Cetuximab is a chimeric monoclonal antibody directed against the extracellular domain of the EGFR, and it is presently approved for use in combination with irinotecan for metastatic colon cancer in the refractory setting or as monotherapy in patients who are deemed to be irinotecan-refractory. Because cetuximab is of the G1 isotype, its antitumor activity may also be mediated, in part, by immunologic-mediated mechanisms. There is growing evidence that cetuximab can be effectively and safely combined with irinotecanand oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer as well. Of note, the efficacy of cetuximab is restricted to only those patients whose tumors express the wild-type RAS gene, which includes both KRAS and NRAS. Combination regimens of cetuximab with cytotoxic chemotherapy may be of particular benefit in the neoadjuvant therapy of patients with liver-limited disease. Although this antibody was initially approved to be administered on a weekly schedule, pharmacokinetic studies have shown that an every-2-week schedule provides the same level of clinical activity as the weekly schedule. This agent is also approved for use in combination with radiation therapy in patients with locally advanced head and neck cancer. Cetuximab is well tolerated, with the main adverse effects being an acneiform skin rash, hypersensitivity infusion reaction, and hypomagnesemia. However, when cetuximab is combined with radiation therapy for head and neck cancer, there is a very low but real increased risk (1%) of sudden death, which has resulted in a black-box warning for the drug.
Panitumumab is a fully human monoclonal antibody directed against the EGFR and works through inhibition of the EGFR signaling pathway. In contrast to cetuximab, this antibody is of the G2 isotype and, as such, would not be expected to exert any immunologic-mediated effects. Panitumumab was originally approved for patients with refractory metastatic CRC who have been treated with all other active agents. However, it is now also approved for use in combination with FOLFOX chemotherapy in the front-line treatment of metastatic CRC. As with cetuximab, this antibody is only effective in patients whose tumors express wild-type RAS. Recent clinical studies have shown that this antibody can also be effectively and safely combined with irinotecanbased chemotherapy in the second-line treatment of metastatic CRC. Acneiform skin rash and hypomagnesemia are the two main adverse effects associated with its use. Despite being a fully human antibody, infusion-related reactions can still be observed, although much less commonly than cetuximab.
Necitumumab is a fully human IgG1 monoclonal antibody directed against EGFR. Like cetuximab and panitumumab, it works through inhibition of the EGFR signaling pathway. However, as with cetuximab, necitumumab is of the G1 isotype, and as such, its antitumor activity may also be mediated, at least in part, through immunologically mediated mechanisms. It is approved for use in combination with gemcitabine and cisplatin chemotherapy for the treatment of squamous NSCLC. The main adverse effects are what have been previously described for other anti-EGFR antibodies, and both venothrombolic and arterioembolic events have also been described.