Elsevier

Clinical Therapeutics

Volume 21, Issue 2, February 1999, Pages 309-318
Clinical Therapeutics

Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer

https://doi.org/10.1016/S0149-2918(00)88288-0Get rights and content
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Abstract

Amplification of the human epidermal growth factor receptor 2 protein (HER2) in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain patients. Trastuzumab (Herceptin®, Genentech, Inc., South San Francisco, California) is a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor. In vitro and in vivo preclinical studies have shown that administration of trastuzumab alone or in combination with paclitaxel or carboplatin significantly inhibits the growth of breast tumor-derived cell lines that overexpress the HER2 gene product. At therapeutic doses in breast cancer patients, the mean half-life of trastuzumab is 5.8 days. Trastuzumab serum concentrations reach steady state with mean trough and peak concentrations of 79 μg/mL and 123 μg/mL, respectively. In a 222-patient, singlearm clinical study, treatment with a loading dose of trastuzumab 4 mg/kg administered IV followed by weekly IV doses of 2 mg/kg produced an overall response rate of 14% (2% complete remission and 12% partial remission). The beneficial effects were greatest in patients with the greatest degree (3+) of HER2 protein overexpression. In another clinical study, 469 women with metastatic breast carcinoma were randomized to a paclitaxel or anthracycline-pluscyclophosphamide regimen with or without trastuzumab. The overall response rate was significantly greater in the trastuzumabplus-chemotherapy group than in the chemotherapy-alone cohort. The magnitude of observed effects was greatest with paclitaxel plus trastuzumab. The most common adverse effects attributed to trastuzumab in clinical studies were fever and chills, pain, asthenia, nausea, vomiting, increased cough, diarrhea, headache, dyspnea, infection, rhinitis, and insomnia. Trastuzumab in combination with chemotherapy can lead to cardiotoxicity, leukopenia, anemia, diarrhea, abdominal pain, and infection. Trastuzumab has been approved by the US Food and Drug Administration as a single agent for the treatment of patients who have metastatic breast cancer involving overexpression of the HER2 protein and who have received 1 or more chemotherapy regimens; in combination with paclitaxel, it has been approved for the treatment of such patients who have not received chemotherapy.

Key words

trastuzumab
HER2 overexpression
metastatic breast cancer
rhuMabHER2

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