FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase–zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer

There are more than 260,000 new cases of and 40,000 deaths from breast cancer in the United States each year and breast cancer remains one of the most common cancers in women (1). HER2 is strongly overexpressed in about 15% of breast cancers and is associated with more aggressive disease and a higher rate of recurrence (2). Trastuzumab (Herceptin) and pertuzumab (Perjeta) are commonly used products to treat HER2-positive breast cancer. Intravenous trastuzumab was initially approved in 1998 and is an infusion administered over 90 minutes for the initial dose, with subsequent doses administered over 30–90 minutes every 1–3 weeks depending on the dose and regimen (3). Intravenous pertuzumab was initially approved in 2012 and is an infusion administered over 60 minutes for the initial dose, with subsequent doses administered over 30–60 minutes every 3 weeks, followed by a 30- to 60-minute observation time (3). For many patients who are receiving both intravenous trastuzumab and pertuzumab, this can add up to more than 4 hours.

Hyaluronidase human injection (Hylenex) received regular FDA approval on December 2, 2005 and is indicated as an adjuvant to increase the dispersion and absorption of other injected drugs (4). Subcutaneous trastuzumab (Herceptin Hylecta, trastuzumab and hyaluronidase-oysk) was approved on February 28, 2019, and provided for an alternate route of administration for trastuzumab over 2–5 minutes every 3 weeks, with hyaluronidase (recombinant human) used to increase the dispersion and absorption of trastuzumab (3).

The approval of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) provides a subcutaneous route of administration for pertuzumab and trastuzumab over 5–8 minutes, every 3 weeks, thereby significantly shortening the amount of time required for patients to receive these HER2-targeted therapies, and could potentially be administered in a patients' home by a qualified health care provider. Herein, we provide a summary of the FDA review of the marketing application for pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo, referred to throughout this article as PH FDC SC) for the treatment of patients with HER2-positive early and metastatic breast cancer (3).

Pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection is supplied as a sterile, preservative-free, clear to opalescent, and colorless to slightly brownish solution provided in two dosage forms and strengths, both in single-dose vials for subcutaneous administration:

• (i) 1,200-mg pertuzumab, 600-mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in a single-dose vial

• (ii) 600-mg pertuzumab, 600-mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in a single-dose vial

Hyaluronidase is an endoglycosidase with a molecular weight of approximately 61 kDA. It is a dispersion agent that modifies the permeability of human subcutaneous connective tissue by local depolymerization of hyaluronan, a glycosaminoglycan contributing to the interstitial fluid content and viscosity in the extracellular matrix (4–7). The target of both pertuzumab and trastuzumab is the cell surface receptor HER2. HER2 is a part of the HER family of transmembrane tyrosine kinases that have been shown to play a role in the regulation of cellular survival, proliferation, adhesion, and differentiation. Pertuzumab is a recombinant humanized monoclonal IgG1 antibody that binds to subdomain II of HER2, with a molecular weight of approximately 148 kDA. Trastuzumab is a humanized IgG1 mAb that binds to subdomain intravenous of HER2, with an approximate molecular weight of 148 kDa.

FeDeriCa (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 patients with HER2-positive early breast cancer, NCT03493854) was a randomized, open-label, multicenter, global comparability study of 500 patients who received either PH FDC SC or intravenous pertuzumab and intravenous trastuzumab (referred throughout this article as P+H IV), administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of early breast cancer. Patients with operable or locally advanced (including inflammatory) HER2-positive breast cancer with a tumor size >2 cm or node-positive disease were eligible, with HER2 overexpression defined as IHC 3+ in >10% of immunoreactive cells or HER2 gene amplification by ISH (using a ratio of HER2 gene signals to centromere 17 of ≥2.0), using an FDA-approved test. Trial patients were randomized to receive four cycles of neoadjuvant chemotherapy (cycles 1–4) followed by four concurrent cycles of either PH FDC SC or P+H IV with chemotherapy (cycles 5–8). Neoadjuvant chemotherapy was determined by the investigators and were one of the following:

• (i) four cycles of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) every 2 weeks followed by paclitaxel (80 mg/m²) weekly for 12 weeks

