A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection was shown to be noninferior to the intravenous (IV) formulation of these 2 drugs in early-stage HER2-positive breast cancer, according to the results of the phase 3 FeDeriCa study.1
Pertuzumab, trastuzumab, and chemotherapy has become a standard-of-care triplet therapy for patients with HER2-positive early-stage and advanced breast cancer. However, IV administration of pertuzumab and trastuzumab is invasive, and individual infusion times for each agent typically approximate 30 to 90 minutes.
On June 29, 2020, the US Food and Drug Administration (FDA) approved a fixed-dose combination of pertuzumab and trastuzumab plus hyaluronidase-zzxf for subcutaneous administration over a period of approximately 5 to 8 minutes for patients with HER2-positive breast cancer.2
The randomized FeDeriCa trial (ClinicalTrials.gov Identifier: NCT03493854) was designed to evaluate the noninferiority, pharmacokinetics, efficacy, and safety of the subcutaneously administered fixed-dose combination of pertuzumab and trastuzumab compared with the delivery of the IV formulations of these drugs, both in combination with chemotherapy, in adults with HER2-positive early-stage breast cancer who were candidates for neoadjuvant treatment. Specifically, the patients enrolled in the study had operable locally advanced or inflammatory breast cancer.1
Treatment consisted of 8 neoadjuvant chemotherapy cycles, comprising 4 cycles of dose-dense doxorubicin plus cyclophosphamide (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks) followed by paclitaxel 80 mg/m2 once weekly for 12 weeks, or 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks followed by 4 docetaxel cycles every 3 weeks. Following completion of the neoadjuvant regimen and subsequent surgery, patients received an additional 14 cycles of HER2-directed therapy.
The primary end point was noninferiority of the cycle 7 pertuzumab serum trough concentration (Ctrough) within the fixed-dose combination for subcutaneous injection vs intravenous pertuzumab plus trastuzumab in the per-protocol pharmacokinetic population. Secondary end points included other pharmacokinetic outcomes, total pathologic complete response (pCR), and safety.
Of the 500 patients who underwent study randomization, 252 and 248 were randomly assigned to the IV infusion and fixed-dose combination arms, respectively. Patients were stratified according to hormone receptor status, clinical stage, and neoadjuvant chemotherapy regimen.
Baseline characteristics were generally well balanced across the 2 study arms, with a median patient age of 49.0 years and 52.0 years for those in the IV infusion and fixed-dose combination groups, respectively. Overall, more than 90% of patients in each group had an Eastern Oncology Cooperative Group (ECOG) performance status of 0, and the clinical stage at presentation was II to IIIA in approximately 80% of all patients.
A key finding of this study was that the geometric mean ratio of the pertuzumab serum Ctrough at cycle 7 was within the prespecified noninferiority margin. Furthermore, 60% of patients in both study arms achieved total pCR.
Regarding safety during administration of neoadjuvant therapy with HER-2-directed therapy plus chemotherapy, findings were very similar for those treated with either the fixed-dose or IV formulations of pertuzumab and trastuzumab. Grade 3/4 adverse events included neutropenia (13% [IV infusion group] vs 14% [fixed-dose group]), febrile neutropenia (6% in both study arms), and diarrhea (5% [IV infusion group] vs 7% [fixed-dose group]).
The primary analysis’ execution after completion of the neoadjuvant phase of therapy represented a study limitation.
In their concluding remarks, the study authors said the data support the FDA approval of the fixed-dose combination of pertuzumab and trastuzumab. “Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety,” they added.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry and/or the medical device industry. Please see the original reference for a full list of disclosures.
- Tan AR, Im S-A, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. doi:10.1016/S1470-2045(20)30536-2
- Phesgo. Prescribing information. Genentech, Inc.; 2020. Accessed January 7, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761170s000lbl.pdf