Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer

SKA Blick, LJ Scott - Drugs, 2007 - Springer
SKA Blick, LJ Scott
Drugs, 2007Springer
Cetuximab (Erbitux®) is a human-mouse chimeric monoclonal antibody, which competitively
binds to the accessible extracellular domain of the epidermal growth factor receptor (EGFR)
to inhibit dimerisation and, subsequently, inhibit tumour growth and metastasis. In the EU
and the US, cetuximab has been approved for use with concomitant radiotherapy in patients
with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and in
combination with irinotecan for the treatment of metastatic colorectal cancer (mCRC) in …
Abstract
Cetuximab (Erbitux®) is a human-mouse chimeric monoclonal antibody, which competitively binds to the accessible extracellular domain of the epidermal growth factor receptor (EGFR) to inhibit dimerisation and, subsequently, inhibit tumour growth and metastasis. In the EU and the US, cetuximab has been approved for use with concomitant radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and in combination with irinotecan for the treatment of metastatic colorectal cancer (mCRC) in patients with EGFR-expressing tumours who are refractory to irinotecan-based therapy. In the US, cetuximab has also been approved as monotherapy in patients with recurrent or metastatic SCCHN for whom platinum-based therapy has failed and in patients with mCRC who are intolerant of irinotecan-based regimens.
In treatment-naive patients with locoregionally advanced SCCHN, cetuximab plus radiotherapy was more effective than radiation therapy alone in prolonging locoregional disease control. In addition, more limited noncomparative data from a large trial indicated a 13% overall objective response rate (ORR) in platinum-refractory patients with SCCHN. In patients with EGFR-expressing mCRC, cetuximab plus irinotecan improved ORR more than cetuximab monotherapy in a trial in irinotecan-refractory patients; however, there was no difference in overall survival (OS) between cetuximab plus irinotecan and cetuximab monotherapy in oxaliplatin-refractory recipients in another trial. In an ongoing trial, progression-free survival (PFS) exceeded 50% after 12 weeks in irinotecan-refractory patients receiving three different dosages of cetuximab plus irinotecan. In another large trial, cetuximab monotherapy prolonged OS compared with best supportive care (BSC) in heavily pretreated patients.
Overall, cetuximab treatment had an acceptable tolerability profile, with the majority of adverse events being mild or moderate in severity and clinically manageable. In particular, cetuximab therapy did not exacerbate toxicities commonly associated with chemo- or radiotherapeutic regimens. Albeit occurring with high incidence, adverse cutaneous reactions appear to be a marker for response.
Results of ongoing head-to-head comparative trials comparing cetuximab with other biological agents will help to establish definitively the role of cetuximab in the management of SCCHN and mCRC. In the meantime, cetuximab, with its highly targeted mechanism of action and synergistic activity with current treatment modalities, is a valuable treatment option in patients with SCCHN and mCRC.
Pharmacological Properties
Cetuximab binds to the readily accessible extracellular domain of the EGFR with high affinity (dissociation constant = 0.39 nmol/L), competing with endogenous ligand binding. This competition, resulting in the blockade of receptor-dependent signal transduction pathways, provides antitumour effects involving a number of different actions including cell-cycle arrest, induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, internalisation and downregulation of the EGFR, antibody-dependent cellular cytotoxicity and enhancement of sensitivity to radio- or chemotherapy. Cetuximab recipients have a low propensity for developing human antichimeric antibodies.
Cetuximab exhibits nonlinear pharmacokinetics in the dose range of 50–500 mg/m2, independent of concurrent administration of radio- or chemotherapy. Greater than dose-proportional increases in mean maximum plasma concentrations and …
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