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Trastuzumab

A Review of its Use in the Treatment of Metastatic Breast Cancer Overexpressing HER2

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Summary

Abstract

Trastuzumab is a humanised monoclonal antibody developed to target the HER2 receptor which is overexpressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumour cells that overexpress HER2.

A large well designed multicentre study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone.

Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 over-expression level of 3+ using immunohistochemical (IHC) assay or a positive HER2 result using fluorescence in situ hybridisation (FISH), benefit more from trastuzumab therapy than those with tumours overexpressing at a level of 2+.

Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined.

Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients.

Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone.

Conclusion: Intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.

Pharmacodynamic Properties

The HER2/neu gene encodes a 185-kd transmembrane glycoprotein receptor (HER2) that has intrinsic tyrosine kinase activity and belongs to the epidermal growth factor receptor family. The HER2 receptor is overexpressed in 25 to 30% of breast cancers and is associated with a poor prognosis. The murine monoclonal antibody (MAb) 4D5, directed against HER2, specifically inhibits the growth of human cancer cells that overexpress the HER2 receptor. MAb 4D5 is humanised by replacing all the mouse-derived components, except the antigen-binding region, with human counterparts. The resulting MAb, trastuzumab, has a high affinity for the extracellular domain (ECD) of HER2 with a similar potency to the murine antibody to inhibit growth of cancer cells (SK-BR-3 cells) overexpressing HER2.

Dose-dependent antitumour activity was observed when trastuzumab was given to nude athymic mice bearing BT-474 human breast cancer cell xenografts overexpressing HER2. Doses ranging from 0.1 to 1 mg/kg intraperitoneally twice a week for 5 weeks resulted in a mean inhibition of tumour growth at 5 weeks of 25 to 80% compared with that in mice treated with a control antibody of nonspecific recombinant MAb immunoglobulin. Trastuzumab caused a similar growth inhibition of tumour volume at 5 weeks to that caused by single-agent doxorubicin or paclitaxel.

In combination studies in mice, treatment with intraperitoneal trastuzumab plus intravenous paclitaxel or doxorubicin caused greater inhibition of tumour growth than any single-agent therapy. Trastuzumab plus paclitaxel inhibited tumour growth more than combination treatment with intravenous doxorubicin.

Trastuzumab, in combination with doxorubicin, cyclophosphamide, methotrexate, etoposide or vinblastine significantly reduced tumour volume when administered to athymic mice bearing HER2-transfected MCF7 human breast cancer xenografts compared with single-agent therapy.

In vitro synergistic cytotoxic activity was demonstrated when trastuzumab was combined with cisplatin, thiotepa and etoposide in SK-BR-3 human breast cancer cells, and additive interactions were observed with paclitaxel, doxorubicin, methotrexate and vinblastine.

Pharmacokinetic Properties

Trastuzumab demonstrated dose-dependent pharmacokinetics with short duration weekly intravenous infusions up to 500mg. At standard doses of 4 mg/kg initially followed by 2 mg/kg/wk, steady-state serum concentrations are produced at approximately 20 weeks. The estimated mean area under the concentration-time curve was 578 mg/L · day and the mean maximum serum concentration and mean minimum serum concentration (Cmin) were approximately 110 and 66 mg/L, respectively.

Detectable levels of baseline circulating ECD HER2 were observed in 64% of 447 patients (mean =11 μg/L) with metastatic breast cancer overexpressing the HER2 receptor. Higher levels of ECD HER2 were associated with a lower Cmin value of trastuzumab. However, most patients with elevated ECD HER2 receptor levels achieved target serum concentration of trastuzumab by week 6.

In all clinical trials of patients with metastatic breast cancer, weekly intravenous infusions of trastuzumab produced a volume of distribution which approximated that of serum volume (2.95L). As only minimal amounts of trastuzumab penetrate into the cerebrospinal fluid, a response to trastuzumab would not be expected in patients with meningeal or cerebral metastases resulting from metastatic breast cancer overexpressing the HER2 receptor.

The mean serum elimination half-life (t½) increased and clearance decreased with increasing doses of intravenous trastuzumab administered once a week to patients with metastatic breast cancer. At standard doses of 4 mg/kg initially then 2 mg/kg/wk, the mean t½ was approximately 28.5 days with a washout period of up to 20 weeks. The mean clearance in clinical trials, following standard doses, was 0.225 L/day.

The disposition of trastuzumab in elderly patients and patients with renal impairment was not altered. No formal drug interaction studies have been performed with trastuzumab.

