Panitumumab is a fully humanised anti-EGFR monoclonal antibody. When used alone in advanced chemo-resistant colorectal cancer, response rates vary from 8 to 13% and disease control is attained in 29–43% of patients.45–47 One randomised phase III trial has demonstrated a small, significant prolongation of progression-free survival (8 versus 7.3 weeks; hazard ration (HR) 0.54; p<0.0001) compared with best supportive care,46 which has led to FDA approval for the use of panitumumab in chemoresistant disease. The lack of any observable difference in overall survival in this study may be in part due to 76% of the control group crossing over to receive panitumumab. Further trials of the use of this antibody in combination with chemotherapy are awaited. Trials in this setting investigating TKIs are small and the available data are limited: monotherapy with gefitinib, erlotinib or lapatinib appears to have poor activity with only 1–5% of patients responding. One study using serial biopsies showed that EGFR inactivation was not achieved by gefitinib at 250 or 500mg.42 A highdose study of gefitinib (750mg) led to stable disease in 33% of patients, but at the expense of higher toxicity with over half of patients requiring dose reductions or discontinuation of therapy.49 Toxicity issues continue to be problematic when TKIs are combined with chemotherapy. In combination with irinotecan, one study reported lack of efficacy and stopped dose escalation because of toxicity,50 and another study demonstrated excessive toxicity with diarrhoea, dehydration and neutropaenic sepsis being common.51 In contrast, however, when gefitinib was combined with a 5-fluorouracil-based oxaliplatin-containing regimen, treatment was better tolerated and about 30% achieved partial response among 69% of patients with overall disease control.52,53 Further trials are required to assess this treatment combination.

First-line Advanced Disease
Table 2 summarises selected studies of EGFR-targeted therapies in chemonaïve patients. Two small phase II studies of cetuximab monotherapy have been performed: objective responses were observed in 4–15% and disease control rates ranged from 39 to 54%.54,55 The latter study importantly demonstrated tolerability and efficacy in an elderly population of patients over the age of 70, providing a feasible therapeutic option for some patients who may not withstand conventional cytotoxics.