Regorafenib in the Treatment of Colorectal Cancer

George P. Kim, MD
Publishded Online: Sep 16, 2013

George P. Kim, MD

George P. Kim, MD

Assistant Professor of Oncology, Department of
Hematology/Oncology, Mayo Clinic, Jacksonville, FL;


Regorafenib is a recently approved oral, multikinase inhibitor for refractory colorectal cancer. Although structurally similar to sorafenib, it more potently inhibits a broader spectrum of critical growth receptor pathways, including those regulating angiogenesis and aberrant cellular proliferation.

Regorafenib was evaluated in an international randomized, placebo-controlled, phase III study of 760 patients in the CORRECT trial. In the study, improvements in overall survival and progression-free survival were observed. The clinical activity with regorafenib was mainly cytostatic, with 41% of patients achieving disease stabilization and only 1% achieving response. Regorafenib proved tolerable, with side effects characteristic of other smallmolecule inhibitors.

Ongoing and future studies with regorafenib are testing its potential role combined with chemotherapy in first- and secondline therapy, as maintenance therapy, and in the postoperative setting. Regorafenib is a welcome, novel, targeted addition to the armamentarium for the treatment of colorectal cancer.


Regorafenib (BAY 73-4506) is a novel, oral, multikinase inhibitor derived from efforts to optimize drug properties, breadth of activity, and potency using a diphenylurea backbone.1 Regorafenib is structurally similar to another drug in this class, sorafenib (Table2-4), which is approved for the treatment of renal and hepatocellular cancers. Regorafenib contains a fluorine atom in the center of a phenyl ring, which results in similar yet distinct biochemical properties. Regorafenib is metabolized into two major human active metabolites M-2 (N-oxideregorafenib) and M-5 (N-oxide- and N-desmethylregorafenib), which are also potent but distinct from regorafenib in in vitro assays.5

M-2 inhibits key targets with similar IC50 values as regorafenib, while those for M-5 are slightly higher. In cell line studies, dose-dependent tumor growth inhibition was observed and was comparable to regorafenib. At steady state, both metabolites attain systemic exposure similar to the parent compound and contribute to clinical activity.6

Within the understanding of the hallmarks of cancer, cells self-perpetuate growth through aberrant signaling and by becoming resistant to growth inhibitory signals.7 Many growth factors and their associated receptors work in complementary, coordinated networks to regulate tumor growth. In addition, the tumor microenvironment is a critical accomplice in nurturing cancer cell processes such as angiogenesis. This complexity provides the rationale for concurrent targeting of multiple growth factors and receptor pathways to optimally develop anticancer therapies.