4.9 Overdose

 There is limited experience with single doses higher than 400 mg/m2 body surface area to date or weekly administrations of doses higher than 250 mg/m2 body surface area. In clinical studies with doses up to 700 mg/m2 given every 2 weeks the safety profile was consistent with that described in section 4.8.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

 Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC06

Mechanism of action

Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermal growth factor receptor (EGFR).

EGFR signalling pathways are involved in the control of cell survival, cell cycle progression, angiogenesis, cell migration and cellular invasion/metastasis.

Cetuximab binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition of the function of the receptor. It further induces the internalisation of EGFR, which can lead to down-regulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-expressing tumour cells (antibody dependent cell-mediated cytotoxicity, ADCC).

Cetuximab does not bind to other receptors belonging to the HER family.

The protein product of the proto-oncogene KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) is a central down-stream signal-transducer of EGFR. In tumours, activation of KRAS by EGFR contributes to EGFR-mediated increased proliferation, survival and the production of pro-angiogenic factors.

KRAS is one of the most frequently activated oncogenes in human cancers. Mutations of the KRAS gene at certain hot-spots (mainly codons 12 and 13) result in constitutive activation of the KRAS protein independently of EGFR signalling.

Pharmacodynamic effects

In both in vitro and in vivo assays, cetuximab inhibits the proliferation and induces apoptosis of human tumour cells that express EGFR. In vitro cetuximab inhibits the production of angiogenic factors by tumour cells and blocks endothelial cell migration. In vivo cetuximab inhibits expression of angiogenic factors by tumour cells and causes a reduction in tumour neo-vascularisation and metastasis.

Immunogenicity

The development of human anti-chimeric antibodies (HACA) is a class effect of monoclonal chimeric antibodies. Current data on the development of HACAs is limited. Overall, measurable HACA titres were noted in 3.4% of the patients studied, with incidences ranging from 0% to 9.6% in the target indication studies. No conclusive data on the neutralising effect of HACAs on cetuximab is available to date. The appearance of HACA did not correlate with the occurrence of hypersensitivity reactions or any other undesirable effect to cetuximab.
Colorectal cancer

A diagnostic assay (EGFR pharmDx) was used for immunohistochemical detection of EGFR expression in tumour material. A tumour was considered to be EGFR-expressing, if one stained cell could be identified. Approximately 75% of the patients with metastatic colorectal cancer screened for clinical studies had an EGFR-expressing tumour and were therefore considered eligible for cetuximab treatment. The efficacy a