Commercial

Medical Policy

Title:

Margetuximab-cmkb (Margenza)

Policy #:

08.01.75c

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

MARGETUXIMAB-CMBK (MARGENZA)

Margetuximab-cmkb (Margenza) injection is considered medically necessary and, therefore, covered in combination with chemotherapy for the treatment of adult individuals with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and left ventricular ejection fraction of 50 percent or greater when any of the following criteria are met, including HER2 protein overexpression testing:

The individual has received two or more prior anti-HER2-based regimens (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, other anti-HER2 therapies) in the metastatic setting, at least one of which was for metastatic disease
Fourth-line therapy and beyond in combination with either capecitabine, eribulin, gemcitabine or vinorelbine for individuals with recurrent unresectable (local or regional) or stage IV (M1) (HER2)-positive disease regardless of hormone receptor status or endocrine therapy
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 regardless of hormone receptor status or endocrine therapy

CONTINUATION THERAPY

Margetuximab-cmkb (Margenza) is considered medically necessary and, therefore, covered for continuation therapy until disease progression, drug intolerance, or unacceptable toxicity.

NOT MEDICALLY NECESSARY

When FDA-approved diagnostic tests do not reveal HER2 protein overexpression, margetuximab-cmkb (Margenza) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support their use in the treatment of those diseases.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of margetuximab-cmkb (Margenza) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company's medical policy on off-label coverage for prescription drugs and biologics

MANDATES

PENNSYLVANIA MEMBERS

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

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

BLACK BOX WARNINGS

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

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2) PROTEIN OVEREXPRESSION TESTING

Coverage of trastuzumab and related biosimilars, fam-trastuzumab deruxtecan-nxki (Enhertu®) requires that HER2 protein overexpression is verified as a positive result by one of the following: FDA-approved diagnostic tests:

Immunohistochemical (IHC) assay with a result of 3+
Fluorescence in situ hybridization (FISH) test (ratio greater than 2.0)
Single-probe in situ hybridization (ISH) test with average HER2 copy number 6.0 signals/cell or greater
Dual-probe ISH test HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater or HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater

Confirmatory tests should be performed for borderline results as follows:

If IHC assay has a result of 2+, confirm with ISH test of the same sample or a new test with IHC or ISH (if new sample available).
If FISH test has a HER2 gene/chromosome 17 ratio of 1.8-2.0, confirm with FISH re-test; additional cell counting and recalculation of the ratio; or IHC assay.
If single-probe ISH assay has an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
If dual-probe ISH assay has a HER2/CEP17 ratio less than 2.0 and an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

DRUG INFORMATION

In accordance with US Food and Drug Administration (FDA) prescribing information, margetuximab-Cmkb (Margenza) is administered 15 mg/kg as an intravenous infusion over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3

weeks for all subsequent doses until disease progression or unacceptable toxicity.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, margetuximab-Cmkb (Margenza) is covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Margetuximab-Cmkb (Margenza) was approved by the FDA on December 16, 2020, to be administered 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.

Description

Margetuximab-cmkb, a human epidermal growth factor receptor 2 (HER2)/neu receptor antagonist, is a chimeric Fc-engineered IgG1 kappa monoclonal antibody. Margetuximab-cmkb binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (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).

In vitro, the modified Fc region of margetuximab-cmkb increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater in vitro ADCC and natural killer (NK) cell activation. Margetuximab has similar HER2-binding and antiproliferative effects as trastuzumab; however, its Fc region is engineered to increase affinity for both alleles of the activating Fc receptor (FcgR)—CD16A—and to decrease affinity for the inhibitory FcgR, CD32B. The low-affinity CD16A-158F allele (which is seen in about 85 percent of the population) has been associated with diminished clinical response to trastuzumab.

The HER2 gene is found on chromosome 17 and is involved in the process of making the HER2 protein. The HER2 protein is a receptor on the surface of the cell and sends messages to the cell to grow and divide more frequently. When cells have more than the normal number of copies of the HER2 gene, the gene is called amplified. Amplification of the HER2 gene results in HER2 protein overexpression, which occurs in approximately 25 percent of breast and gastric cancer cases. HER2 gene amplification and HER2 protein overexpression are highly correlated with faster tumor growth, shortened disease-free survival time, and shortened overall survival for individuals with breast or gastric cancer.

