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New Targeted Treatment May Slow Disease in Patients with Advanced GIST

A new oral drug, regorafenib (Stivarga®), may delay the progression of advanced gastrointestinal stromal tumors (GIST) that are resistant to treatment. Results from an international clinical trial published November 22, 2012, in The Lancet demonstrated that patients treated with regorafenib lived longer without their disease progressing than patients who received a placebo.

GIST is a relatively rare cancer that is driven, in most cases, by mutations that activate the KIT or PDGFRA kinase signaling pathways. Because this type of GIST is resistant to standard chemotherapy, most tumors are surgically removed if the disease has not spread.

The tyrosine kinase inhibitor imatinib (Gleevec®) was the first drug approved for inoperable GIST. However, most GIST tumors develop resistance to imatinib after about 2 years of treatment. Patients with imatinib-resistant tumors are then treated with sunitinib (Sutent®), but the disease usually develops resistance to sunitinib and progresses within 1 year. Patients with advanced GIST that is resistant to both imatinib and sunitinib have no other standard treatment options.

Based on results from an earlier phase II trial, George D. Demetri, M.D., of the Dana-Farber Cancer Institute and his colleagues compared regorafenib with placebo in patients with metastatic or inoperable GIST who had been treated previously with imatinib and sunitinib. Regorafenib, which inhibits multiple kinases, was approved in September for metastatic colorectal cancer.

The randomized, placebo-controlled phase III trial included 199 patients with advanced GIST, of whom 133 were randomly assigned to receive regorafenib and 66 to receive a placebo. Those who received regorafenib lived without their cancer progressing for a median of 4.8 months, compared with 0.9 months among patients who received a placebo. There was no difference in overall survival between the patients who initially received regorafenib and those who received the placebo. The authors suggested, however, that this could have been due to crossover: 85 percent of patients assigned to receive the placebo crossed over to receive regorafenib after their disease progressed.

All patients who received regorafenib experienced side effects. Just over 60 percent reported a severe drug-related adverse event, compared with 14 percent of patients who received the placebo.

“The case for routine use of this drug in patients who have failed imatinib and sunitinib is strong,” the authors of an accompanying editorial wrote. Dr. Demetri said, “It’s encouraging to have developed this third targeted drug to manage a disease that was uniformly untreatable before 2000.”

The maker of the drug, Bayer Healthcare Pharmaceuticals, has filed for Food and Drug Administration approval of regorafenib to treat GIST.

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