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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.
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 mean area under the plasma concentration-time curve were observed with cetuximab doses up to 500 mg/m2; the volume of distribution was approximately equal to that of vascular space. The major route of cetuximab clearance is hypothesised to be via internalisation of the antibody-receptor complex. Cetuximab has a long terminal elimination half-life of approximately 112 hours. Importantly, no significant pharmacokinetic interactions were observed with the concomitant administration of cetuximab and irinotecan in patients with mCRC.
In clinical trials, cetuximab was generally administered as a 120-minute intravenous infusion of 400 mg/m2, followed by weekly 60-minute infusions of 250 mg/m2, with treatment continuing until disease progression or unacceptable toxicity.
In a large (n >400), randomised, open-label, phase III trial in treatment-naive patients with SCCHN, combining cetuximab with high-dose radiation therapy significantly increased locoregional control (primary endpoint), compared with radiation monotherapy, with a 32% reduction in the risk of locoregional progression. Combination treatment was also associated with a significantly lower risk of disease progression, higher PFS rates and a greater ORR. In a noncomparative study in 103 platinum-refractory patients with SCCHN, cetuximab monotherapy was associated with an overall ORR (primary endpoint) of 13% and a disease control rate of almost 50%.
As second- and subsequent-line therapy in the large (n >300) well designed BOND trial in EGFR-positive patients with mCRC who were refractory to irinotecan, cetuximab plus irinotecan was associated with significantly greater ORR than cetuximab monotherapy. In this trial, there was a 46% reduction in the risk of progression in the combination group; however, no significant between-group difference in OS was observed. There was also no significant between-group difference in OS in another large (n ≈1300), well designed trial (EPIC) [primary endpoint], although cetuximab plus irinotecan therapy was associated with significantly higher overall response rates and longer PFS than irinotecan monotherapy. The primary endpoint of PFS at 12 weeks exceeded the predicted rate of 50% in an ongoing trial evaluating three dosages of irinotecan combined with cetuximab. In a large (n = 572) randomised trial in heavily pretreated patients with mCRC, the addition of cetuximab treatment to BSC significantly improved median OS times (primary endpoint) and ORR compared with BSC and reduced the risk of disease progression by 32%.
In patients with mCRC or SCCHN, the addition of cetuximab to chemotherapy or radiotherapy did not negatively impact on health-related quality of life (HR-QOL), compared with either monotherapy. Furthermore, compared with BSC, cetuximab plus BSC was associated with significantly less deterioration in HR-QOL, and cetuximab plus irinotecan was associated with less deterioration in pain, nausea and global health status than irinotecan monotherapy.
Findings from modelling studies from a healthcare payer perspective showed that the predicted incremental costs per quality-adjusted life-year gained of a cetuximab treatment regimen relative to the comparator were generally below recognised thresholds of acceptability. These models predict that the direct medical cost of cetuximab in combination with either radiotherapy or irinotecan is higher than that of other treatments; however, the higher cost is partly offset by increases in life expectancy and reductions in the incidence and costs of complications.
Adverse events directly attributable to cetuximab therapy are difficult to determine given the morbidity of the patient population and the effects of concomitant therapies such as chemo- or radiotherapy. Cetuximab, added to chemo- or radiotherapy regimens, did not exacerbate toxicities commonly associated with such regimens. Cetuximab has an acceptable tolerability profile; the majority of adverse events that occurred during clinical trials were of mild or moderate intensity and tended to resolve on cessation of cetuximab. In pooled analyses, the most common adverse events associated with cetuximab administration that occurred in ≥25% of patients with SCCHN or mCRC in any treatment group were: acneform rash (skin eruptions), weight loss, asthenia, diarrhoea, xerostomia, dysphagia, nausea, abdominal pain, anorexia, constipation, vomiting, fever, pharyngitis, dehydration, stomatitis, leukopenia and headache. The incidence of severe adverse events during clinical trials was low and included infusion reactions, acneform rash, hypersensitivity, cardiopulmonary arrest, hypomagnesaemia and pulmonary toxicity; a black box warning has been included in the US manufacturer’s prescribing information regarding infusion reactions and cardiopulmonary arrest.
KeywordsOverall Survival Epidermal Growth Factor Receptor Irinotecan Cetuximab Metastatic Colorectal Cancer
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