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION

HER2 protein overexpression is detected either by immunohistochemical (IHC) assay that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample or with a type of in situ hybridization (ISH) test for gene amplification (e.g., fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], dual in situ hybridization [DISH]). The FDA has approved several commercially available tests to aid in the selection of breast cancer individuals for fam-trastuzumab deruxtecan-nxki (Enhertu®) therapy. The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines (2018) further recommend that IHC assay and ISH testing should only be done at laboratories that are accredited to perform HER2 testing.

An IHC test result is reported as 0 or 1+ (negative), 2+ (borderline), or 3+ (positive).
A FISH test result is reported as a HER2 gene/chromosome 17 ratio less than 1.8 (negative), a ratio of 1.8 to less than 2.0 (borderline), or a ratio of 2.0 or greater (positive).
A single-probe ISH test result is reported as: average HER2 copy number less than 4.0 signals/cell (negative); 4.0 to less than 6.0 signals/cell (borderline); 6.0 or greater signals/cell (positive).
A dual-probe ISH test result is reported as HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater (positive); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number less than 4.0 signals/cell (negative); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 4.0 to less than 6.0 signals/cell (borderline); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater (positive).

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

IHC assay result of 2+: confirm with ISH test (if the same sample), or with a new IHC or ISH test (if new sample available).
FISH assay: confirm with either a repeat FISH test or an additional cell counting and recalculation of the ratio. If a repeat FISH test remains equivocal, then an IHC assay is recommended for confirmation.
Single-probe ISH assay: confirm with dual-probe ISH or with IHC (if the same sample), or with a new ISH or IHC (if new sample available).
Dual-probe ISH assay: confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

PEER-REVIEWED LITERATURE

SUMMARY

The efficacy of margetuximab-Cmkb (Margenza) plus chemotherapy was evaluated in phase III, a randomized, multicenter, open-label trial SOPHIA (NCT02492711). 536 individuals were selected with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Individuals were randomized (1:1) to margetuximab-Cmkb (Margenza) plus chemotherapy or trastuzumab plus chemotherapy. Individuals have progressed on or after the most recent line of therapy. Individuals were treated with margetuximab-Cmkb (Margenza) or trastuzumab in combination with chemotherapy until disease progression or unacceptable toxicity. The primary endpoints were progression-free and overall survival. Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR). The median age was 56 years (range: 27-86); 78 percent of individuals were older than 65 years. The majority of individuals were female (99.4 percent), and the majority were white (80 percent). Individuals had an ECOG performance status of 0 (58 percent) or 1 (42 percent) at baseline. The median number of prior lines of therapy in the locally advanced/metastatic setting was two (range: 1-4). All study participants had previously received trastuzumab, all but one individual had previously received pertuzumab, and 91 percent had previously received ado-trastuzumab emtansine.

The risk of disease progression was reduced by 24 percent in the central blinded review (primary endpoint), based on a median progression-free survival of 5.8 months with margetuximab/chemotherapy vs 4.9 months with trastuzumab chemotherapy (hazard ratio [HR] = 0.76; P = 0.033). Risk reduction was 30 percent according to investigator assessment (secondary endpoint).

Serious adverse reactions included febrile neutropenia (1.5 percent), neutropenia/neutrophil count decrease (1.5 percent) and infusion-related reactions (1.1 percent). Fatal adverse reactions occurred in 1.1 percent of individuals who received margetuximab-Cmkb (Margenza), including viral pneumonia (0.8 percent) and aspiration pneumonia (0.4 percent). Permanent discontinuation due to an adverse reaction occurred in 3 percent of individuals who received margetuximab-Cmkb (Margenza). Adverse reactions that resulted in permanent discontinuation in less than one percent of individuals who received margetuximab-Cmkb (Margenza) included left ventricular dysfunction and infusion-related reactions.

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Drug Information 2023. Margetuximab-Cmkb. [Lexicomp Online Web site]. 04/21/23. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed May 8, 2023.

