Adding Hyaluronidase-zzxf to Pertuzumab plus Trastuzumab Shortens Infusion Time

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in about one-fifth of breast cancers, and pertuzumab plus trastuzumab with chemotherapy is a standard treatment for this condition.¹ Approved by the FDA on June 29, 2020, pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo; Genentech) combines these anti-HER2 therapies into a single, subcutaneous injection, offering several advantages.²

The pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy requires just 5 to 8 minutes for administration, versus 1 to 2.5 hours for intravenous (IV) pertuzumab plus trastuzumab infusions.¹ Once patients have completed their concomitant chemotherapy, the combination therapy eliminates the need for IV access and offers the possibility of home administration.²

Additionally, preparation of the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy is simple, with no reconstitution, dilution, or weight-based dose adjustments required.³ A crossover study found that 85% of patients preferred the combination therapy to IV pertuzumab plus trastuzumab, mainly due to its shorter administration time.¹

The pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy plus chemotherapy is indicated for:³

1. Neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early stage breast cancer
2. Adjuvant treatment of high-risk HER2-positive early breast cancer
3. Treatment of HER2-positive metastatic breast cancer in patients without prior anti-HER2 therapy or chemotherapy for metastatic disease

The FDA approved the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy based on the phase 3, randomized, open-label, non-inferiority FeDeriCa trial, which enrolled 500 participants with HER2-positive early breast cancer.

During the trial, patients received neoadjuvant pertuzumab, trastuzumab, and hyaluronidase-zzxf or IV pertuzumab plus trastuzumab with chemotherapy. After surgery, patients continued the same anti-HER2 therapy in the adjuvant setting.

The results from the FeDeriCa trial demonstrated:³

1. Non-inferiority of pertuzumab, trastuzumab, and hyaluronidase-zzxf-treated patients’ pertuzumab Cycle 7 serum troughs
2. Pathological complete response (absence of invasive neoplastic cells in the breast or axillary lymph nodes) in 59.7% and 59.5% of pertuzumab, trastuzumab, and hyaluronidase-zzxf-treated and IV pertuzumab plus trastuzumab-treated patients, respectively
3. Similar safety profiles for pertuzumab, trastuzumab, and hyaluronidase-zzxf and IV pertuzumab plus trastuzumab (except for injection site reactions due to the subcutaneous administration of pertuzumab, trastuzumab, and hyaluronidase-zzxf)

Mechanism of Action

Pertuzumab binds to subdomain II of HER2, ultimately inhibiting the mitogen-activated protein (MAP) kinase and the phosphoinositide 3-kinase (PI3K) signaling pathways, which then arrests cell growth and promotes apoptosis. On the other hand, trastuzumab binds to subdomain IV of HER2, inhibiting both HER2-mediated cell proliferation and the PI3K signaling pathway.

Pertuzumab and trastuzumab also both show antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing cancer cells. Since hyaluronidase is an enzyme, its addition to pertuzumab and trastuzumab adds to the mechanism of action by increasing the permeability of subcutaneous tissue.³

Dosage and Administration

There are 2 pertuzumab, trastuzumab, and hyaluronidase-zzxf doses, each supplied in a single dose vial:³

1. A 15 mL loading dose containing 1200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase. This dose is given at the start of pertuzumab, trastuzumab, and hyaluronidase-zzxf therapy, and if 6 or more weeks have elapsed since the previous dose.
2. A 10 mL maintenance dose containing 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase. This dose is given every 3 weeks.

