As reported in The Lancet Oncology by Tan et al, the phase III FeDeriCa trial showed comparable pharmacokinetics and pathologic complete response rates with a subcutaneous (SC) fixed-dose combination of pertuzumab and trastuzumab vs the same combination administered intravenously (IV)—both given with neoadjuvant chemotherapy and then postoperatively—in patients with HER2-positive early breast cancer.
The study supported the June 2020 U.S. Food and Drug Administration (FDA) approval of the SC fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf in this setting.
Antoinette R. Tan, MD
The open-label noninferiority trial included 500 patients from sites in 19 countries with HER2-positive, locally advanced or inflammatory, stage II–IIIC disease and a left ventricular ejection fraction of ≥ 55%. Patients were randomly assigned between June 2018 and December 2018 to the SC fixed-dose combination group (n = 248) or the IV combination group (n = 252).
The SC fixed-dose combination regimen consisted of pertuzumab at 1,200 mg and trastuzumab at 600 mg in 15 mL as a loading dose, followed by 600 mg of pertuzumab plus 600 mg of trastuzumab maintenance doses in 10 mL administered every 3 weeks with neoadjuvant chemotherapy; the fixed-dose combination contained hyaluronidase at 2,000 U/mL.
The IV regimen consisted of pertuzumab at a loading dose of 840 mg followed by 420 mg maintenance doses, plus trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg maintenance doses every 3 weeks with neoadjuvant chemotherapy.
Investigators selected chemotherapy with either dose-dense doxorubicin plus cyclophosphamide every 2 weeks followed by paclitaxel every week, or doxorubicin plus cyclophosphamide every 3 weeks followed by docetaxel every 3 weeks. Four cycles of HER2-targeted therapy were administered concurrently with the taxane. After surgery, patients continued to receive HER2-targeted therapy for an additional 14 cycles.
The primary endpoint was noninferiority of the cycle 7 pertuzumab serum trough concentration (Ctrough) for the SC vs IV regimens in the per-protocol pharmacokinetic population, consisting of 206 patients in the SC group and 203 in the IV group. Noninferiority was achieved if the lower bound of the 90% confidence interval (CI) of the geometric mean ratio was ≥ 0.8.
Pharmacokinetics and Response
The geometric mean ratio of pertuzumab serum Ctrough for the SC vs IV group was 1.22 (90% CI = 1.14–1.31), with noninferiority thus being established.
In the intention-to-treat population, pathologic complete response was achieved in 148 patients (59.7%; 95% CI = 53.3%–65.8%) in the SC group and in 150 patients (59.5%; 95% CI = 53.3%–65.8%) in the IV group (difference = 0.15%, 95% CI = –8.67%–8.97%).
The most common grade 3 or 4 adverse events during neoadjuvant treatment with HER2-targeted therapy plus chemotherapy were neutropenia (14% in SC group vs 13% in IV group), decreased neutrophil count (11% vs 12%), febrile neutropenia (6% vs 6%), diarrhea (7% vs 5%), and decreased white blood cell count (4% vs 7%). Treatment-related serious adverse events occurred in 10% of patients in each group. Adverse events considered unrelated to treatment led to death in one patient in the SC group (due to myocardial infarction) and one patient in the IV group (due to urosepsis).
The investigators concluded, “The study met its primary endpoint: the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection provides noninferior cycle 7 pertuzumab serum Ctrough concentrations to intravenous pertuzumab plus trastuzumab in the neoadjuvant setting, with comparable total pathological complete response rates, supporting the FDA approval. Safety was similar between treatment groups, and in line with other pertuzumab, trastuzumab, and chemotherapy trials. Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety.”
Antoinette R. Tan, MD, of the Levine Cancer Institute, Atrium Health, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by F. Hoffmann-La Roche and Genentech. For full disclosures of the study authors, visit thelancet.com.