American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Clinical Practice Guideline Update. [CAP Web site]. 05/2020. Available at: https://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2019-0904-SA. Accessed May 8, 2023.

Beser AR et al. HER-2, TOP2A and chromosome 17 alterations in breast cancer. Pathol Oncol Res. 2007;13:180-5.

Centers for Medicare & Medicaid Services (CMS). Agency for Healthcare Research and Quality (AHRQ) Technology Assessment Program. Technology assessment: Compendia for coverage of off-label uses of drugs and biologics in an anticancer chemotherapeutic regimen. Final report. [CMS Web site]. 05/07/07. Available at: http://www.cms.gov/medicare-coverage-database/details/technology-assessments-details.aspx?TAId=46&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=Pennsylvania&KeyWord=compendia&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAAAA==&. Accessed May 8, 2023.

Centers for Medicare & Medicaid Services (CMS). Medicare Benefit Policy Manual.Chapter 15: Covered medical and other health services. §50.4.5: Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen. Rev 212, Issued: 11/06/15, Effective: 08/12/15. Implementation 02/10/16. [CMS Web site]. Available at: https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Internet-Only-Manuals-Ioms-Items/Cms012673.html and https://www.cms.gov/Regulations-and-guidance/Guidance/Manuals/Downloads/bp102c15.pdf. Accessed May 8, 2023.

ClinicalTrials.gov. Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in the Treatment of HER2+ Metastatic Breast Cancer (SOPHIA). ClinicalTrials.gov Identifier: NCT02492711. First Posted: July 9, 2015; Last Update Posted: November 23, 2022. Available at: https://clinicaltrials.gov/ct2/show/record/NCT02492711. Accessed April 28, 2022.

Elsevier's Clinical Pharmacology Compendium .Margetuximab-Cmkb (Margenza).[Clinical Key Web site]. 12/30/20. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed May 8, 2023.

Lexi-Drugs Compendium. Margetuximab-Cmkb (Margenza). [Lexicomp Online Web site]. 05/10/2023. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed May 8, 2023.

Rugo HS et al. SOPHIA primary analysis: a Phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(Suppl 15): 1000.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Margetuximab-Cmkb (Margenza). Greenwood Village, CO. [Micromedex® Solutions Web site]. 03/07/2023. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed May 8, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. margetuximab-Cmkb (Margenza). [FDA Web site]. Original: 12/16/20. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed May 8, 2023.

US Food and Drug Administration (FDA). Devices @ FDA (HER2). Available at: http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm. Accessed May 8, 2023.

US Food and Drug Administration (FDA). Margetuximab-Cmkb (Margenza) prescribing information & approval letter. [FDA Web site]. 12/2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761106Orig1s000lbl.pdf. Accessed May 8, 2023.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment A.

HCPCS Level II Code Number(s)

J9353 Injection, margetuximab-cmkb, 5 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 08.01.75c:

06/19/2023

This version of the policy will become effective 06/19/2023

This policy was updated to communicate the criteria for margetuximab-Cmkb (Margenza) for metastatic HER2 positive breast cancer in accordance with the National Comprehensive Cancer Network (NCCN).

Revisions From 08.01.75b:

06/20/2022

This version of the policy will become effective 06/20/2022

This policy was updated to communicate the coverage position changes and criteria for margetuximab-Cmkb (Margenza) for metastatic HER2 positive breast cancer in accordance with the National Comprehensive Cancer Network (NCCN).

Revisions From 08.01.75a:

07/01/2021

This policy has been identified for the HCPCS code update, effective 07/01/2021.
The following HCPCS code has been termed from this policy:
C9399 Unclassified drugs or biologics
J3590 Unclassified biologics

The following HCPCS code has been added to this policy:

J 9353 Injection, margetuximab-cmkb, 5 mg

Revisions From 08.01.75:

03/01/2021

This version of the policy will become effective 03/01/2021.

This new policy has been issued to communicate the Company’s coverage position and criteria for margetuximab-Cmkb (Margenza).

Version Effective Date:

6/19/2023

Version Issued Date: