5047

The epidermal growth factor receptor (EGFR) pathway plays an important role in tumor growth and progession in a variety of tumor types. Cetuximab (Erbitux®) is a chimeric monoclonal antibody which binds to the extracellular ligand binding domain of the EGFR and blocks EGFR-dependent signaling. Gefitinib (Iressa®, ZD1839) is an orally active EGFR tyrosine kinase inhibitor (EGFR-TKI) which has been shown to inhibit downstream EGFR signaling. Currently, cetuximab is approved for metastatic colon cancer while gefitinib is used as a monotherapy versus some non-small cell lung cancers; however, whether activity of these compounds is additive or synergistic in these or other tumor models remain unclear. To test this possibility, we examined cetuximab and gefitinib as single agents or in combination versus the EGFR-expressing MX-1 human breast tumor model in athymic nu/nu mice. Intravenous injection of cetuximab (10 mg/kg; 2xwkly to end) or oral administration of gefitinib (100 or 200 mg/kg; daily to end) alone resulted in no appreciable tumor growth inhibition. However, significant tumor growth inhibition was reported following co-treatment with 10 mg/kg cetuximab and 100 mg/kg (TGI = 40.1%) or 200 mg/kg (TGI = 35.3%) gefitinib. Minimal weight loss in single agent and combination groups was also noted, suggesting the possibility of increased dosing levels in future studies. Results from this experiment indicate synergistic tumor growth inhibition in this model and suggests cetuximab and gefitinib in combination may demonstrate significant antitumor activity in additional tumor models.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]