Medicare Advantage

Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf (Phesgo®)
MA08.129a

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

Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo), administered subcutaneously by a healthcare professional, is  considered medically necessary and, therefore, covered when any of the following criteria are met:
  • Use in combination with chemotherapy in individuals with a left ventricular ejection fraction (LVEF) greater than 55 percent for either of the following:
    • Neoadjuvant treatment of individuals with Human Epidermal growth Receptor 2 (HER2)-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.
    • Adjuvant treatment of individuals with HER2-positive early breast cancer at high risk of recurrence 
  • Use in combination with docetaxel for treatment of individuals with HER2­-positive metastatic breast cancer (MBC), with a LVEF greater than 50 percent, who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease
  • Use as a substitute for the combination of intravenous pertuzumab and intravenous trastuzumab when given as part of systemic therapy​ for either invasive breast cancer (i.e., lobular, mixed, metaplastic, ductal/NST, or micropapillary histology) or inflammatory breast cancer in individuals with a LVEF greater than 50 percent. 
Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) are contraindicated in individuals with known hypersensitivity to pertuzumab, trastuzumab, hyaluronidase, or to any of their excipients.

HER2 PROTEIN OVEREXPRESSION TESTING
Coverage of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) requires that HER2 protein overexpression is verified as a positive result, and is considered medically necessary and, therefore, covered​ by one of the following Food and Drug Administration (FDA)​-approved diagnostic tests:
  • Immunohistochemical (IHC) assay with a result of 3+
  • Fluorescence in situ hybridization (FISH) test (HER2 gene/chromosome 17 ​ratio greater than 2.0)
  • Single-probe in situ hybridization (ISH) test with average HER2 copy number of 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 ​of 6.0 signals/cell or greater
Confirmatory tests should be performed for borderline results by using the same specimen with an alternative test or by using a new specimen with the same or alternative test as follows:
  • If IHC assay has a result of 2+
  • If FISH test has a HER2 gene/chromosome 17 ratio of 1.8-2.0
  • If single-probe ISH assay has an average HER2 copy number result of 4.0 to less than 6.0 signals/cell
  • 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
NOT MEDICALLY NECESSARY

When FDA-approved diagnostic tests do not reveal HER2 protein overexpression, pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) are 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 for pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

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 service.​

Guidelines

BLACK BOX WARNINGS 

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

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) are covered under the medical benefits of the Company's products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) were approved by the FDA on June 29, 2020 for metastatic breast cancer and neoadjuvant and adjuvant breast cancer.​​

Refer to the Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) prescribing information for further information on FDA-approved tests for determining HER2 protein overexpression and HER2 gene amplification.​

PEDIATRIC INDIVIDUALS 
The safety and effectiveness of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) have not been established in the pediatric population. 

Description

Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) are administered subcutaneously (SC). Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain of the human epidermal growth factor receptor 2 (HER2, previously called HER-2/neu), blocking HER2 activity. Trastuzumab is a monoclonal antibody that also binds to the HER2 protein, blocking HER2 activity in a different pathway than pertuzumab. Hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.

The HER2 gene is found on chromosome 17 and is involved in the process for making the HER2 protein. The HER2 protein is a receptor on the surface of the cell 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 cancer cases.

HER2 gene amplification and HER2 protein overexpression are highly correlated with faster tumor growth, shortened disease-free survival time, and shortened overall survival for individuals with breast cancer.

On June 29, 2020, the U.S. Food and Drug Association (FDA) approved pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) for the following indications:
  • Use in combination with chemotherapy as:
    • neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.
    • adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence 
  • Use in combination with docetaxel for treatment of patients with HER2­ positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
BREAST CANCER TREATMENT

METASTATIC BREAST CANCER TREATMENT
In a randomized, double-blind placebo-controlled phase 3 clinical trial, 808 individuals with HER2-positive metastatic breast cancer were assigned to a control group that received placebo plus trastuzumab plus docetaxel (n=406), or to a pertuzumab group that received pertuzumab, trastuzumab, and docetaxel (n-402) as a first-line treatment. The pertuzumab group has a significantly prolonged median progression-free survival compared to the control group, 18.5 months versus 12.4 months, respectively, with no increase in rates of cardiac dysfunction. 

