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The VEGF inhibitor bevacizumab and the EGFR inhibitor cetuximab have both been approved in combination with chemotherapy for the frontline treatment of patients with metastatic colorectal cancer (mCRC) for over a decade. Various studies have been formed to compare these agents, including the CALGB/SWOG 80405 study. This study began accruing patients nearly 10 years ago, with results still pending, notes Alan P. Venook, MD.
In the meantime, the FIRE-3 study was completed, which compared upfront FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in patients with KRAS wild-type mCRC. The overall response rate and progression-free survival were similar between the two arms. However, there was a 3.7 month overall survival (OS) benefit in favor of cetuximab compared with bevacizumab. Given these inconsistent results, investigators are exploring the second-, third-, and fourth-lines of therapy. Although, Venook notes, these data have not been made available at this time.
The most fascinating finding, Venook believes, is that the Kaplan-Meier curves for OS do not split until the 20-month mark. Adding to the dilemma, when the broader definition of RAS mutations was applied to the results, the OS advantage improved to 7.5 months for cetuximab with the same split in the curves at 20 months. These findings are difficult to explain biologically, suggesting that treatment sequencing may be the cause, Venook believes.