Coverage Policy Manual
Policy #: 2020021
Category: Pharmacy
Initiated: August 2020
Last Review: August 2023
  Pertuzumab, trastuzumab and hyaluronidase-zzxf (e.g., PHESGO™)
Description:
Both pertuzumab and trastuzumab are monoclonal antibodies and human epidermal growth factor receptor 2, (HER2)/neu receptor antagonists, they bind to different sites on HER2.   Hyaluronidase-zzxf is an endoglycosidase used to increase the dispersion and absorption of coadministered drugs when administered subcutaneously.  This allows this formulation to be given by a healthcare professional in a treatment center or at an individual's home.
 
Pertuzumab is a humanized recombinant IgG1 monoclonal antibody that binds to the extracellular dimerization domain (subdomain II) of the HER2 protein.   It blocks ligand-dependent heterodimerization of HER2 and other epidermal growth factor receptors including HER3 and HER4. Two intracellular signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K), are inhibited resulting in cell growth arrest and apoptosis.  It also demonstrates antibody-dependent cell-mediated cytotoxicity.  Pertuzumab differs from trastuzumab from where it binds to HER2; pertuzumab binds to the dimerization domain and trastuzumab binds in the juxtamembrane region.  Combining these 2 drugs has demonstrated enhanced tumor activity in HER2 amplified breast cancer in xenograft models.  This combination may also reduce trastuzumab resistance.
 
Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER2.  This inhibits ligand, independent, HER2-mediated cell proliferation and P13K signaling.  Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) preferentially acts on cancer cells that overexpress HER2 compared with cancer cells that do not overexpress HER2.  The overexpression of HER2 in tumor cells is closely associated with increase angiogenesis and expression of vascular epidermal growth factor (VEGF); when this pathway is inhibited, tumor growth is suppressed.  In the trastuzumab treated cells, the HER2 receptor is downregulated, cyclin -dependent kinase inhibitor p27 accumulates, and cell cycle arrest occurs.  It also inhibits the constitutive HER2 cleavage/shedding mediated by metalloproteases, which may correlate with the clinical activity of trastuzumab.
 
Hyaluronidase is an endoglycosidase used to increase dispersion and absorption of coadministered drugs when administered subcutaneously.  It increases permeability of the subcutaneously.  It increases permeability of the subcutaneous tissue by depolymerizing hyaluronan, which is a polysaccharide found in extracellular matrix of the subcutaneous tissue.  Unlike the stable structural component of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days; the effects of hyaluronidase are reversible, and permeability of subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase has been shown to increase the rate of absorption of a trastuzumab product into the systemic circulation.  
 
Regulatory Status
 
On June 29,2020 the FDA approved pertuzumab (e.g., Perjeta) and trastuzumab (e.g., Herceptin) plus hyaluronidase that is administered subcutaneously into the thigh over 5 minutes.  It is approved for use in combination with chemotherapy for HER2 advanced, inflammatory or early stage breast cancer, and early breast cancer at high risk for recurrence. This medication comes with a black box warning for serious cardiotoxicity, pulmonary toxicity and, embryo-fetal death and birth defects if used during pregnancy.  
 
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 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
    1. The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria that there be scientific evidence of effectives in improving health outcomes in adults with early breast cancer for use in combination with chemotherapy for (FDA, 2020):
a. Neoadjuvant treatment of adult individuals with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm diameter or node positive) as part of a complete treatment regimen for early breast cancer.
b. Adjuvant treatment of individuals with HER2-positive early breast cancer at high risk of recurrence, when ALL of the following are met:
i. Must be > 18 years old (FDA, 2020).  
ii. Must have documentation of locally advanced, inflammatory, or early stage HER2-positive breast cancer (FDA, 2020; ASCO 2018):
                1. Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
                2. If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive.
                3. The primary tumor is larger than 2 cm in diameter or individual is lymph node positive (for clinically evident by cytology and/or histopathology or on imaging).
                4. Women must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization (FDA, 2020).
c. Must be dosed in accordance with the FDA label.
2. The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria that there be scientific evidence of effectives in improving health outcomes in adults with metastatic breast cancer when Indicated for the use in combination with docetaxel for the treatment of adult individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2020) when ALL the following criteria are met:
a. Must be > 18 years old (FDA, 2020).  
b. Must have documentation of metastatic HER2 breast cancer (FDA, 2020; ASCO 2018):
i. Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
ii. If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive.
c. Must be used in combination with docetaxel (FDA, 2020).
d. Must have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2020)
e. Women must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization (FDA, 2020).  
f. Must be dosed in accordance with the FDA label unless otherwise specified.
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the individual meeting all 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 individual meeting specified criteria (See policy #2000030).
  
