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The phase III FIRE-3 study compared bevacizumab plus FOLFIRI to cetuximab plus FOLFIRI as a frontline treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), explains Alan P. Venook, MD. The primary endpoint of the study was objective response rate (ORR) with secondary endpoints of progression-free survival (PFS) and overall survival (OS).
A thorough examination of the data from this study raises several questions, notes Venook. For instance, no advantage was observed in ORR and PFS for either treatment but OS was significantly extended in favor of cetuximab. Interestingly, Venook notes, the survival curves do not split until between 18 and 24 months, which is difficult to explain biologically, Venook elaborates.
A possible explanation for the OS advantage was a protocol of the trial that allowed for second-line therapies. Overall, a similar number of patients received second-line therapies; however, the sequence is unknown. Additionally, Venook notes, further analysis of RAS
mutations in the study is warranted.
As a result of these many questions, Venook does not believe one agent was shown to be superior to the other. Given the endpoint of ORR and the wild-type KRAS status, Axel Grothey, MD, expected the trial would be positive in favor of cetuximab. However, at this point, the findings are primarily hypothesis generating.
Other clinical studies are comparing bevacizumab to cetuximab, explains Venook. The CALGB/SWOG 80405 study is comparing FOLFOX or FOLFIRI plus cetuximab and/or bevacizumab as a treatment for mCRC. However, only a minority of patients on this trial received FOLFIRI plus bevacizumab or cetuximab, making this comparison difficult, notes Venook. However, the trial should provide a broad picture of VEGF versus EGFR inhibition.