Novel Therapies in Development for mCRC

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BRAF mutations occur in approximately 5% to 10% of patients with metastatic colorectal cancer (mCRC). In general, these mutations indicate a poorer prognosis. Unfortunately, treatment with single-agent BRAF inhibitors has not demonstrated clinical benefits for patients with mCRC, states Alan P. Venook, MD. However, a more thorough blockade of the MAP kinase pathway with dual BRAF and MEK inhibition has shown some activity for patients with mCRC, Venook points out. The challenge now for this combination is to discover possible resistance mechanisms, Venook believes.

Recent data suggesting that RAS mutations, not just KRAS mutations, are predictive for benefit to EGFR inhibitors has broaden the population of EGFR-ineligible patients to approximately 50%, Fadi Braiteh, MD, CPI, states. Unfortunately, RAS and KRAS mutations are difficult to target, requiring smarter targeting downstream. As a result, MEK inhibitors are intriguing as treatments for patients with RAS mutations.

The mild MEK inhibitor sunitinib has been studied in combinations for mCRC. Altogether, at this point sunitinib combinations appear to show reasonable safety with similar efficacy to existing treatments. However, the optimal companion drug for this therapy has yet to be discovered and still needs to be evaluated, Braiteh believes.

Patients with KRAS wild-type tumors often develop resistance to EGFR inhibitors, which may be the result of MET upregulation. In a phase II study, the MET inhibitor tivantinib was combined with irinotecan and cetuximab for patients with relapsed or refractory mCRC. Overall, there was a trend toward prolongation in progression free survival (PFS) and improved objective response rates in favor of the tivantinib combination, Tanios Bekaii-Saab, MD, explains. Additionally, a subgroup analysis from this study revealed that HGF levels might help predict which patients benefit from MET inhibitors.

These targeted therapies have showed some results but chemotherapy remains the most important drug in mCRC, suggests Axel Grothey, MD. Building on this, the cytotoxic agent TAS-102 demonstrated promising data in a phase II trial and is currently being explored in a phase III trial. Treatment with TAS-102 nearly doubled survival when compared to best supportive care in patients with refractory mCRC.

Unfortunately, despite promise in other tumor types, immunotherapies have not been thoroughly explored in CRC, Venook believes. Moreover, John L. Marshall, MD, suggests that early data stalled efforts examining checkpoint inhibition with PD-1 or CTLA-4 targeted agents in CRC. Consequently, Marshall feels that researchers should take a second look at checkpoint inhibitors in mCRC.