Dosage and Administration
Dosing per FDA Guidelines
 
Do not substitute pertuzumab, trastuzumab and hyaluronidase-zzxf for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.   
 
Pertuzumab, trastuzumab and hyaluronidase-zzxf is for subcutaneous use only in the thigh.   
 
Pertuzumab, trastuzumab and hyaluronidase-zzxf has different dosage and administration instructions than IV pertuzumab, IV trastuzumab and SC trastuzumab when administered alone.  
 
May be substituted anywhere that the combination of Intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy.  (NCCN 2A)
 
Pertuzumab, trastuzumab and hyaluronidase-zzxf must always be administered by a healthcare professional.  
 
In individuals with early breast cancer receiving docetaxel or paclitaxel with pertuzumab, trastuzumab and hyaluronidase-zzxf, administer those medications after pertuzumab, trastuzumab and hyaluronidase-zzxf.
 
In individuals with metastatic breast cancer receiving docetaxel, administer docetaxel after pertuzumab, trastuzumab and hyaluronidase-zzxf.
 
Recommended Doses and schedules
Initial Dose                                                                         Administration Instructions
1,200 mg pertuzumab, 600 mg trastuzumab                            Administer SC over approximately 8 minutes.
And 30,000 units hyaluronidase in 15 mL
(1,200 mg, 600 mg and 30,000 units/15mL
 
Maintenance (administer every 3 weeks)
600 mg pertuzumab, 600 mg trastuzumab,                             Administer SC over approximately 5 minutes
And 20,000 units hyaluronidase in 10 mL                            
(600 mg, 600 mg and 20,000 units/10mL)
 
Neoadjuvant treatment of Breast Cancer
 
Administer every 3 weeks for 3-6 cycles as part of the treatment regimen for early breast cancer.  
 
Following surgery, individuals should continue to receive pertuzumab, trastuzumab and hyaluronidase-zzxf to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity.
 
Adjuvant treatment of breast cancer
 
Administer every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity as part of a complete regimen; including standard anthracycline-and/or taxane-based chemotherapy.  Start pertuzumab, trastuzumab and hyaluronidase-zzxf on day 1 of the first taxane containing cycle.
 
Metastatic Breast Cancer
 
The recommended initial dose of docetaxel is 75 mg/square meters administered as an IV infusion.  The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.  Administer pertuzumab, trastuzumab and hyaluronidase-zzxf until disease progression or unmanageable toxicity.
 
Combination of pertuzumab and trastuzumab (e.g., Phesgo) is available as 1,200 mg pertuzumab, 600 mg trastuzumab and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in a single-dose vial and 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in a single-dose 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 pertuzumab, trastuzumab and hyaluronidase - zzxf in any condition or circumstance other than listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectives in improving health outcomes.
 
For individuals with contracts without primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes, the use of pertuzumab, trastuzumab and hyaluronidase - zzxf in any condition or circumstance other than listed above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective August 2022 to July 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
    1. The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria in adults with early breast cancer for use in combination with chemotherapy for (FDA, 2020):
      • Neoadjuvant treatment of adult individuals with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm 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, when ALL of the following are met:
        • Must be > 18 years old (FDA, 2020).  
        • Must have documentation of locally advanced, inflammatory, or early stage HER2-positive breast cancer (FDA, 2020; ASCO 2018):
          • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive;
          • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive;
          • The primary tumor is larger than 2 cm in diameter or individual is lymph node positive (for clinically evident by cytology and/or histopathology or on imaging).
          • Women must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization (FDA, 2020).
        • Must be dosed in accordance with the FDA label unless otherwise specified.
2. The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria in adults with metastatic breast cancer when Indicated for the use in combination with docetaxel for the treatment of adult individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2020) when ALL the following criteria are met:
      • Must be > 18 years old (FDA, 2020).  
      • Must have documentation of metastatic HER2 breast cancer (FDA, 2020; ASCO 2018):
        • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
        • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive
      • Must be used in combination with docetaxel (FDA, 2020).
      • Must have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2020)
      • Women must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization (FDA, 2020).  
      • Must be dosed in accorance with the FDA label unless otherwise specified.
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the individual meeting all 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 individual meeting specified criteria (See policy #2000030).
  