NEOADJUVANT AND ADJUVANT BREAST CANCER TREATMENT
A phase 3, two-arm, open-label, multicenter, randomized study evaluated the pharmacokinetics, efficacy, and safety of pertuzumab and trastuzumab administered SC in combination with chemotherapy in 500 individuals with operable or locally advanced (including inflammatory) HER2 -positive early breast cancer with a tumor size >2 cm or node-positive in the neoadjuvant/adjuvant setting. Individuals were randomized to the control group, which received pertuzumab and trastuzumab intravenously (IV) concurrently with chemotherapy (n= 242), or the SC group, which received pertuzumab and trastuzumab SC concurrently with chemotherapy (n=234). The trough serum concentration of pertuzumab SC was non-inferior to pertuzumab IV.

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION
HER2 protein overexpression is detected either by immunohistochemical (IHC) assay or with a type of in situ hybridization (ISH) test for gene amplification (e.g., fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], dual in situ hybridization [DISH]). The FDA has approved several commercially available tests to aid in the selection of breast cancer patients for pertuzumab (Perjeta) therapy. The National Comprehensive Cancer Network (​NCCN) and American Society of Clinical Oncology (ASCO) guidelines further recommend that IHC assay and ISH testing should only be done at laboratories that are accredited to perform HER2 testing:
  • An IHC test result is reported as 0 or 1+ (negative), 2+ (borderline), or 3+ (positive).
  • A FISH test result is reported as a HER2 gene/chromosome 17 ratio less than 1.8 (negative), a ratio of 1.8 to less than 2.0 (borderline), or a ratio of 2.0 or greater (positive).
  • A single-probe ISH test result is reported as average HER2 copy number less than 4.0 signals/cell (negative); 4.0 to less than 6.0 signals/cell (borderline); 6.0 or greater signals/cell (positive).
  • A dual-probe ISH test result is reported as HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater (positive); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number less than 4.0 signals/cell (negative); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 4.0 to less than 6.0 signals/cell (borderline); HER2/CEP17 ratio less than 2.0 ​AND average HER2 copy number 6.0 signals/cell or greater (positive).
The NCCN and ASCO both have issued guidelines for HER2 testing in invasive breast cancer that call for confirming a borderline or e​quivocal result by using an alternative test on the same specimen or using the same or alternative test on a new specimen (if available) if:
  • IHC 2+ based on circumferential membrane staining that is incomplete and/or weak to moderate and within >10 percent of the invasive tumor cells or complete and circumferential membrane staining that is intense and within 10 percent or less of the invasive tumor cells​
  • ISH equivocal based on:
    • Single-probe ISH average HER2 copy number of 4 to 6 signals/cell​
    • Dual-probe HER2/CEP17 ratio of <2 with an average HER2 copy number of 4 to 6 signals/cell​

References

American Hospital Formulary Service (AHFS). P ertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo®). AHFS Drug Information 2021. [Lexicomp Web site]. 02/26/2021. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed September 15, 2021.

Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119. Available at: https://www.nejm.org/doi/10.1056/NEJMoa1113216?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0www.ncbi.nlm.nih.gov. Accessed September 15, 2021.

Elsevier/Gold Standard. Patient education. Pertuzumab; trastuzumab; hyaluronidase (Phesgo®). [Clinical Key Web site]. 08/17/2021. Available at: https://www.clinicalkey.com/phamacology/ [via subscription only]. Accessed September 15, 2021.

Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
 
IBM Micromedex® DRUGDEX® (electronic version). Pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo®). [Micromedex Web site]. IBM Watson Health, Greenwood Village, Colorado, USA. 02/14/2021. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed September 15, 2021.

Lexi-Drugs Compendium. Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo®). [Lexicomp Web site]. 08/20/2021. Available at: https://online.lexi.com/lso/action/home [via subscription only]. Accessed September 15, 2021.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology® - Breast Cancer. V8.2021. [NCCN Web site]. 08/13/2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via subscription only]. Accessed September 15, 2021.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium®. [NCCN Web site]. Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed September 15, 2021.

Novitas Solutions, Inc. Local Coverage Determination (LCD) 35396: Biomarkers for oncology. Original: 10/01/2015 (Revised: 12/13/2020). Available at: https://www.novitas-solutions.com/webcenter/portal/NovitasSolutions?_adf.ctrl-state=z55qb9g44_4. Accessed September 15, 2021. 

Tan AR, Im SA, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomized, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Phesgo® (pertuzumab, trastuzumab, and hyaluronidase-zzxf). Prescribing Information. [FDA Web site]. 06/29/2020. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed September 15, 2021.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Phesgo®​ (pertuzumab, trastuzumab, and hyaluronidase-zzxf). Biologics license approval letter. [FDA Web site]. 12/18/2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/761170Orig1s000ltr.pdf. Accessed September 15, 2021.