Clinical Efficacy

A large well designed, multicentre, randomised, single-blind trial compared the efficacy of trastuzumab combined with chemotherapy with that of chemotherapy alone in 469 women with metastatic breast cancer overexpressing the HER2 receptor. None had received previous chemotherapy for metastatic disease. Doxorubicin (or epirubicin) and cyclophosphamide were given to patients who had not previously received adjuvant (postoperative) therapy with an anthracycline, with or without trastuzumab. Patients who had previously received adjuvant anthracycline were treated with paclitaxel with or without trastuzumab.

The addition of intravenous trastuzumab to either regimen was associated with a significantly longer time to disease progression. Patients receiving trastuzumab in combination with either type of chemotherapy showed disease progression at a median time of 7.4 months versus 4.6 months for either type of chemotherapy alone. A significantly higher rate of objective (complete plus partial) response, a longer duration of response, a longer survival and a lower incidence of death during the first year were also observed in trastuzumab-treated groups compared with chemotherapy alone. Combination therapy with trastuzumab lowered the relative risk of death by 20% at a median follow-up of 30 months.

Despite patients aged >60 years appearing to have a less favourable overall clinical outcome than patients aged ≤60 years, there was still a survival benefit in this older group.

In several phase II noncomparative trials (most reported in abstracts), trastuzumab, in combination with a range of chemotherapy agents, has demonstrated clinical efficacy in patients with metastatic breast cancer overexpressing the HER2 receptor.

Data from noncomparative studies suggest that objective response rates to trastuzumab therapy are higher in previously untreated patients than in those who have received extensive prior therapy for metastatic disease.

Single-agent trastuzumab produced a response in 15% of 222 extensively pretreated patients with metastatic breast cancer overexpressing the HER2 receptor (intent-to-treat analysis). The median duration of response was 9.1 months and the median duration of survival was 13 months. Low and high dosages of trastuzumab monotherapy, in a study of previously untreated patients, demonstrated a similar objective response rate in both treatment groups of the intent-to-treat population (overall 26%). A higher response was observed in patients with an HER2 overexpression level of 3+ by immunohistochemical (IHC) assay (35%), and those who were HER2-positive by fluorescence in situ hybridisation (FISH) method of assay (41%).

Data from other clinical trials have also demonstrated that patients with a HER2 overexpression level of 3+ using IHC assay or a positive HER2 result using FISH, benefit more from trastuzumab therapy than those with tumours over-expressing at a level of 2+ (IHC assay). Recent reports suggest that FISH may be a better method for selecting patients for trastuzumab therapy than IHC; particularly those with an overexpression level of 2+. However, strict adherence to test protocols and quality control programmes may improve the consistency of IHC results.

Trastuzumab, alone or in combination with chemotherapy, was associated with an improvement in global quality of life in all three studies assessing patients who participated in the major clinical trials. The level of fatigue also improved in patients receiving trastuzumab, alone or in combination with chemotherapy, as first-line treatment for metastatic breast cancer compared with baseline or with chemotherapy alone.

Tolerability

Trastuzumab, administered intravenously as a single agent or in combination with chemotherapy, is tolerated well by most patients. The most significant adverse events are acute fever and/or chills and a potential to cause symptomatic or asymptomatic cardiac dysfunction.

The most common adverse events (incidence >35%) associated with trastuzumab monotherapy are fever, chills, pain, asthenia and nausea. In most cases events are mild to moderate. Fever and/or chills occurred during or shortly after the first infusion of trastuzumab monotherapy in 40% of patients (n = 222), but recurred in less than 3% and usually responded to treatment with paracetamol (acetaminophen) and diphenhydramine. Compared with chemotherapy, trastuzumab was well tolerated and typical chemotherapy-induced events, such as alopecia, mucositis and haematologic toxicity, occurred in no more than 4% of patients.

Adverse events which occurred in >40% of 234 patients receiving intravenous trastuzumab in combination with standard doses of chemotherapy (anthracycline and cyclophosphamide or paclitaxel) include nausea, pain, asthenia, alopecia, fever, diarrhoea, headache, infection, vomiting, leucopenia, dyspnoea and increased cough. Most events were mild or moderate in intensity and led to treatment withdrawal in 25 patients (19 in the group receiving an anthracycline, cyclophosphamide and trastuzumab, and six in the group receiving paclitaxel and trastuzumab).

Infection (mild to moderate in intensity) occurred in 47% of patients who received chemotherapy plus trastuzumab compared with 29% of patients given chemotherapy alone.

