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Evolution of regorafenib from bench to bedside in colorectal cancer: Is it an attractive option or merely a “me too” drug?

Authors Goel G

Received 18 September 2017

Accepted for publication 23 December 2017

Published 6 March 2018 Volume 2018:10 Pages 425—437


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo

Video abstract presented by Goel.

Views: 124

Gaurav Goel

Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Abstract: Colorectal cancer (CRC) is a major public health problem in the United States with an estimated 50,260 deaths in 2017. Over the past two decades, several agents have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRC (mCRC). Regorafenib (BAY 73-4506) is a small-molecule multikinase inhibitor that was approved for the treatment of mCRC in 2012. This agent is a novel oral diphenylurea-based multikinase inhibitor that is active against several angiogenic receptor tyrosine kinases (RTKs; VEGFR-1, VEGFR-2, VEGFR-3, TIE-2), oncogenic RTKs (c-KIT, RET), stromal RTKs (PDGFR-B, FGFR-1), and intracellular signaling kinases (c-RAF/RAF-1, BRAF, BRAFV600E). Preclinical studies have documented its broad-spectrum activity against different solid tumor types including CRC. Phase I studies showed that it had an acceptable safety profile in advanced refractory mCRC. A subsequent Phase III trial (CORRECT) demonstrated significant clinical efficacy of regorafenib in patients with refractory or advanced mCRC, which eventually led to its FDA approval for the treatment of mCRC in September 2012. However, the drug was associated with significant toxicity in clinical practice when administered at the approved doses, which necessitated a thorough reassessment of its dosing schedule and toxicity profile. This review summarizes the development of regorafenib from the initial preclinical studies to the Phase III trials and critically examines the current clinical space occupied by regorafenib in the treatment of mCRC, at 5 years after its initial FDA approval.

Keywords: regorafenib, multikinase inhibitor, angiogenesis, colorectal cancer, colon cancer, stivarga, BAY 73-4506

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