US Food and Drug Administration (FDA). In Vitro Diagnostics. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). [FDA Web site]. 09/02/2021. Available at: ​https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools. Accessed September 15, 2021.​

Wolff AC, Hale Hammond ME, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Onc. 2018;36(20):2105-2122.​

Coding

CPT Procedure Code Number(s)

N/A



ICD - 10 Procedure Code Number(s)

N/A



ICD - 10 Diagnosis Code Number(s)


C50.011    Malignant neoplasm of nipple and areola, right female breast

C50.012    Malignant neoplasm of nipple and areola, left female breast

C50.019    Malignant neoplasm of nipple and areola, unspecified female breast

C50.021    Malignant neoplasm of nipple and areola, right male breast

C50.022    Malignant neoplasm of nipple and areola, left male breast

C50.029    Malignant neoplasm of nipple and areola, unspecified male breast

C50.111    Malignant neoplasm of central portion of right female breast

C50.112    Malignant neoplasm of central portion of left female breast

C50.119    Malignant neoplasm of central portion of unspecified female breast

C50.121    Malignant neoplasm of central portion of right male breast

C50.122    Malignant neoplasm of central portion of left male breast

C50.129    Malignant neoplasm of central portion of unspecified male breast

C50.211    Malignant neoplasm of upper-inner quadrant of right female breast

C50.212    Malignant neoplasm of upper-inner quadrant of left female breast

C50.219    Malignant neoplasm of upper-inner quadrant of unspecified female breast

C50.221    Malignant neoplasm of upper-inner quadrant of right male breast

C50.222    Malignant neoplasm of upper-inner quadrant of left male breast

C50.229    Malignant neoplasm of upper-inner quadrant of unspecified male breast

C50.311    Malignant neoplasm of lower-inner quadrant of right female breast

C50.312    Malignant neoplasm of lower-inner quadrant of left female breast

C50.319    Malignant neoplasm of lower-inner quadrant of unspecified female breast

C50.321    Malignant neoplasm of lower-inner quadrant of right male breast

C50.322    Malignant neoplasm of lower-inner quadrant of left male breast

C50.329    Malignant neoplasm of lower-inner quadrant of unspecified male breast

C50.411    Malignant neoplasm of upper-outer quadrant of right female breast

C50.412    Malignant neoplasm of upper-outer quadrant of left female breast

C50.419    Malignant neoplasm of upper-outer quadrant of unspecified female breast

C50.421    Malignant neoplasm of upper-outer quadrant of right male breast

C50.422    Malignant neoplasm of upper-outer quadrant of left male breast

C50.429    Malignant neoplasm of upper-outer quadrant of unspecified male breast

C50.511    Malignant neoplasm of lower-outer quadrant of right female breast

C50.512    Malignant neoplasm of lower-outer quadrant of left female breast

C50.519    Malignant neoplasm of lower-outer quadrant of unspecified female breast

C50.521    Malignant neoplasm of lower-outer quadrant of right male breast

C50.522    Malignant neoplasm of lower-outer quadrant of left male breast

C50.529    Malignant neoplasm of lower-outer quadrant of unspecified male breast

C50.611    Malignant neoplasm of axillary tail of right female breast

C50.612    Malignant neoplasm of axillary tail of left female breast

C50.619    Malignant neoplasm of axillary tail of unspecified female breast

C50.621    Malignant neoplasm of axillary tail of right male breast

C50.622    Malignant neoplasm of axillary tail of left male breast

C50.629    Malignant neoplasm of axillary tail of unspecified male breast

C50.811    Malignant neoplasm of overlapping sites of right female breast

C50.812    Malignant neoplasm of overlapping sites of left female breast

C50.819    Malignant neoplasm of overlapping sites of unspecified female breast

C50.821    Malignant neoplasm of overlapping sites of right male breast

C50.822    Malignant neoplasm of overlapping sites of left male breast

C50.829    Malignant neoplasm of overlapping sites of unspecified male breast

C50.911    Malignant neoplasm of unspecified site of right female breast

C50.912    Malignant neoplasm of unspecified site of left female breast

C50.919    Malignant neoplasm of unspecified site of unspecified female breast

C50.921    Malignant neoplasm of unspecified site of right male breast

C50.922    Malignant neoplasm of unspecified site of left male breast

C50.929    Malignant neoplasm of unspecified site of unspecified male breast​​



HCPCS Level II Code Number(s)

J9316 Injection, pertuzumab, trastuzumab, and hyaluronidase-zzxf, per 10 mg



Revenue Code Number(s)

N/A




Coding and Billing Requirements


Policy History

3/21/2022
3/21/2022
MA08.129
Medical Policy Bulletin
Medicare Advantage
No