• (ii) four cycles of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks followed by four cycles of docetaxel (75 mg/m² for the first cycle and then 100 mg/m² at subsequent cycles at the investigator's discretion) every 3 weeks

After completing neoadjuvant treatment, patients underwent surgery and then went on to continue a year of HER2-targeted therapy (an additional 14 cycles in the adjuvant setting, every 3 weeks). Adjuvant radiotherapy and endocrine therapy were also permitted per the treating physician and standard of care. In the adjuvant setting, trial patients who received intravenous trastuzumab in the neoadjuvant setting were eligible to switch to subcutaneous trastuzumab at the treating physician's discretion and if available.

The pharmacokinetic endpoints were tested hierarchically, with noninferiority of subcutaneous pertuzumab compared with intravenous pertuzumab tested first and if statistically significant, followed by hierarchical testing of subcutaneous trastuzumab compared with intravenous trastuzumab, with both primary endpoints meeting statistical significance. A secondary efficacy endpoint was pathologic complete response (pCR) in the breast and axilla (defined as the absence of invasive neoplastic cells in the breast and in the axillary lymph nodes, i.e., ypT0/isypN0), according to local pathologist assessment of the surgical specimen at the time of definitive surgery after cycle 8. Safety was an additional secondary endpoint.

The PHranceSCa (a study to evaluate patient preference and satisfaction of subcutaneous administration of the fixed-dose combination of pertuzumab and trastuzumab in patients with HER2-positive early breast cancer, NCT03674112) study was conducted to determine whether patients had a preference over the route of administration. PHranceSCa was a randomized, multicenter, open-label, cross-over study in 160 trial patients with HER2-positive breast cancer who were undergoing adjuvant treatment following previous neoadjuvant therapy with pertuzumab, trastuzumab, and surgery. Trial patients were randomized to receive either three cycles of P+H IV followed by three cycles of PH FDC SC (arm A; n = 80) or three cycles of PH FDC SC followed by three cycles of P+H IV (Arm B; n = 80), which made up the cross-over period. After completing the cross-over period, patients could choose to continue their treatment with PH FDC SC or PH IV to complete 18 total cycles of HER2-targeted therapy.

The pharmacokinetics of pertuzumab and trastuzumab was characterized in the FeDeriCa study, with parameters described in Table 1 (5). Trial patient demographics was balanced between the two study arms, with a median age of 51 years (range, 25–81), and the majority of patients reporting as White (66%) with hormone receptor–positive disease (61%) or node-positive disease (58%). In at least 95% of patients, trastuzumab is estimated to reach concentrations that are <1 mcg/mL by 7 months. The pharmacokinetic endpoints were tested hierarchically and the pertuzumab cycle 7 C_trough of PH FDC SC (88.7 mcg/mL) was noninferior to intravenous pertuzumab (72.4 mcg/mL), with a geometric mean ratio (GMR) of 1.22 [90% confidence interval (CI), 1.14–1.31]. Trastuzumab cycle 7 C_trough was then tested second hierarchically and also showed noninferiority of PH FDC SC (58.7 mcg/mL) compared with intravenous trastuzumab (44.1 mcg/mL), with a GMR of 1.33 (90% CI, 1.24–1.43).

Additional population pharmacokinetic models were analyzed, and effect of lean body weight and baseline serum albumin level were used as significant covariates for pertuzumab, while body weight for trastuzumab, respectively, with results indicating no dose adjustments based on body weight or baseline albumin level are needed for both compounds because the changes in exposure are not clinically relevant. Furthermore, no clinically significant differences in the pharmacokinetics of pertuzumab and trastuzumab were observed on the basis of age, race, or renal impairment. The effects of hepatic impairment on the pharmacokinetics of pertuzumab and trastuzumab are unknown.

Pathologic complete response was a secondary endpoint. The pCR rate was 59.7% (95% CI, 53.3–65.8) in the PH FDC SC arm and 59.5% (95% CI, 53.2–65.6) in the P+H IV arm.