Dosage and Administration
    1. Do not substitute pertuzumab, trastuzumab and hyaluronidase-zzxf for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.   
    2. Pertuzumab, trastuzumab and hyaluronidase-zzxf is for subcutaneous use only in the thigh.   
    3. Pertuzumab, trastuzumab and hyaluronidase-zzxf has different dosage and administration instructions than IV pertuzumab, IV trastuzumab and SC trastuzumab when administered alone.  
    4. May be substituted anywhere that the combination of Intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy.  (NCCN 2A)
    5. Pertuzumab, trastuzumab and hyaluronidase-zzxf must always be administered by a healthcare professional.  
    6. In patients with early breast cancer receiving docetaxel or paclitaxel with pertuzumab, trastuzumab and hyaluronidase-zzxf, administer those medications after pertuzumab, trastuzumab and hyaluronidase-zzxf.
    7. In patients with metastatic breast cancer receiving docetaxel, administer docetaxel after pertuzumab, trastuzumab and hyaluronidase-zzxf.
 
Recommended Doses and schedules
Initial Dose                                                                         Administration Instructions
1,200 mg pertuzumab, 600 mg trastuzumab                           Administer SC over approximately 8 minutes.
And 30,000 units hyaluronidase in 15 mL
(1,200 mg, 600 mg and 30,000 units/15mL
 
Maintenance (administer every 3 weeks)
600 mg pertuzumab, 600 mg trastuzumab,                             Administer SC over approximately 5 minutes
And 20,000 units hyaluronidase in 10 mL                            
(600 mg, 600 mg and 20,000 units/10mL)
 
Neoadjuvant treatment of Breast Cancer
    1. Administer every 3 weeks for 3-6 cycles as part of the treatment regimen for early breast cancer.  
    2. Following surgery, individuals should continue to receive pertuzumab, trastuzumab and hyaluronidase-zzxf to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity.
 
Adjuvant treatment of breast cancer
    1. Administer every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity as part of a complete regimen; including standard anthracycline-and/or taxane-based chemotherapy.  Start pertuzumab, trastuzumab and hyaluronidase-zzxf on day 1 of the first taxane containing cycle.
 
Metastatic Breast Cancer
    1. The recommended initial dose of docetaxel is 75 mg/m2 administered as an IV infusion.  The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.  Administer pertuzumab, trastuzumab and hyaluronidase-zzxf until disease progression or unmanageable toxicity.
 
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  pertuzumab, trastuzumab and hyaluronidase - zzxf in any other condition than listed above does not meet member benefit certificate primary coverage criteria.
 
For individuals with contracts without primary coverage criteria that there be scientific evidence of effectiveness, the use of pertuzumab, trastuzumab and hyaluronidase - zzxf in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective September 2021 to July 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
  1. The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria in adults with early breast cancer for use in combination with chemotherapy for (FDA, 2020):
    • Neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm 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, when ALL of the following are met:
      • Must be > 18 years old (FDA, 2020).  
      • Must have documentation of locally advanced, inflammatory, or early stage HER2-positive breast cancer (FDA, 2020; ASCO 2018):
        • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive;
        • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive;
        • The primary tumor is larger than 2 cm in diameter or individual is lymph node positive (for clinically evident by cytology and/or histopathology or on imaging).
        • Women must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization (FDA, 2020).
2. The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria in adults with metastatic breast cancer when Indicated for the use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2020) when ALL the following criteria are met:
    • Must be > 18 years old (FDA, 2020).  
    • Must have documentation of metastatic HER2 breast cancer (FDA, 2020; ASCO 2018):
        • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
        • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive
    • Must be used in combination with docetaxel (FDA, 2020).
    • Must have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2020)
    • Women must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization (FDA, 2020).  
 
