Dr. Demetri Describes the MOA of Regorafenib in GIST

George D. Demetri, MD
Published: Monday, Sep 10, 2012

George Demetri, MD, director of the Ludwig Center at Dana-Farber Cancer Institute and Sarcoma Center at Harvard Medical School in Boston, Massachusetts, discusses the oral multikinase inhibitor regorafenib that is being investigated for patients with gastrointestinal stromal tumors (GISTs).

GISTs are driven primarily by mutations in the KIT kinase pathway, Demetri explains. Overtime, 90% of patients receiving imatinib (Gleevec) and sunitinib (Sutent) for their GIST will develop resistance. Following progression, the unique shape of the regorafenib molecule allows it to bind to targets that have developed resistance to sunitinib and imatinib, according to Demetri.

Overall, regorafenib has a very different profile than the other agents used to treat GIST. Its ability to specifically inhibit fibroblast growth factor receptors (FGFR) is still being investigated as a possible route for overcoming resistance. In total, regorafenib inhibits VEGFR1-3, TIE2, PDGFR, FGFR, KIT and RET.

For the treating oncologist, Demetri notes that the unique activity of regorafenib, as demonstrated in the phase III GRID trial, justifies the agent for patients with GIST who have no other therapeutic options. In the trial, the risk of disease progression was reduced by 73% when compared to placebo for patients who were resistant to imatinib or sunitinib.
 
George Demetri, MD, director of the Ludwig Center at Dana-Farber Cancer Institute and Sarcoma Center at Harvard Medical School in Boston, Massachusetts, discusses the oral multikinase inhibitor regorafenib that is being investigated for patients with gastrointestinal stromal tumors (GISTs).

GISTs are driven primarily by mutations in the KIT kinase pathway, Demetri explains. Overtime, 90% of patients receiving imatinib (Gleevec) and sunitinib (Sutent) for their GIST will develop resistance. Following progression, the unique shape of the regorafenib molecule allows it to bind to targets that have developed resistance to sunitinib and imatinib, according to Demetri.

Overall, regorafenib has a very different profile than the other agents used to treat GIST. Its ability to specifically inhibit fibroblast growth factor receptors (FGFR) is still being investigated as a possible route for overcoming resistance. In total, regorafenib inhibits VEGFR1-3, TIE2, PDGFR, FGFR, KIT and RET.

For the treating oncologist, Demetri notes that the unique activity of regorafenib, as demonstrated in the phase III GRID trial, justifies the agent for patients with GIST who have no other therapeutic options. In the trial, the risk of disease progression was reduced by 73% when compared to placebo for patients who were resistant to imatinib or sunitinib.
 



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