Safety was a secondary endpoint and found to be similar between the two study arms and consistent with the known safety profiles of intravenous pertuzumab and intravenous trastuzumab, aside from administration-related reactions seen with PH FDC SC due to the route of administration. Cardiomyopathy, pulmonary toxicity, and embryo-fetal toxicity were included as black box warnings in the product label, as these are also black box warnings for intravenous trastuzumab, intravenous pertuzumab, and subcutaneous trastuzumab. Serious adverse reactions occurred in 16% of trial patients who received PH FDC SC, including febrile neutropenia (4%), neutropenic sepsis (1%), and neutrophil count decreased (1%). One trial patient died of acute myocardial infarction, and occurred prior to the start of HER2-targeted treatment with PH FDC SC. Eight percent of trial patients experienced an adverse reaction resulting in permanent discontinuation of any study drug, with ejection fraction decreased (1.2%), cardiac failure (0.8%), and pneumonitis/pulmonary fibrosis (0.8%) as causes of permanent discontinuation of PH FDC SC. There were 40% of trial patients who experienced dosage interruptions due to an adverse reaction. Adverse reactions which required dosage interruption of PH FDC SC included neutropenia (8%), neutrophil count decreased (4%), and diarrhea (7%). The incidence of hypersensitivity was 1.2% in the PH FDC SC arm and administration-related reactions occurred in 21% of trial patients [most commonly injection site reaction (15%) and injection site pain (2%)].

After six cycles, 85% of trial patients reported preferring the subcutaneous administration of PH FDC SC over P+H IV, with less time in clinic being the primary reason. Fourteen percent of patients preferred intravenous pertuzumab and trastuzumab over PH FDC SC, with the most common reason being it felt more comfortable during administration. One percent of patients had no preference. There were no new safety signals.

The FeDeriCa study was conducted in the neoadjuvant and adjuvant settings. Extrapolation to the metastatic breast cancer indication was based on the totality of evidence, supported by comparable pharmacokinetic profiles of in the neoadjuvant and adjuvant treatment settings, sensitivity of the early breast cancer treatment setting for establishing clinical similarity of efficacy and immunogenicity, and the same mode of action for pertuzumab and trastuzumab in both the early and metastatic breast cancer settings. The study met its pharmacokinetic endpoints and the secondary endpoint of pCR was comparable between the two study arms. Aside from administration-related reactions due to the route of administration, safety was comparable with what is known for intravenous pertuzumab and intravenous trastuzumab. The PHranceSCa study was an additional study conducted to evaluate patient preference and the majority of patients preferred the subcutaneous route of administration over intravenous due to it requiring less time in clinic.

With the ongoing worldwide COVID-19 pandemic, treatment options for patients with cancer remains an area of significant unmet need, particularly in at-home settings. Patients who are immunocompromised, such as those with cancer, need additional treatment options that can help decrease their risk of exposure to the coronavirus, in the clinic and at home. The PH FDC SC product offers patients with breast cancer a different route of administration than intravenous pertuzumab and intravenous trastuzumab, and PH FDC SC is administered over a shorter duration. Furthermore, if a physician believes it is in the patient's best interest, PH FDC SC could be administered at home by a qualified health care provider once the chemotherapy portion of the cancer treatment regimen is completed. The FDA review teams carefully evaluated the scientific evidence and weighed the benefit-risk of PH FDC SC compared with P+H IV and this application was ultimately approved approximately 4 months ahead of the FDA goal date. During the review process, the FDA also worked with the product sponsor to implement an expanded access program (NCT04395508) to provide patients earlier access to PH FDC SC in home setting administered by a health care professional to enable continuity of care during the COVID-19 pandemic.

In summary, PH FDC SC demonstrated a favorable benefit-risk profile for the treatment of adult patients with HER2-positive breast cancer. The safety profile of PH FDC SC was comparable with that of intravenous pertuzumab and intravenous trastuzumab, aside from administration-related reactions due to the route of administration. Results from the patient preference study (PhranceSCa) suggest patients preferred the subcutaneous product due to lessened administration time. These results supported a regular approval for this application.

Y. Gong reports other from BeiGene outside the submitted work. No disclosures were reported by the other authors.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.