The FDA has approved a subcutaneous injection of pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo®, Genentech, Inc.) for adults with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This fixed-dose combination treatment is approved in combination with chemotherapy as neoadjuvant therapy for patients who have locally advanced, inflammatory, or early stage (either greater than 2 cm in diameter or node positive) disease; as adjuvant treatment for patients with HER2-positive early breast cancer at high risk of recurrence; and 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.
The approval was based on FeDeriCa (NCT03493854), a phase 3 clinical trial which enrolled 500 patients with centrally confirmed operable or locally advanced HER2-positive invasive breast cancer, defined as tumors greater than two cm in diameter or node-positive disease. Patients were randomized in a 1:1 ratio. Arm A received eight cycles of neoadjuvant chemotherapy in combination with intravenous pertuzumab/trastuzumab. Arm B received eight cycles of chemotherapy plus the fixed-dose subcutaneous pertuzumab/trastuzumab combination. Chemotherapy consisted of investigator's choice of four cycles of doxorubicin/cyclophosphamide every two weeks followed by four cycles of weekly paclitaxel, or four cycles of doxorubicin/cyclophosphamide every three weeks followed by four cycles of docetaxel every three weeks. In both arms, pertuzumab/trastuzumab was administered every three weeks during Cycles 5-8. The study's primary end point was noninferiority of subcutaneous pertuzumab/trastuzumab, with secondary end points of total pathologic complete response and safety.
Subcutaneous pertuzumab/trastuzumab was found to be noninferior to the intravenous administration, with a geometric mean ratio of 1.22 for pertuzumab and 1.33 for trastuzumab. Total pathologic complete response was similar between patients receiving subcutaneous and intravenous treatment (59.7% vs 59.5%). Safety was similar between treatment arms, with the exception of a higher rate of administration-related reactions in patients receiving subcutaneous injection.
Adverse events of any grade occurring in at least 30% of patients receiving subcutaneous pertuzumab/trastuzumab included alopecia (77.0%), nausea (58.9%), and diarrhea (58.5%). Grade 3/4 adverse events occurred in 52.8% of patients receiving subcutaneous pertuzumab/trastuzumab and in 48.8% of patients receiving intravenous administration.
"Subcutaneous pertuzumab/trastuzumab fixed-dose combination demonstrated a noninferior pre-dose cycle…to that of [intravenous pertuzumab/trastuzumab]," concluded the trial's investigators, led by first author Antoinette R. Tan, MD, MHS, Chief of Breast Medical Oncology at Levine Cancer Institute of Carolinas HealthCare System, in their presentation of the results at the 2019 San Antonio Breast Cancer Symposium. "Pertuzumab/trastuzumab fixed-dose combination offers a faster and simpler method of pertuzumab/trastuzumab administration for HER2-positive breast cancer."
The recommended dose for the initial subcutaneous injection of pertuzumab/trastuzumab/hyaluronidase-zzxf in combination with chemotherapy is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase-zzxf administered over 8 minutes. This dose should be followed every three weeks by 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase-zzxf administered over 5 minutes. Upon completion of chemotherapy, the injection can be administered by a health care professional in a treatment center or at home.
For More Information
Tan AR, Im SA, Mattar A, et al (2020). Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Cancer Res (San Antonio Breast Cancer Symposium abstracts), 80(suppl_4). Abstract PD4-07. DOI:10.1158/1538-7445.SABCS19-PD4-07
Clinicaltrials.gov (2020). A study to evaluate the pharmacokinetics, efficacy, and safety of subcutaneous administration of the fixed-dose combination of pertuzumab and trastuzumab in combination with chemotherapy in participants with HER2-positive early breast cancer (FeDeriCa). NLM identifier: NCT03493854.
Phesgo® (pertuzumab/trastuzumab/hyaluronidase-zzxf) prescribing information (2020). Genentech, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761170s000lbl.pdf
US Food and Drug Administration (2020). FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf for HER2-positive breast cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-combination-pertuzumab-trastuzumab-and-hyaluronidase-zzxf-her2-positive-breast-cancer
Image credit: Ewa Krawczyk. Courtesy of the National Cancer Institute and Georgetown Lombardi Comprehensive Cancer Center