November 15, 2020 - The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for the fixed-dose combination of pertuzumab plus trastuzumab with hyaluronidase-zzxf for administration via subcutaneous injection in combination with intravenous chemotherapy in the treatment of patients with early and metastatic HER2-positive breast cancer
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the fixed-dose combination of pertuzumab (Perjeta) plus trastuzumab (Herceptin) with hyaluronidase-zzxf (Phesgo) for administration via subcutaneous injection in combination with intravenous (IV) chemotherapy in the treatment of patients with early and metastatic HER2-positive breast cancer.1
The CHMP recommendation is based on data from the phase 3 FeDeriCa trial, where the combination proved to have noninferiority to IV formulations of the 2 agents in terms of pharmacokinetics, clinical efficacy, and safety.2
“We are delighted that Phesgo, the first combination of 2 established monoclonal antibodies with our ENHANZE technology, administered in just 5-8 minutes, is one step closer to becoming available for patients with HER2-positive breast cancer in the European Union,” Helen Torley, MB, MRCP, president and chief executive officer of Halozyme Therapeutics, Inc, stated in a press release.
The initial loading dose of the combination is estimated to take about 6 minutes to give, with each subsequent maintenance dose taking about 5 minutes. Generally, infusion of a loading dose of standard IV formulations of either agent take about 150 minutes to administer; subsequent maintenance infusions of the 2 drugs can take anywhere from 60 minutes to 150 minutes. The fixed-dose subcutaneous combination would allow for administration by a healthcare professional in a treatment center or at home.
A total of 500 patients were enrolled to the FeDeriCa trial, which met its primary end point after demonstrating noninferiority on the basis of predose cycle 8 serum Ctrough for the pertuzumab component of the fixed-dose combination; the mean value was 93.7 µg/mL versus 78.5 µg/mL for IV pertuzumab. Geometric means were 88.7 µg/mL and 72.4 µg/mL, respectively (geometric mean ratio [GMR], 1.22; 90% CI, 1.14-1.31).
Moreover, data from the trial showed noninferiority for the predose cycle 8 serum Ctrough for the trastuzumab component of the fixed-dose combination versus with IV trastuzumab, at 62.9 µg/mL versus 48.1 µg/mL, respectively. Geomertic means were 58.7 µg/mL for the subcutaneous formulation and 44.1 µg/mL for the IV formulation of trastuzumab (GMR 1.33; 90% CI, 1.24-1.43).
Additionally, total pathologic complete response (tpCR) in the breast and axilla, as well as safety, was found to be comparable between the 2 treatment regimens.
IV pertuzumab in combination with IV trastuzumab and chemotherapy has demonstrated improved outcomes for patients with HER2-positive breast cancer compared with IV trastuzumab and chemotherapy alone.
In the phase 1b dose-finding HannaH trial, the appropriate dose of trastuzumab and hyluronidase-oysk (Herceptin Hylecta) was identified.3 The appropriate dose of subcutaneous pertuzumab was identified in a phase 1b dose-finding trial.4
The new combination (SC FDC) was compared with the conventional IV approach as neoadjuvant therapy in patients with newly diagnosed stage II-IIIC HER2-positive breast cancer; these patients were enrolled at 122 sites onto the trial. Patients were randomized to receive 4 cycles of doxorubicin and cyclophosphamide chemotherapy followed by 4 cycles of docetaxel given with randomized therapy: IV pertuzumab and trastuzumab or the SC FDC.
After undergoing surgery, patients were administered adjuvant therapy with the same pertuzumab/trastuzumab formulation that they had received in the neoadjuvant setting. The primary analysis for the trial was done before adjuvant treatment was started.
The median age of participants was 50 years, 80% had stage II-IIIA disease, and 61% had hormone receptor–positive disease.
The comparison of predose cycle 8 Ctrough values for IV pertuzumab and trastuzumab and the individual components of the FDC resulted in GMRs that fell within the 90% confidence intervals for noninferiority.
The 2 treatment arms demonstrated almost identical rates of tpCR, which was defined as ypT0/Tis, ypN0. The tpCR was 59.5% with the IV agents versus 59.7% with the SC FDC.
Regarding safety, the most frequently reported adverse effects observed with the combination comprised alopecia, nausea, diarrhea, anemia, and asthenia. The combination can also result in the worsening of chemotherapy-induced neutropenia.
In June 2020, the FDA has approved the fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase-zzxfgiven in a subcutaneous injection in combination with IV chemotherapy for use in patients with early and metastatic HER2-positive breast cancer.