For early breast cancer, pertuzumab, trastuzumab, and hyaluronidase-zzxf’s prescribing information recommends 3 to 6 preoperative cycles and 1 year of postoperative treatment for up to 18 cycles. During treatment, patients with metastatic breast cancer receive pertuzumab, trastuzumab, and hyaluronidase-zzxf until disease progression or unmanageable toxicity.³

Health care professionals administer pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneously in the thigh and observe the patient for at least 15 minutes, or 30 minutes following the loading dose. Emergency medications must be readily available for treatment of hypersensitivity or other administration reactions as well.³

When preparing pertuzumab, trastuzumab, and hyaluronidase-zzxf for administration:³

1. Visually inspect for particulate matter and discoloration (solution should be clear to opalescent and colorless to slightly brown)
2. Draw into syringe using transfer needle, and replace needle with syringe closing cap unless using immediately
3. Store at room temperature for up to 4 hours, or under refrigeration for up to 24 hours
4. Just prior to administration, attach a 25G to 27G hypodermic injection needle and adjust the volume to 15 mL or 10 mL

Adverse Effects

Like IV pertuzumab plus trastuzumab, the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy carries risks of cardiomyopathy, embryo-fetal toxicity, and pulmonary toxicity; its prescribing information includes boxed warnings for these adverse effects (AEs).³

Pertuzumab, trastuzumab, and hyaluronidase-zzxf can cause cardiac symptoms including hypertension, arrhythmias, and clinical cardiac failure. In the FeDeriCa study’s pertuzumab, trastuzumab, and hyaluronidase-zzxf arm, 1.2% and 0.8% of patients experienced New York Heart Association (NYHA) Class II and NYHA Class III/IV cardiac failure, respectively.

Before starting pertuzumab, trastuzumab, and hyaluronidase-zzxf, patients should undergo a thorough cardiac assessment with evaluation of left ventricular ejection fraction (LVEF). Providers should assess LVEF every 12 weeks throughout treatment, and the prescribing information provides criteria for when to hold, restart, or permanently discontinue pertuzumab, trastuzumab, and hyaluronidase-zzxf based on LVEF changes. After completing pertuzumab, trastuzumab, and hyaluronidase-zzxf, patients should have their LVEF assessed every 6 months for at least 2 years.³

The embryo-fetal toxicity warning is based on IV trastuzumab post-marketing reports and IV pertuzumab animal studies. These identified a risk of oligohydramnios, or low amniotic fluid volume, potentially leading to pulmonary hypoplasia, skeletal abnormalities, delayed fetal kidney development, and embryo-fetal or neonatal death. Pertuzumab, trastuzumab, and hyaluronidase-zzxf’s prescribing information advises females of reproductive potential to use effective contraception during, and for 7 months after, treatment.³

IV trastuzumab can cause serious pulmonary toxicity, and pertuzumab, trastuzumab, and hyaluronidase-zzxf is expected to carry the same risk. Pulmonary AEs may include dyspnea, interstitial pneumonitis, acute respiratory distress syndrome, pleural effusions, and pulmonary infiltrates, edema, or fibrosis. Patients with preexisting lung disease or tumor involvement may be at higher risk.³

In the FeDeriCa study, 1.2% of pertuzumab, trastuzumab, and hyaluronidase-zzxf-treated patients experienced hypersensitivity reactions, and 21% experienced other administration-related reactions. Health care providers administering pertuzumab, trastuzumab, and hyaluronidase-zzxf should monitor patients for angioedema, breathing problems, chest pain, dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, or injection site pain.³

Based on data from IV trastuzumab clinical trials, pertuzumab, trastuzumab, and hyaluronidase-zzxf is expected to increase chemotherapy-induced neutropenia risk.³

Gabrielle Ruggiero, PharmD, BCPS, is a pharmacist at Johnson Memorial Hospital in Stafford Springs, Connecticut.

REFERENCES

• Tan A, Im S, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomized, open-label, multicentre, non-inferiority, phase 3 study. The Lancet Oncology. January 2021. Accessed July 27, 2021. https://doi.org/10.1016/S1470-2045(20)30536-2
• FDA approves breast cancer treatment that can be administered at home by health care professional [News release]. FDA. June 29, 2020. Accessed July 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-breast-cancer-treatment-can-be-administered-home-health-care-professional
• Phesgo. Prescribing information. Genentech; 2020. Accessed July 27, 2021. https://www.gene.com/download/pdf/phesgo_prescribing.pdf