Treating Unresectable Metastatic Colorectal Cancer

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Treatment options for patients with unresectable metastatic colorectal cancer (CRC) have evolved from 5-FU to oxaliplatin, capecitabine, and targeted therapies. However, until recently, new drug development has been fairly stagnant, placing emphasis on the optimal use of existing treatments through the use of biological markers and molecular testing.

At this point, Heinz-Josef Lenz, MD, states, the only clinically validated predictive marker is KRAS, which is an oncogene in the MAP kinase pathway. The status of this gene plays a significant role in the efficacy of EGFR targeted treatments. However, Lenz notes, questions still linger over the optimal use of this marker, particularly the accuracy of tests and the exon of the mutation. Along these lines, in the future, the FDA will be more involved in the approval of molecular tests, Lenz believes.

Looking more closely at location, moderator John L. Marshall, MD, poises the question of selecting treatment for patients with KRAS G13D mutations. Johanna Bendell, MD, explains that recent findings contradict the initial pooled analysis of the CRYSTAL and OPUS trials, which showed that cetuximab was beneficial in patients with KRAS G13D mutations. As a result, she believes the role of the G13D is unclear and patients who test positive should be enrolled in clinical trials.

The role of BRAF mutations in CRC has evolved, as more data becomes available. Axel Grothey, MD, explains that approximately 8% of patients with metastatic CRC have a BRAF mutation. Unfortunately, Grothey notes, BRAF mutations denote a poorer prognosis and a standard therapy currently does not exist. The treatment of BRAF mutant metastatic CRC is evolving, Lenz states. Moreover, he notes, these tumors seem to respond to immunotherapies.

The need for effective treatment approaches in this space enhances the importance of molecular testing and enrollment in clinical trials. At this point, Bendell notes, research is just beginning to scratch the surface of what is possible in the treatment of CRC. The panel remains optimistic that a target will be found that shows dramatic responses, similar to those seen in lung cancer with ALK and EGFR and in breast cancer with HER2.