Treatment of Unresectable RAS Wild-type Metastatic CRC

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The frontline treatment of patients with unresectable metastatic colorectal cancer (CRC) has become more challenging as a result of recent studies focused on RAS mutations. Evidence from the FIRE-3 study and retrospective RAS analyses suggest that cetuximab could be superior to bevacizumab as a frontline therapy, notes Marwan Fakih, MD. As a result, the EGFR inhibitors have moved forward in the treatment paradigm for patients with wild-type RAS.

Studies suggest that survival is superior when patients receive at least one EGFR inhibitor compared with at least one angiogenesis inhibitor, Fakih states. As a result, EGFR inhibition should be administered upfront, in order to ensure that at least one of these therapies is administered, Fakih believes.

Until conclusive evidence is presented that one therapy is more effective, Johanna Bendell, MD, says that she plans to continue the frontline administration of bevacizumab for patients with RAS wild-type metastatic CRC. This decision is based largely upon the comparison of side effects between the two drugs, with a particular emphasis on dermatological toxicity.

In an expanded RAS analysis of the FIRE-3 study, the overall survival advantage was 7.5 months in favor of cetuximab compared with bevacizumab. This benefit, in conjunction with other RAS-focused studies, warrants the consideration of cetuximab in the first-line setting, believes Heinz-Josef Lenz, MD. Overall, the efficacy and toxicity for each agent should be discussed with patients before a decision is made, Lenz notes.

Alan P. Venook, MD, suggests that he doesn’t commonly use biologic agents in the frontline setting for patients with metastatic CRC. However, results from the CALGB/SWOG 80405 study may provide more details on an optimal frontline therapy between cetuximab and bevacizumab. The median survival appears extraordinarily long for patients in the study, based on the length of time that has lapsed while the data matures, Venook states.