Notification



Notification Issue Date:



Medicare Advantage Policy

Title:Pertuzumab (Perjeta®)
Policy #:MA08.063c

This policy is applicable to the Company’s Medicare Advantage products only. Policies that are applicable to the Company’s commercial products are accessible via a separate commercial policy database.


The Company makes decisions on coverage based on the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, benefit plan documents and contracts, and the member’s medical history and condition. If CMS does not have a position addressing a service, the Company makes decisions based on Company Policy Bulletins. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable. Although the Medicare Advantage Policy Bulletin is consistent with Medicare’s regulations and guidance, the Company’s payment methodology may differ from Medicare.

When services can be administered in various settings, 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. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.


This Policy Bulletin document describes the status of CMS coverage, medical terminology, and/or benefit plan documents and contracts at the time the document was developed. This Policy Bulletin will be reviewed regularly and be updated as Medicare changes their regulations and guidance, scientific and medical literature becomes available, and/or the benefit plan documents and/or contracts are changed.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.

When services can be administered in various settings, 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. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

MEDICALLY NECESSARY

Pertuzumab (Perjeta®) is considered medically necessary and, therefore, covered for the indication(s) identified below in individuals who meet the applicable criteria, and whose tumors have human epidermal growth factor receptor 2 (HER2) protein overexpression verified as a positive result by one of the following US Food and Drug Administration (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).

NEOADJUVANT TREATMENT OF BREAST CANCER
Pertuzumab (Perjeta®) is considered medically necessary and, therefore, covered for preoperative (neoadjuvant)* treatment of individuals with HER2 positive, breast cancer, when all of the following criteria are met:
  • The HER2 status has been verified by one of the FDA-approved diagnostic tests listed above
  • The individual has a left ventricular ejection fraction of 50% or greater
  • For one of the following conditions:
    • The individual has locally advanced, inflammatory, or early stage breast cancer and both of the following:
      • Tumors are greater than 2 centimeter in diameter or node positive
      • Used in combination with trastuzumab (Herceptin®) as part of a complete treatment regimen for early breast cancer
    • The individual has stage T2-3, N0-1, M0 tumors, in those who desire breast preservation and fulfill criteria for breast-conserving surgery except for tumor size or for locally advanced disease (stage T0-4, N1-3, M0 or T2-4, N0, M0) when used with one of the following treatment regimens:
      • in combination with trastuzumab (Herceptin®) and paclitaxel (Taxol®, Abraxane®, Onxol®) following AC (doxorubicin and cyclophosphamide) regimen (NCCN-preferred regimen)
      • in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) following AC (doxorubicin and cyclophosphamide) regimen
      • in combination with TCH (docetaxel, carboplatin, and trastuzumab) regimen (NCCN-preferred regimen)

*Individuals, who begin Pertuzumab (Perjeta®) and trastuzumab (Herceptin®) in the neoadjuvant setting should receive three to six cycles before surgery and should continue treatment after surgery, every three weeks, to complete one year (up to 18 cycles).

ADJUVANT TREATMENT OF BREAST CANCER

Pertuzumab (Perjeta®) is considered medically necessary and, therefore, covered for the adjuvant treatment of individuals with HER2 positive locally advanced, inflammatory, or early stage breast cancer or individuals, who are at high risk of recurrence when all of the following criteria are met:
  • The HER2 status has been verified by one of the FDA-approved diagnostic tests listed above
  • The individual has a left ventricular ejection fraction of 50% or greater
  • One of the following regimens is used for a maximum of 18 cycles:
    • In combination with trastuzumab (Herceptin®) and paclitaxel (Taxol®, Abraxane®, Onxol®) following AC (doxorubicin and cyclophosphamide) regimen (NCCN-preferred regimen)
    • In combination trastuzumab (Herceptin®) and docetaxel (Taxotere®) following AC (doxorubicin and cyclophosphamide) regimen
    • In combination with TCH (docetaxel, carboplatin, and trastuzumab) regimen (NCCN-preferred regimen)

RECURRENT OR METASTATIC BREAST CANCER
Pertuzumab (Perjeta®) is considered medically necessary and, therefore, covered for the treatment of individuals with HER2 positive recurrent or stage IV (M1) breast cancer, who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, when all of the following criteria are met :
  • The HER2 status has been verified by one of the FDA-approved diagnostic tests listed above
  • The individual has a left ventricular ejection fraction of 50% or greater
  • The breast cancer is hormone receptor-negative, or hormone receptor-positive
  • One of the following regimens is used:
    • In combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) or paclitaxel (Taxol®, Abraxane®, Onxol®) regimen (NCCN-preferred regimen).
    • The individual, previously treated with chemotherapy in combination with trastuzumab (Herceptin®) in the absence of pertuzumab (Perjeta®), may be considered for treatment with trastuzumab (Herceptin®) plus pertuzumab (Perjeta®) with or without cytotoxic therapy (e.g., vinorelbine, taxane).
    • In combination with trastuzumab with or without cytotoxic therapy (eg, vinorelbine or taxane) for one line of therapy

