Herceptin Hylecta (trastuzumab and hyaluronidase-oysk)

General Information for Herceptin Hylecta

Herceptin Hylecta is a fixed dose combination of trastuzumab, a HER2/neu receptor antagonist, with Halozyme’s proprietary recombinant human hyaluronidase enzyme (Enhanze technology), which has been shown to increase the absorption rate of a trastuzumab.

Herceptin Hylecta is for the following

  • Adjuvant treatment of adults with HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature breast cancer
  • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • And also as part of a treatment regimen with docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline based therapy.
  • Select patients for therapy based on an FDA-approved companion diagnostic for trastuzumab.

Metastatic Breast Cancer in adults

  • in combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
  • Select patients for therapy based on an FDA-approved companion diagnostic for trastuzumab.

Herceptin Hylecta is in the form of an injection for subcutaneous administration. Prior to administration select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens. The recommended dose of Herceptin Hylecta is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2-5 minutes once every three weeks. However, there is no requirement of loading dose. There is also no requirement of dose adjustments for patient body weight or for different concomitant chemotherapy regimens.

Duration of treatment: Patients with adjuvant breast cancer should be under treatmennt for 52 weeks or until disease recurrence, whichever occurs first. Extending treatment in adjuvant breast cancer beyond one year might not be efficient. Patients with metastatic breast cancer must be under proper treatment until progression of disease.

Clinical Results

FDA Approval

The FDA approval of Herceptin Hylecta for adjuvant breast cancer was based on a comparability study between Herceptin Hylecta administered subcutaneously and intravenous trastuzumab was established in the HannaH study. The HannaH study was conducted in patients with HER2 overexpressing breast cancer in the neoadjuvant and adjuvant settings with co-primary endpoints of pathological complete response (pCR) and the PK endpoint of Ctrough at cycle 7. The HannaH study was a randomized, multicenter, open-label, clinical trial in 596 patients with HER2-positive operable or locally advanced breast cancer (LABC), including inflammatory breast cancer.

HER2 positivity was defined as IHC 3+ or ISH+. Patients were randomized to receive 8 cycles of either Herceptin Hylecta or intravenous trastuzumab concurrently with chemotherapy (docetaxel followed by 5FU, epirubicin, and cyclophosphamide), followed by surgery and continued therapy with Herceptin Hylecta or intravenous trastuzumab as treated prior to surgery, for an additional 10 cycles, to complete 18 cycles of therapy. The trial to demonstrate non-inferiority of treatment with Herceptin Hylecta versus intravenous trastuzumab based on the co-primary endpoints. The analysis of the efficacy co-primary outcome, pCR, defined as absence of invasive neoplastic cells in the breast, resulted in rates of 45.4% in the Herceptin Hylecta arm and 40.7% in the intravenous trastuzumab arm. Nevertheless, the PK endpoint demonstrated non-inferiority.

FDA Approval

The FDA approval of Herceptin Hylecta for metastatic breast cancer was based on the SafeHER study, a prospective, two-cohort, non-randomized, multinational, open-label study designed to assess the overall safety and tolerability of Herceptin Hylecta with chemotherapy in 1,864 patients with HER2-positive breast cancer. Furthermore, the patients received a fixed dose of 600 mg Herceptin Hylecta every 3 weeks for a total of 18 cycles throughout the study. Herceptin Hylecta treatment can be either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination with neo-adjuvant chemotherapy followed by trastuzumab therapy. In the ITT population (n=1,867), 126 patients (7%) had a DFS event (recurrence, contralateral invasive breast cancer or death) and 28 patients (1.5%) had an OS event at the time of clinical cut-off. 

Side Effects

Adverse effects associated with the use of Herceptin Hylecta for Adjuvant Breast Cancer may include, the following:

  • fatigue
  • arthralgia
  • diarrhea
  • injection site reaction
  • upper respiratory tract infection
  • rash
  • myalgia
  • nausea
  • headache
  • edema
  • flushing
  • pyrexia
  • cough
  • pain in extremity

Adverse effects

  • fever
  • chills
  • headache
  • infection
  • congestive heart failure
  • insomnia
  • cough
  • rash

The Herceptin drug label comes with the following Black Box Warning:

  • Cardiomyopathy: Herceptin can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Herceptin for cardiomyopathy.
  • Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
  • Embryo-Fetal Toxicity: Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception

Mechanism of Action

Herceptin Hylecta is a fixed dose combination of trastuzumab, a HER2/neu receptor antagonist, with Halozyme’s proprietary recombinant human hyaluronidase enzyme (Enhanze technology). The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab , in both in vitro assays and in animals, inhibits the proliferation of human tumor cells that overexpress HER2.

Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells in comparison with cancer cells that do not overexpress HER2.

Hyaluronan is a polysaccharide 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. While Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in Herceptin Hylecta acts transiently and locally.