An overview of experimental and investigational multikinase inhibitors for the treatment of metastatic colorectal cancer

Abstract

Introduction: The era of molecular-targeted agents, particularly bevacizumab and cetuximab, has revolutionized the treatment paradigm for metastatic colorectal cancer (mCRC). Amongst the multikinase inhibitors (MKIs) examined, regorafenib was the first to establish its role in mCRC. Despite its modest efficacy, this finding had reignited interest in exploring MKIs with the hope of maximizing their therapeutic potential in mCRC.

Areas covered: This review summarizes the previous studies of MKIs in mCRC, targeting two signaling pathways activated through vascular endothelial growth factor receptors and epidermal growth factor receptors. The article provides discussion with a focus on: the challenges encountered when combining MKI with chemotherapy, the lack of predictive markers, and strategies utilized to address escape pathways through combining MKIs with other targeted agents.

Expert opinion: Clinical progress using MKIs in mCRC has been disappointing due to their limited efficacy. The exact role of regorafenib, apart from in chemo-refractory disease setting, requires further delineation. The role of MKIs in combination with other targeted agents or chemotherapy and in the maintenance setting is still considered experimental and warrants further investigation. The broader role of the current generation of MKIs will depend upon the accurate identification of patients with specific molecular phenotypes and better pharmacodynamic understanding of these agents to minimize toxicity.

Keywords:

• metastatic colorectal cancer
• multikinase inhibitors
• regorafenib
• signalling cascade
• tyrosine kinase inhibitor

Declaration of interest

M Michael has received funding from Pfizer Inc., Novartis, and Roche. He is also a member of the advisory board for Novartis, Pfizer Inc., Eli Lilly and Company, Ipsen Ltd and Sanofi Aventis. J Zalcberg has received research and/or travel support from Roche, Bayer Healthcare, Merck Serono, Amgen Inc., and Sanofi Aventis. He has also received honoraria from speaking and/or is a member of the advisory board from Roche, Bayer Healthcare, Amgen Inc., and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes