Second-Line Therapies for Patients With mCRC

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In the United States, the frontline standard of care for patients with metastatic colorectal cancer (mCRC) is bevacizumab in combination with chemotherapy; however, this approach is used less frequently in Europe. Following progression on this regimen, the selection of an optimal second-line treatment remains a challenge, given the lack of an adequate biomarker or clearly superior agent.

The TML study was formed to examine the efficacy of continuing bevacizumab plus chemotherapy after progression. In this trial the median overall survival was 11.2 months in the bevacizumab group versus 9.8 months for chemotherapy alone, a difference of 1.4 months, Claus-Henning Köhne, MD, PhD, states. Additionally, the E3200 and the ML18147 (a subanalysis of the VELOUR trial) demonstrated similar findings, suggesting bevacizumab is superior beyond progression.

The first data suggesting a benefit for continuing bevacizumab beyond progression came from the BRiTE registry, in 2008. Heinz-Josef Lenz, MD, notes that he was surprised by the consistent benefit observed for continuing antiangiogenic therapy in the second-line. Moreover, he adds, in each trial looking at continuing antiangiogenic therapy, regardless of the agent used, survival was extended by approximately 1.4 months. Pulling all of this data together, Johanna Bendell, MD, explains that a clear patient population benefited more from continued antiangiogenic therapy, which further emphasizes the need for a predictive biomarker.

The phase III VELOUR trial examined FOLFIRI alone or in combination with aflibercept, following progression on an oxaliplatin-based regimen. Additionally, Bendell explains, approximately a third of patients enrolled had received prior treatment with bevacizumab in the frontline. Similar to other trials looking at second-line treatment with antiangiogenic therapies, the overall survival benefit was 1.4 months, Bendell adds.

Since the survival benefit was similar between aflibercept in the VELOUR trial and bevacizumab in TML, physicians look to other indicators to determine the most appropriate treatment. As such, the adverse event profiles for each agent are considered and vary between the two, with a leading concern being the diarrhea, neutropenia, and asthenia experienced with aflibercept. However, Bendell suggests, the FDA marks both agents as acceptable treatment options.