EXPERIMENTAL/INVESTIGATIONAL

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

NOT MEDICALLY NECESSARY

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

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.
Policy Guidelines

There is no Medicare policy addressing this service; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, pertuzumab (Perjeta®) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

Certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy benefit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when pertuzumab (Perjeta®) is covered under a member's medical benefit (Part B benefit). It does not address instances when pertuzumab (Perjeta®) is covered under a member’s pharmacy benefit (Part D benefit).

BLACK BOX WARNINGS

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

DRUG SAFETY

The safety of pertuzumab (Perjeta®) as part of a doxorubicin-containing regimen has not been established.

US FOOD AND DRUG ADMINISTRATION (FDA)

Pertuzumab (Perjeta®) was approved by the FDA on June 8, 2012 for use in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) chemotherapy, for the treatment of individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2/neu therapy or chemotherapy for metastatic disease.

In September 2013, pertuzumab (Perjeta®) received a subsequent approval by the FDA as a neoadjuvant treatment in combination with trastuzumab and docetaxel for individuals with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as complete breast cancer regimen for early breast cancer.

Description

Pertuzumab (Perjeta®) 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). Amplification of the HER2 gene results in HER2 protein overexpression. Pertuzumab (Perjeta®) is administered intravenously in combination with another monoclonal antibody, trastuzumab (Herceptin®) and docetaxel (Taxotere®) chemotherapy. Pertuzumab (Perjeta®) is believed to work by targeting a different part of the HER2 receptor than trastuzumab (Herceptin®), and works in a way that is complementary to trastuzumab (Herceptin®), resulting in further reduction in growth and survival of HER2-positive breast cancer cells. Note: Pertuzumab (Perjeta®) is not indicated in breast cancer that does not overexpress the HER2 protein.

METASTATIC BREAST CANCER TREATMENT

In June 2012, pertuzumab (Perjeta®) was approved by the US Food and Drug Administration (FDA) for the treatment of individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER-2 therapy or chemotherapy for metastatic disease in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) chemotherapy.

PEER-REVIEWED LITERATURE
Summary

The approval of pertuzumab (Perjeta®) is based on a randomized, double-blind, placebo-controlled, Phase III clinical trial involving 808 individuals with HER2-positive metastatic breast cancer who were tested prior to treatment to determine whether the HER2 protein was increased. Individuals were randomly assigned to receive pertuzumab (Perjeta®), trastuzumab (Herceptin®), and docetaxel (Taxotere®), or trastuzumab (Herceptin®) and docetaxel (Taxotere®) with a placebo. The primary endpoint of the randomized trial was progression-free survival (PFS) as assessed by an independent review facility. Pertuzumab (Perjeta®) in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) significantly extended PFS by 6.1 months compared with placebo plus trastuzumab (Herceptin®) and docetaxel (Taxotere®) in the first-line treatment of individuals with HER2-positive metastatic breast cancer.

NEOADJUVANT TREATMENT OF BREAST CANCER

In September, 2013, the FDA granted accelerated approval of pertuzumab (Perjeta®) as part of a complete treatment regimen, in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®), before surgery (neoadjuvant setting) in women with locally advanced, inflammatory, or early-stage breast cancer greater than 2 cm. This makes pertuzumab (Perjeta®) the first FDA-approved drug for the neoadjuvant treatment of breast cancer. This indication was based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.

PEER-REVIEWED LITERATURE
Summary

Pertuzumab's (Perjeta®) accelerated approval, for neoadjuvant treatment, was based on an international, randomized, open-label, phase II trial (NeoSpare; n=417), which was designed to measure pathologic complete response (pCR). Women, with primary tumor greater than 2 cm in diameter, were randomly assigned in one of four neoadjuvant treatment regimens: trastuzumab (Herceptin®) plus docetaxel (Taxotere®); pertuzumab (Perjeta®) plus trastuzumab (Herceptin®) and docetaxel (Taxotere®); pertuzumab (Perjeta®) plus trastuzumab (Herceptin®); or pertuzumab (Perjeta®) plus docetaxel (Taxotere®). Neoadjuvant treatment with pertuzumab (Perjeta®) plus trastuzumab (Herceptin®) and docetaxel (Taxotere®) resulted in statistically significantly greater pCR compared with docetaxel (Taxotere®) plus either trastuzumab (Herceptin®) or pertuzumab (Perjeta®) (45.8% vs. 29%; 45.8% vs. 24%).

