The monoclonal antibody cetuximab in combination with irinotecan received an accelerated approval in 2004 as a treatment for EGFR-positive patients with refractory metastatic colorectal cancer (mCRC). This approval was based on findings from the phase II BOND study, which demonstrated that cetuximab had clinical activity alone and in combination for patients with mCRC. These results were the first to demonstrate single-agent activity for an antibody in the refractory setting, notes Heinz-Josef Lenz, MD.

Results from the BOND study were the basis for the extended clinical development of cetuximab in mCRC. Since it’s initial approval, the drug moved from an unselected refractory treatment to a first-line therapy with RAS status as a selective biomarker. This development process stands as an example of the importance of molecular biology and proper patient selection, believes Lenz.

The Canadian CO.17 trial was one of the first studies to show that cetuximab improved overall survival, notes Marwan Fakih, MD. This study examined best supportive care with or without cetuximab in EGFR-positive patients with refractory mCRC. A post-hoc analysis from this study was one of the first to demonstrate that KRAS status was an important predictor of benefit for EGFR inhibition, suggests Fakih. Additionally, the level of benefit observed in this trial set the bar for expectations in the first- and second-lines of therapy.

Adding to the growing data on cetuximab, the phase III EPIC trial examined the treatment as a second-line therapy for patients with mCRC. In this study, cetuximab plus irinotecan improved response and progression-free survival but not overall survival. Johanna Bendell, MD, believes the lack of improvement in survival was a result of the large amount of patients who received cetuximab plus irinotecan poststudy. This realization suggested that overall survival is the same, regardless of when cetuximab is administered in the sequence, suggests Bendell.