA labeling and ALL of the following criteria are met:
 
    1. Member is diagnosed with metastatic HER2-positive breast cancer (documentation submitted) AND
    2. Member is 18 years of age or older AND
    3. Member has received at least two prior therapies for HER2-positive breast cancer with one prior therapy having been for metastatic disease AND
    4. Member has no evidence of significantly reduced left ventricular ejection fraction (<40%) or diagnosis of congestive heart failure (CHF) at the time of initiation AND
    5. Member has a current ECOG* performance status of 2 or lower
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
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 all of specified criteria (See policy #2000030).
 
Dosage and Administration
 
The recommended dose of margetuximab-cmkb is 15mg/kg over 120 minutes for the initial dose, then over 30 minutes every three weeks until disease progression or unacceptable toxicity.
 
Margetuximab-cmkb is available as a 250mg/10ml 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
 
Margetuximab-cmkb does not meet member benefit certificate primary coverage criteria for any other indication.
 
For members with contracts without primary coverage criteria, the use of margetuximab-cmkb in any other condition than listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Margetuximab is a modified version of trastuzumab, with the Fc component of the drug reengineered to make the medication work better in patients who carry the CD16A-158F allele. This engineering increases its ability to mediate Fc domain–dependent activities, including enhanced tumor cell killing via antibody-dependent cell-mediated cytotoxicity, with the potential to overcome resistance to Herceptin. In vitro, the modified Fc region of Margenza increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to the inhibitory Fc receptor FCGR2B (CD32B).
 
The efficacy and safety of margetuximab-cmkb plus chemotherapy was evaluated in a randomized, multicenter, open-label, phase 3 study. Eligible patients were diagnosed with HER2-positive advanced breast cancer and had progressive disease after two or more lines of HER-2 targeted therapy. This therapy included pertuzumab and one to three lines of nonhormonal metastatic breast cancer therapy. 536 patients were randomized in a one-to-one ratio to receive margetuximab-cmkb plus chemotherapy or trastuzumab plus chemotherapy. Chemotherapy choice included capecitabine, eribulin, gemcitabine, or vinorelbine. Randomization was stratified by chemotherapy choice, number of lines of therapy in metastatic setting, and number of metastatic sites. Patients were given margetuximab-cmkb at a dose of 15mg/kg intravenously every 3 weeks administered over 120 minutes for the initial administration and then over 30 to 120 minutes thereafter. Patients were given trastuzumab at a dose of 8mg/kg intravenously over 90 minutes, followed by 6mg/kg over 30 minutes every three weeks thereafter. Each regimen was given until disease progression or unacceptable toxicity.  
 
Primary endpoints were progression free survival and overall survival. Secondary endpoints included safety, clinical benefit rate, objective response rate, response duration, and antidrug antibodies. At the time of study analysis margetuximab-cmkb plus chemotherapy demonstrated improved progression free survival compared with trastuzumab plus chemotherapy with a 24% risk reduction, median progression free survival of 5.8 months vs 4.9 months, respectively. The overall survival analysis after 270 deaths occurred was 49.2% with margetuximab-cmkb plus chemotherapy vs 51.5% with trastuzumab plus chemotherapy. Median overall survival was 21.6 months with margetuximab-cmkb and 19.8 months with trastuzumab.
 
Common adverse effects in both treatment arms were fatigue, nausea, diarrhea, and neutropenia, as well as vomiting in the margetuximab-cmkb group and anemia in the trastuzumab group. Discontinuation of treatment due to adverse effects were similar in both groups, 3% in margetuximab-cmkb vs 2.6% in trastuzumab. Adverse events leading to death were reported in 5 patients, 3 in margetuximab-cmkb and 2 in trastuzumab. None were considered treatment related. (Rugo, 2021)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement.
 
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2025.
CPT/HCPCS:
J3490Unclassified drugs
J3590Unclassified biologics
J9353Injection, margetuximab-cmkb, 5 mg
References: Margenza [package insert]. Rockville, MD; MacroGenics, Inc. 2020

National Comprehensive Cancer Network (NCCNA)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Breast Cancer-Invasive Breast Cancer v.3.2023. Available at https://www.nccn.org. Accessed March 8, 2023.

National Comprehensive Cancer Network (NCCNA)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Breast Cancer-Special consideration: Inflammatory Breast Cancer v.3.2023. Available at https://www.nccn.org. Accessed March 8, 2023.

National Comprehensive Cancer Network, Inc (NCCN).(2021) 2021 Practice Guidelines in Oncology—Breast Cancer v.7.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed September 1, 2021.

Rugo HS, Im SA, Cardoso F, et al.(2021) SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncology. 2021 Jan 22.

U.S. Food and Drug Administration (FDA).(2020) Margenza. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761150s000lbl.pdf
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 © 2025 American Medical Association.