Early in 2019, trastuzumab and the endoglycosidase hyaluronidase-oysk for subcutaneous injection was approved in the treatment of HER2-positive breast cancer.^1,2 The agent is indicated for adjuvant treatment of patients with HER2-overexpressing node-positive or node-negative (estrogen receptor/progesterone receptor–negative or with one high-risk feature) breast cancer: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as a single agent after multimodality anthracycline-based therapy. It is also indicated for patients with metastatic breast cancer in combination with paclitaxel for the first-line treatment of HER2-overexpressing metastatic breast cancer and as a single agent for HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Patients must be selected for therapy based on a U.S. Food and Drug Administration–approved companion diagnostic for trastuzumab.

Supporting Data

Approval is based on efficacy findings in the HannaH trial (ClinicalTrials.gov identifier NCT00950300) and safety findings in the HannaH trial and the SafeHER trial (NCT01566721).² In HannaH, 596 patients with HER2-positive operable or locally advanced breast cancer were randomly assigned to receive 8 cycles of either neoadjuvant subcutaneous trastuzumab and hyaluronidase-oysk or intravenous (IV) trastuzumab concurrently with chemotherapy, followed by surgery and continued therapy with either subcutaneous trastuzumab and hyaluronidase-oysk or IV trastuzumab for an additional 10 cycles.

The HannaH trial showed comparability between trastuzumab/hyaluronidase-oysk and IV trastuzumab for the co-primary endpoints of pathologic complete response and pharmacokinetics. Pathologic complete response was seen in 45.4% of the trastuzumab/hyaluronidase-oysk group and 40.7% of the IV trastuzumab group (difference = 4.7%, 95% confidence interval for difference = –4.0% to 13.4%). With median follow-up over 70 months, no difference in event-free or overall survival was observed in the final analysis between the two groups.

How It Works

The HER2 proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab has been shown in both in vitro assays and in animals to inhibit the proliferation of human tumor cells that overexpress HER2. Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity. In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2-overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in trastuzumab/hyaluronidase-oysk acts transiently and locally. The effects of hyaluronidase are reversible, and permeability of the subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into the systemic circulation when given in the subcutis of animals.

How It Is Used

Trastuzumab/hyaluronidase-oysk is for subcutaneous use only. It has different dosage and administration instructions than IV trastuzumab products. It must not be substituted for or with trastuzumab emtansine.

The recommended dose of trastuzumab/hyaluronidase-oysk is 600 mg/10,000 U given subcutaneously over approximately 2 to 5 minutes once every 3 weeks, with no loading dose. No dose adjustments for patient body weight or for concomitant chemotherapy regimens are required. Patients with adjuvant breast cancer should be treated for 52 weeks or until disease recurrence; extending adjuvant treatment beyond 1 year is not recommended. Patients with metastatic breast cancer should be treated until disease progression.

Product labeling provides dosage modification instructions for cardiomyopathy. Left-ventricular ejection fraction should be assessed prior to initiation of treatment and at regular intervals during treatment. Treatment should be withheld for at least 4 weeks for ≥ 16% absolute decrease in left-ventricular ejection fraction from pretreatment values or below institutional limits of normal and ≥ 10% absolute decrease from pretreatment values. Treatment may be resumed if within 4 to 8 weeks, left-ventricular ejection fraction returns to normal limits, and the absolute decrease from baseline is up to 15%. Treatment should be permanently discontinued for persistent (> 8 weeks) left-ventricular ejection fraction decline or for suspension of dosing on more than three occasions for cardiomyopathy.

Safety Profile

Safety data supporting approval come from the HannaH and SafeHER trials. In HannaH, the most common grade ≥ 3 adverse events were neutropenia, febrile neutropenia, leukopenia, and diarrhea. Adverse events led to interruption of any study drug in the trastuzumab/hyaluronidase-oysk group in 34% of patients, with the most common causes being neutropenia, leukopenia, alanine transaminase increase, pyrexia, anemia, bronchitis, and left-ventricular dysfunction. In SafeHER, the most common grade ≥ 3 adverse events were neutropenia, febrile neutropenia, and hypertension. Adverse events that led to study drug discontinuation were decreased left-ventricular ejection fraction and left-ventricular dysfunction.

Trastuzumab/hyaluronidase-oysk has boxed warnings for cardiomyopathy, pulmonary toxicity, and embryofetal toxicity. Treatment should be discontinued for cardiomyopathy as well as for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Exposure to trastuzumab/hyaluronidase-oysk during pregnancy can result in oligohydramnios. Patients should be advised of these risks and the need for effective contraception during treatment.

Trastuzumab/hyaluronidase-oysk also carries warnings/precautions for exacerbation of chemotherapy-induced neutropenia and hypersensitivity reactions and administration-related reactions. Severe administration-related reactions, including anaphylaxis, have been reported. Patients should be monitored for systemic hypersensitivity reactions. Treatment should be permanently discontinued in patients experiencing anaphylaxis or severe hypersensitivity reactions. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves new formulation of Herceptin for subcutaneous use. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm632294.htm. Accessed December 10, 2019.

2. Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) injection, for subcutaneous use, prescribing information, Genentech, Inc, ­February 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/­label/2019/761106s000lbl.pdf. Accessed December 10, 2019.