OTHER INDICATIONS

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

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION

HER2 protein overexpression is detected either by immunohistochemical (IHC) assay or with a type of in situ hybridization (ISH) test for gene amplification (e.g., fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], dual in situ hybridization [DISH]). The FDA has approved several commercially available tests to aid in the selection of breast cancer patients for pertuzumab (Perjeta®) therapy. The NCCN and American Society of Clinical Oncology (ASCO) guidelines further recommend that IHC assay and ISH testing should only be done at laboratories that are accredited to perform HER2 testing.
  • 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 same sample), or with a new IHC or ISH test (if new sample available).
  • FISH assay: confirm with either a repeat FISH test or an additional cell counting and recalculation of the ratio. If a repeat FISH test remains equivocal, then an IHC assay is recommended for confirmation.
  • Single-probe ISH assay: confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
  • Dual-probe ISH assay: confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

References

American Hospital Formulary Service (AHFS). Drug Information 2017. Pertuzumab (Perjeta®). [Lexicomp Online Web site]. 04/17/2019. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed April 23, 2019.

Baselga J, Cortes J, Sung-Bae K, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366:109-119.

Breastcancer.org WebSite. HER2 status. 03/19/2019. Available at: http://www.breastcancer.org/symptoms/diagnosis/her2#. Accessed April 23, 2019.

Burstein H. Adjuvant medical therapy for HER2-positive breast cancer. [Uptodate Web site]. 04/08/2019. Available at: http://www.uptodate.com/contents/adjuvant-medical-therapy-for-her2-positive-breast-cancer. Accessed April 23, 2019.

Carlson B. New automated HER2 test promises faster, more accurate testing. Biotechnol Healthc. 2011;8(4): 32–33.

Elsevier Gold Standard's Clinical Pharmacology Compendium.Pertuzumab (Perjeta®). 12/28/2017. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed April 23, 2019.

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 Jan;13(1):25-32.

Giordano SH, Temin S, Kirshner JJ, et al. 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. 2014 May 5.

Hammond MEH, Hayes DF, Dowsett M, et al. ASCO-CAP guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784-2795.

Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287-5312.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Breast Cancer. V1.2019. [NCCN Web site]. 03/14/2019. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed April 23, 2019.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium.Pertuzumab (Perjeta®). [NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=383 . [via subscription only]. Accessed April 23, 2019.

Perjeta® (pertuzumab). [prescribing information] South San Francisco, CA: Genentech, Inc.; 2017. 12/2018. Available at: https://www.gene.com/download/pdf/perjeta_prescribing.pdf. Accessed April 23, 2019.

Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-83.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Pertuzumab (Perjeta®). [Micromedex® Solutions Web site]. 12/26/2018. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed April 23, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Pertuzumab (Perjeta®). prescribing information. [FDA Web site]. December 2018. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails . Accessed April 23, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Pertuzumab (Perjeta®). Biologics license approval letter. [FDA Web site]. 06/08/2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/125409Orig1s000ltr.pdf. Accessed April 23, 2019.

Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol.2013;31(31):3997-4013.

Yamauchi H, Hayes D. HER2 and predicting response to therapy in breast cancer. [Uptodate Web site]. 09/05/2018. Available at: http://www.uptodate.com/contents/her2-and-predicting-response-to-therapy-in-breast-cancer. Accessed April 23, 2019.



Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

See Attachment A


HCPCS Level II Code Number(s)

J9306 Injection, pertuzumab, 1mg




Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References

Attachment A: Pertuzumab (Perjeta®)
Description: ICD-10-CM Codes and Narratives






Policy History

MA08.063c
07/01/2019This version of the policy will become effective 07/01/2019.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria were updated to clarify tumor staging for treatments of breast cancer.

Not medically necessary statement was added.

MA08.063b
11/01/2017This version of the policy will become effective 11/01/2017.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria were updated to clarify tumor staging for neoadjuvant treatment of breast cancer.

MA08.063a
11/06/2015This policy was updated to include revised indications, with criteria, for the treatment of breast cancer according to FDA labeling (including criteria for left ventricular ejection fraction) and NCCN Guidelines. The testing for human epidermal growth factor receptor 2 (HER2) protein status has also been updated.

MA08.063
01/01/2015This is a new policy.






Version Effective Date: 07/01/2019
Version Issued Date: 07/01/2019
Version Reissued Date: N/A