Regorafenib Approved to Treat GIST

George Demetri, MD

The FDA approved regorafenib (Stivarga) for the treatment of gastrointestinal stromal tumors (GIST) that cannot be removed surgically and no longer respond to other FDA-approved treatments for the disease.

The announcement, following a priority review, marks the second approved indication for regorafenib. In September, the FDA approved the drug for patients with metastatic colorectal cancer (mCRC) whose disease has progressed after chemotherapy.

Regorafenib is a multikinase inhibitor that blocks targets and receptors including VEGFR1-3, TIE2, PDGFR, FGFR, KIT and RET, which are associated with angiogenesis and tumor progression.

“Stivarga is the third drug approved by the FDA to treat gastrointestinal stromal tumors,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “It provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective.”

The FDA has also approved imatinib (Gleevec) and sunitinib (Sutent) for the treatment of GIST, a disease that is diagnosed at a rate of 3300 to 6000 new cases per year in the United States, according to the National Cancer Institute.

The approval was based on the results of the phase III GRID trial, which were presented at the 2012 meeting of the American Society of Clinical Oncology (ASCO). In that trial, 199 patients with metastatic and/or unresectable GIST that had become resistant to imatinib and sunitinib were randomized 2:1 to receive regorafenib (160 mg orally once daily on a 3 weeks on/1 week off cycle) or a placebo, plus best supportive care.

The study found that patients who received regorafenib had a period of progression-free survival of 4.8 months compared with 0.9 months in patients who received a placebo, a statistically significant 3.9 month improvement (hazard ratio [HR] = 0.27; 95% CI, 0.19—0.39; P <.0001). There was no statistically significant difference in overall survival, but the authors noted that this was expected, since patients in the placebo arm were allowed to cross over unblinded into the regorafenib arm.

According to the FDA, weakness and fatigue, hand-foot syndrome, diarrhea, loss of appetite, high blood pressure, mouth sores, infection, changes in voice volume or quality, pain, weight loss, stomach pain, rash, fever, and nausea were the most common side effects. Some serious side effects that occurred in less than 1% of patients included liver damage, severe bleeding, blistering and peeling of skin, very high blood pressure requiring emergency treatment, heart attacks, and intestinal perforations.

“While great progress has been made in the treatment of GIST since the introduction of kinase inhibitors as effective therapies for this orphan disease, we have been looking for additional, effective treatments for GIST patients whose disease worsens despite currently approved therapies,” said George D. Demetri, MD, Principal Investigator of the GRID study and Director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston, MA, in a statement. “These data show that regorafenib can slow disease progression in patients who are no longer responding to other approved therapies and may provide another avenue for GIST patients who would otherwise have no FDA-approved treatment option.

Stivarga is marketed by Bayer HealthCare Pharmaceuticals based in Wayne, NJ, and partner Onyx Pharmaceuticals in San Francisco, CA.

Demetri GD, Reichardt P, Kang YK, et al. Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial. J Clin Oncol. 2012;30(suppl; abstr LBA10008).