Author: [AUTHOR] Published on 7/20/2020 1:03:00 PM
FDA Approves PHESGO (Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf) in Combination with Chemotherapy for Patients with HER2-Positive Early Breast Cancer, or in Combination with Docetaxel for Patients with HER2-Positive Metastatic Breast Cancer who have not Received Prior Anti-HER2 Therapy or Chemotherapy for Metastatic Disease
On June 29, 2020, the US Food and Drug Administration (FDA) approved PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) for:
- Early breast cancer (EBC) 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 EBC.
- Adjuvant treatment of patients with HER2-positive EBC at high risk of recurrence.
- Metastatic breast cancer (MBC) in combination with docetaxel for treatment of patients with HER2-positive MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic test. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics
The approved recommended dosage is as follows:
- Initial dose: PHESGO 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes.
- Maintenance dose: PHESEGO 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes every 3 weeks.
- Neoadjuvant: PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion preoperatively for 3 to 6 cycles.
- Adjuvant: PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion postoperatively for a total of 1 year (up to 18 cycles).
- MBC: PHESGO by subcutaneous injection and docetaxel by intravenous infusion every 3 weeks.
PHESGO must always be administered by a healthcare professional by subcutaneous injection only in the thigh. PHESGO has different dosage and administration instructions than intravenous pertuzumab, intravenous trastuzumab, and subcutaneous trastuzumab when administered alone.
PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving PHESGO with anthracycline-containing chemotherapy regimens. Evaluate cardiac function prior to and during treatment with PHESGO. Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function.
Exposure to PHESGO can result in embryo-fetal death and birth defects, including oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.
PHESGO administration can result in serious and fatal pulmonary toxicity. Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Monitor patients until symptoms completely resolve.
Additional information regarding dosage and administration as well as warnings and precautions about cardiomyopathy, embryo-fetal toxicity, pulmonary toxicity, exacerbation of chemotherapy-induced neutropenia, and hypersensitivity and administration-related reactions can be found in the full prescribing information linked below.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
- MOA: PHESGO is a combination of pertuzumab and trastuzumab, HER2/neu receptor antagonists, and hyaluronidase, an endoglycosidase.
- General PK: Following subcutaneous administration of PHESGO, the mean Cycle 7 Cmax and AUC0-21 of pertuzumab were 34% lower and 5% higher, respectively, than that following intravenous administration of pertuzumab. The mean Cycle 7 Cmax and AUC0-21 of trastuzumab were 31% lower and 9% higher, respectively, than that following intravenous administration of trastuzumab.
- Absorption: The absolute bioavailability of pertuzumab and trastuzumab was 0.7 and 0.8, respectively. Tmax was 4 days for both compounds.
- Distribution: The volume of central compartment of pertuzumab and trastuzumab was 2.8 L and 2.9 L, respectively.
- Elimination: The linear elimination clearance of pertuzumab and trastuzumab was 0.2 L/day and 0.1 L/day, respectively. Trastuzumab also exhibits non-linear elimination.
- Immunogenicity: The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-recombinant human hyaluronidase PH20 antibodies after treatment with PHESGO is unknown.
Avoid anthracycline-based therapy for up to 7 months after stopping PHESGO. If use of anthracyclines is unavoidable, carefully monitor the patient's cardiac function. Patients who receive anthracycline after stopping PHESGO may be at increased risk of cardiac dysfunction because of PHESGO's long washout period.
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of pertuzumab and trastuzumab were observed based on age (25 to 80 years), race (Asian and non-Asian), body weight, baseline albumin level, or renal impairment (CLcr ≥ 30 mL/min, Cockcroft-Gault). The effects of hepatic impairment on the pharmacokinetics of pertuzumab and trastuzumab are unknown.
Efficacy and Safety
Efficacy of PHESGO was demonstrated for use in combination with chemotherapy for the treatment of patients with HER2-positive EBC, and in combination with docetaxel for the treatment of patients with HER2-positive MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Use of PHESGO for these indications is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing early and metastatic breast cancer. Additional information regarding efficacy trials can be found in the full prescribing information linked below.
In neoadjuvant and adjuvant treatment of breast cancer, the most common adverse reactions (> 30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia. In MBC based on intravenous pertuzumab, the most common adverse reactions (> 30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.