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 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
  1. Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.   
  2. PHESGO is for subcutaneous use only in the thigh.   
  3. PHESGO has different dosage and administration instructions than IV pertuzumab, IV trastuzumab and SC trastuzumab when administered alone.  
  4. May be substituted anywhere that the combination of Intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy.  (NCCN 2A)
  5. PHESGO must always be administered by a healthcare professional.  
  6. In patients with early breast cancer receiving docetaxel or paclitaxel with PHESGO, administer those medications after PHESGO.
  7. In patients with metastatic breast cancer receiving docetaxel, administer docetaxel after PHESGO.
 
Recommended Doses and schedules
Initial Dose                                                                         Administration Instructions
1,200 mg pertuzumab, 600 mg trastuzumab                           Administer SC over approximately 8 minutes.
And 30,000 units hyaluronidase in 15 mL
(1,200 mg, 600 mg and 30,000 units/15mL
 
Maintenance (administer every 3 weeks)
600 mg pertuzumab, 600 mg trastuzumab,                             Administer SC over approximately 5 minutes
And 20,000 units hyaluronidase in 10 mL                            
(600 mg, 600 mg and 20,000 units/10mL)
 
Neoadjuvant treatment of Breast Cancer
    • Administer every 3 weeks for 3-6 cycles as part of the treatment regimen for early breast cancer.  
    • Following surgery, Patients should continue to receive PHESGO to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity.
 
Adjuvant treatment of breast cancer
    • Administer every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity as part of a complete regimen; including standard anthracycline-and/or taxane-based chemotherapy.  Start PHESGO on day 1 of the first taxane containing cycle.
 
Metastatic Breast Cancer
    • The recommended initial dose of docetaxel is 75 mg/m2 administered as an IV infusion.  The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.  Administer PHESGO until disease progression or unmanageable toxicity.
 
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  pertuzumab, trastuzumab and hyaluronidase - zzxf in any other condition than listed above does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of pertuzumab, trastuzumab and hyaluronidase - zzxf in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of 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 2020 - August 2021
 
Policy/guidelines:
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria in adults with early breast cancer for use in combination with chemotherapy for:
    • Neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm 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; when ALL of the following are met:
 
  1.  Must be > 18 years old.  
  2.  Must have documentation of locally advanced, inflammatory or early stage HER2-positive breast cancer:
    • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
    • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive.
3.  The primary tumor is larger than 2 cm in diameter or individual is lymph node positive (for clinically evident by cytology and/or histopathology or on imaging);
4.  Individual has en ECOG performance status of 0-1  
5.  Must agree to use at least one highly effective non-hormonal contraceptive method or two effective non-hormonal contraceptives during treatment and for 7 months after the last dose of HER2-targeted therapy.  
6.  Women – must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization.  
 
The use of pertuzumab, trastuzumab and hyaluronidase meets primary coverage criteria in adults with metastatic breast cancer when Indicated for the use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.                                                                 
 
  1.  Must be > 18 years old.  
  2.  Must have documentation of metastatic HER2 breast cancer:
    • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
    • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive
3.  Individual has en ECOG performance status of 0-1.  
4.  Must be used in combination with docetaxel.
5.  Must have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
6.  Must agree to use at least one highly effective non-hormonal contraceptive method or two effective non-hormonal contraceptives during treatment and for 7 months after the last dose of HER2-targeted therapy.  
7.  Women – must have a neg serum pregnancy test prior to treatment, unless they have undergone surgical sterilization.  
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
  1.  0 = Fully active, able to carry on all pre-disease performance without restriction
  2.  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
  3.  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
  4.  3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
  5.  4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
  6.  5 = Dead
 
NCCN 1 and 2A recommendations are covered in accordance with Coverage Policy #2000030
 
Administration
 
  1. Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.  
 
2. PHESGO has different dosage and administration instructions than IV pertuzumab, IV trastuzumab and SC trastuzumab when administered alone.  
 
3. PHESGO must always be administered by a healthcare professional.  
 
4. In patients with early breast cancer receiving docetaxel or paclitaxel with PHESGO, administer those medications after PHESGO.
 