Cardiac dysfunction (symptomatic or asymptomatic and generally categorised as >10% reduction in ejection fraction or cardiomyopathy) occurs in some patients receiving trastuzumab as monotherapy or as a component of combination therapy. The incidence was greater in patients receiving trastuzumab in combination with an anthracycline and cyclophosphamide (27%) than in patients receiving an anthracycline and cyclophosphamide alone (8%). 13% of 91 women treated with trastuzumab and paclitaxel, and 1% of 95 patients receiving paclitaxel alone developed symptomatic or asymptomatic cardiac dysfunction. Cardiac function improved in 75% of patients after the initiation of standard medical care.

Trastuzumab monotherapy was associated with an incidence of 4.7% of cardiac dysfunction in women with metastatic breast cancer overexpressing the HER2 receptor. Patients heavily pretreated with anthracyclines, those with preexisting systolic dysfunction and those over 65 years of age are more likely to experience symptoms of systolic dysfunction.

Serious adverse events, including death, have occurred in 0.25% of patients treated with trastuzumab. Serious events fall into three categories: infusion reaction; hypersensitivity reaction, including fatal anaphylaxis; and pulmonary events, including adult respiratory distress syndrome. In most cases symptoms occurred during or immediately after the infusion or during the first 24 hours after administration. An increased risk of a fatal infusion reaction may exist in patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities.

Dosage and Administration

Trastuzumab is indicated for patients with metastatic breast cancer overexpressing the HER2 receptor. In combination with paclitaxel, intravenous trastuzumab is indicated for first-line treatment. In patients who have previously received one or more regimens of chemotherapy for metastatic disease, trastuzumab can be used as a single agent.

The recommended initial loading dose of trastuzumab is 4 mg/kg administered via intravenous infusion over 90 minutes. A weekly dose of 2 mg/kg follows, given over 30 minutes if the initial infusion was well tolerated.

Trastuzumab administration can cause symptomatic or asymptomatic cardiac dysfunction and extreme caution should be taken in treating patients with symptomatic heart failure, a history of hypertension, or documented coronary artery disease. Before therapy with trastuzumab, patients should have a thorough cardiac assessment and cardiac function should be monitored frequently throughout treatment. In clinical trials, the incidence of cardiac dysfunction was highest in patients receiving trastuzumab in combination with an anthracycline and cyclophosphamide and, for this reason, trastuzumab is currently not approved in combination with anthracyclines except in a well controlled setting with cardiac monitoring.

As trastuzumab may remain in the circulation for up to approximately 18 weeks after treatment is stopped, it is recommended that anthracycline therapy should be avoided for up to 22 weeks after therapy is discontinued.

Trastuzumab may be given in an outpatient setting but patients should be observed for infusion-related symptoms, most commonly fever and chills. Rarely, hypersensitivity reactions including anaphylaxis and pulmonary events have also been reported. If patients experience dyspnoea or clinically significant hypotension the infusion should be interrupted and the patient monitored until symptoms resolve. In the case of anaphylaxis, angioedema or acute respiratory distress syndrome, the infusion should be terminated. Trastuzumab is contraindicated in patients with severe dyspnoea at rest due to complications of advanced malignancy or those requiring supplementary oxygen therapy.

No well controlled studies exist of the use of trastuzumab in pregnant women, and therapy should only be initiated if clearly indicated.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Kate McKeage & Caroline M. Perry

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  1. Kate McKeage
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  2. Caroline M. Perry
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Correspondence to Kate McKeage.

Additional information

Various sections of the manuscript reviewed by: N. Bangemann, Medical Center Benjamin Franklin, Free University, Berlin, Germany; H. Burstein, Dana-Faber Cancer Institute, Boston, Massachussetts, USA; L. A. Carey, UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; I.O. Ellis, Department of Histopathology, City Hospital, Nottingham, England; V. Harvey, Department of Clinical Oncology, Auckland Hospital, Auckland, New Zealand; J. Horton, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA; B. Leyland-Jones, Department of Oncology, McGill University, Montreal, Canada; R. Seshadri, Flinders Medical Centre, Bedford Park, South Australia, Australia.

Data Selection

Sources: Medical literature published in any language since 1983 on trastuzumab, identified using AdisBase (a proprietary database of Adis International), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘trastuzumab’ or ‘anti-HER-2-monoclonal-antibody’ or ‘HER-2’. Medline search terms were ‘trastuzumab’ or ‘HER-2’. EMBASE search terms were ‘trastuzumab’ or ‘HER-2’. Searches were last updated 28 Nov 2001.

Selection: Studies in patients with metastatic breast cancer overexpressing HER2 who received trastuzumab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Metastatic breast cancer, monoclonal antibody, pharmacodynamics, pharmacokinetics, therapeutic use.

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McKeage, K., Perry, C.M. Trastuzumab. Drugs 62, 209–243 (2002). https://doi.org/10.2165/00003495-200262010-00008

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