, Volume 66, Issue 4, pp 449-475
Date: 17 Sep 2012

Trastuzumab

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Summary

Abstract

Trastuzumab (Herceptin®) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis.

The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.

Pharmacological Properties

Trastuzumab is a humanised monoclonal antibody that binds selectively and with high affinity to the extracellular domain of HER2. Although the mechanism of its antitumour action has not been fully elucidated, trastuzumab promotes antibody-dependent cellular toxicity and the degradation of HER2 receptors, affects tumour growth and other signalling pathways, induces apoptosis and has antiangiogenic effects. Additive or synergistic effects have been demonstrated with trastuzumab and various cytotoxic drugs (e.g. paclitaxel, docetaxel, anthracyclines, cisplatin, carboplatin, vinorelbine, capecitabine) in HER2-overexpressing breast cancer cell lines and/or human breast tumour xenograft models.

Following a short-duration intravenous infusion of trastuzumab, peak serum concentrations are achieved after approximately 3–4 hours, and the drug is distributed into a volume approximately equal to that of serum. Although most clinical trials have used a once-weekly regimen of trastuzumab, population pharmacokinetic data based on a two-compartment model indicate that the elimination half-life is much longer than initially reported (28.5 vs ≈6 days), thus allowing for administration once every 3 weeks, as has been used in some recent clinical trials.

Therapeutic Efficacy

The addition of trastuzumab to paclitaxel therapy was associated with statistically and clinically significant improvements in the time to disease progression, objective response rate and duration of response, with little additional toxicity, compared with paclitaxel alone in a randomised phase III trial in women with HER2-positive (2+ or 3+ by immunohistochemistry [IHC]) metastatic breast cancer who had not previously received chemotherapy for their metastatic disease. In the same trial, which included two treatment arms of trastuzumab plus standard chemotherapy (paclitaxel or a combination of anthracycline plus cyclophosphamide) and two standard chemotherapy arms, a survival advantage was also demonstrated for trastuzumab plus chemotherapy versus chemotherapy alone. Subgroup and retrospective analyses from this and other trials in patients with HER2-positive breast cancer indicate that trastuzumab is effective only against those tumours with HER2 overexpression at the 3+ level (by IHC) or gene amplification (i.e. fluorescence in situ hybridisation [FISH]-positive).

In a subsequent randomised, multicentre trial in a more homogeneous group of patients (IHC 3+ or FISH-positive), the combination of trastuzumab plus docetaxel was associated with improvements in various parameters including time to disease progression and overall survival compared with docetaxel only. Various other combinations for first-line therapy in HER2-positive metastatic breast cancer have shown promising results in smaller phase II trials, and the use of trastuzumab monotherapy as second- or third-line treatment demonstrated beneficial effects in a large phase II trial.

Recent data from several large, phase III trials in patients with HER2-positive early-stage breast cancer have demonstrated that the addition of trastuzumab to chemotherapy in the adjuvant setting significantly improves disease-free survival. An interim combined analysis of two US Cooperative Group trials showed significant improvements in the primary endpoint of disease-free survival and the secondary endpoint of overall survival with trastuzumab-containing adjuvant therapy (an anthracycline-based regimen then paclitaxel plus trastuzumab) compared with adjuvant therapy comprising an anthracycline-based regimen followed by paclitaxel. Across four phase III trials (NCCTG N9831, NSABP B-31, HERA and BCIRG 006), interim/preliminary results indicate that trastuzumab-containing adjuvant therapy was associated with a 39–52% reduction in the risk of cancer recurrence compared with chemotherapy-only adjuvant regimens in patients with HER2-positive (IHC 3+ and/or FISH-positive) early-stage breast cancer.

Tolerability

The most common adverse events associated with trastuzumab are infusion-related symptoms, such as fever and chills, usually occurring during administration of the first dose. In pivotal trials in which women with metastatic breast cancer received trastuzumab as monotherapy or in combination with paclitaxel, the following adverse events were attributed to trastuzumab and were reported in ≥10% of patients: abdominal pain, asthenia, chest pain, chills, fever, headache, pain, diarrhoea, nausea, vomiting, arthralgia, myalgia and rash.

Trastuzumab is also associated with a number of serious adverse events including cardiac events, severe hypersensitivity reactions (including anaphylaxis), infusion-related reactions and pulmonary events. The risk of ventricular dysfunction and congestive heart failure in patients treated with trastuzumab alone or in combination with paclitaxel or docetaxel is particularly increased if administered in combination with anthracycline-containing chemotherapy. Patients should undergo a thorough cardiac assessment prior to beginning trastuzumab therapy, and cardiac function should be monitored during trastuzumab therapy. Trastuzumab can also increase chemotherapy-induced neutropenia.

Various sections of the manuscript reviewed by: N. Bangemann, Medical Center Benjamin Franklin, Free University, Berlin, Germany; E.B. Elkin, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, USA; I.O. Ellis, Department of Histopathology, Nottingham City Hospital, Nottingham, England; G. Fountzilas, 1st Department of Internal Medicine, Oncology Section, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; J. Horton, Comprehensive Breast Cancer Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA; B. Leyland-Jones, Department of Oncology, McGill University, Montreal, Quebec, Canada; F. Montemurro, Unit of Medical Oncology, Institute for Cancer Research and Treatment, Torino, Italy.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘trastuzumab’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). 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: MEDLINE search terms were ‘trastuzumab’ and ‘breast cancer’. EMBASE search terms were ‘trastuzumab’ and ‘breast cancer’. AdisBase search terms were ‘trastuzumab’ and ‘breast cancer’. Searches were last updated 8 February 2006.
Selection: Studies in patients with HER2-positive breast cancer 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: Trastuzumab, metastatic breast cancer, early-stage breast cancer, adjuvant therapy, neoadjuvant therapy, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, pharmacoeconomics.