5. In patients with metastatic breast cancer receiving docetaxel, administer docetaxel after PHESGO.
 
Recommended Doses and schedules
 
Initial Dose                                                                         Administration Instructions
1,200 mg pertuzumab, 600 mg trastuzumab                            Administer SC over approximately 8 mins.
And 30,000 units hyaluronidase in 15 mL
(1,200 mg, 600 mg and 30,000 units/15mL
 
Maintenance (administer every 3 weeks)
600 mg pertuzumab, 600 mg trastuzumab,                             Administer SC over approximately 5 mins
And 20,000 units hyaluronidase in 10 mL                                every 3 weeks.
(600 mg, 600 mg and 20,000 units/10mL)
 
Neoadjuvant treatment of Breast Cancer
  • Administer every 3 weeks for 3-6 cycles as part of the treatment regimen for early breast cancer.  
  • Following surgery, Patients should continue to receive PHESGO to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity.
 
Adjuvant treatment of breast cancer
  • Administer every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity as part of a complete regimen; including standard anthracycline-and/or taxane-based chemotherapy.  Start PHESGO on day 1 of the first taxane containing cycle.
 
Metastatic Breast Cancer
  • The recommended initial dose of docetaxel is 75 mg/m2 administered as an IV infusion.  The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.  Administer PHESGO until disease progression or unmanageable toxicity.
 
 
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 pertuzumab, trastuzumab and hyaluronidase - zzxf in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Rationale:
A new subcutaneous (SC) formulation combining two monoclonal antibodies, pertuzumab and trastuzumab with recombinant human hyaluronidase in one vial, was developed.  It is to be administered SC in the thigh over 5-8 minutes.  The dose of trastuzumab was confirmed in a phase III HannaH trial (NCT00950300) and the dose of pertuzumab SC was established in a phase Ib study (NCT02738970).  The FeDeriCa study (NCT03493854) was designed to assess the pharmacokinetics, efficacy, and safety of this SC pertuzumab + trastuzumab novel formulation compared with trastuzumab IV and pertuzumab IV in patients with positive HER2-positive early breast cancer in the neoadjuvant-adjuvant setting.  
 
Five hundered patients with operable or locally advanced (including inflammatory) HER2-positive breast cancer with a tumor size >2 cm or node-positive were in an open-label, multicenter, randomized study.  HER2 overexpression was shown using an FDA approved test.  The patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either PHESGO or IV pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Following surgery, therapy was continued with PHESGO or IV pertuzumab and trastuzumab as treated prior to surgery, for an additional 14 cycles to complete 18 cycles of anti-HER2 therapy.  Patients also received adjuvant radiotherapy and endocrine therapy as per the investigator’s discretion. In the adjuvant period, substitution of IV trastuzumab for SC trastuzumab was permitted.  PHESGO demonstrated noninferior pre-dose cycle 8 pertuzumab plus trastuzumab Ctrough to that of IV pertuzumab and trastuzumab, with comparable efficacy and safety.    
 
Metastatic Breast Cancer
The effectiveness of PHESGO for use in combination with docetaxel has been established for the treatment of patients with HER2 -positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.  The use of PHESGO for this indication is supported by evidence from adequate, well controlled studies conducted with IV pertuzumab and IV trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing metastatic cancer (NCT00567190). FeDeriCa demonstrated comparable pharmacokinetics and safety profiles between PHESGO and IV pertuzumab and trastuzumab.  
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 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 August 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J3490Unclassified drugs
J3590Unclassified biologics
J9316Injection, pertuzumab, trastuzumab, and hyaluronidase-zzxf, per 10 mg
J9999Not otherwise classified, antineoplastic drugs
References: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.(2018) Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. https://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2018-her2-testing-algorithms.pdf. Accessed August 23, 2021.

Kirschbrown WP, Wynne C, Kagedal M;(2018) Development of a Subcutaneous Fixed-dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose-Finding Study. . J Clin Pharmacol. 2019 May; 59(5): 702–716. Published online 2018 Dec 19. doi: 10.1002/jcph.1362

National Comprehensive Cancer Network.(2021) Breast Cancer (Version 7.2021). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed August 23, 2021.

Pertuzumab; Trastuzumab; Hyaluronidase. In: Clinical Pharmacology [database on the Internet]. Tampa (FL): Elsevier. 2020 [accessed 08/20]. Available from: www.clinicalpharmacology.com. Subscription required to view.

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Tan Antoinette, Im Seock-Ah, Mattar Andre, et al.(2020) ); Abstract PD4-07: Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: AACR Cancer Research. 2020 Feb 14; 80 (4supplement): DOI:10.1158/1538-7445.SABCS19-PD4-07.
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