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Compared with placebo, sunitinib malate (Sutent) doubled progression-free survival (PFS) in a phase III trial involving patients with pancreatic neuroendocrine tumors (NETs). Data were presented at the 2010 Gastrointestinal Cancers Symposium in January. Sunitinib currently is approved as a treatment for advanced renal cell carcinoma and for gastrointestinal stromal tumors that show resistance to or intolerance of imatinib mesylate (Gleevec).
From June 2007 to April 2009, investigators randomized 171 patients (median age, 56 y) with progressive, well-differentiated, malignant pancreatic NETs to 37.5 mg per day of sunitinib plus best supportive care (n = 86) or to placebo plus best supportive care (n = 85). The primary endpoint was PFS.
Investigators had a target enrollment of 340 patients, but the Data Monitoring Committee recommended the study be stopped prior to full accrual. “The study was stopped early because patients were doing so well on Sutent compared to placebo,” trial investigator Aaron I. Vinik, MD, PhD, Eastern Virginia Medical School, Norfolk, Virginia, said in an interview. At the time the trial was ended, Vinik said data showed “The primary endpoint [of] PFS…more than doubled with sunitinib compared with placebo.”
Median PFS for patients in the sunitinib arm was 11.4 months compared with 5.5 months for patients in the placebo arm (hazard ratio [HR], 0.418; P < .001). The objective response rate with sunitinib was 9.3%, with 2 complete responses and 6 partial responses (95% confidence interval, 3.2%-15.4%). Vinik noted that overall survival (OS) was a secondary endpoint of the trial and was also “improved in patients in the sunitinib arm” compared with the placebo group (HR, 0.409; P = .0204). “The HR at the time of the study stop showed a clinically significant improvement in survival time,” he said. Median OS was not reached in either arm at the time the study was ended (HR, 0.404; P = .0186); the placebo arm recorded 21 deaths during the study period, however, compared with 9 for the sunitinib arm.
The safety profile for sunitinib in this patient population was described as acceptable, with adverse events similar to those observed in other sunitinib studies. The most commonly reported grade 3-4 adverse events were neutropenia (12%), hypertension (9.6%), hand-foot syndrome (6%), leukopenia (6%) abdominal pain (4.8%), diarrhea (4.8%), asthenia (4.8%), fatigue (4.8%), and hypoglycemia (4.8%). Grade 5 cardiac failure was experienced by 1.2% of the patients receiving sunitinib.
Pancreatic NETs are rare, reported in 2 to 4 people per million annually worldwide, and current treatment options are limited. “In clinical practice, we have been faced with no single treatment option that causes regression of these tumors and improves PFS, OS, and an overall response,” Vinik said. “For the first time, we have a new drug for patients with advanced, well-differentiated pancreatic NET.” He said sunitinib was the first treatment in many years to demonstrate such a “clinically significant survival advantage.”
Asked what role he saw for sunitinib in clinical practice for advanced pancreatic NET, Vinik said because no approved standard of care exists for this malignancy, he expected sunitinib would be used as a long-term treatment after surgery. “Once you start a patient in this population on treatment with sunitinib, I expect they will continue it indefinitely.” Vinik said the design of this phase III trial included progressive, well-differentiated tumors and he expected patients that are octreotide negative or unresponsive to octreotide would receive Sutent as adjunctive therapy. “After surgery, if patients continue to progress, they’ll receive Sutent as a treatment option,” he said, adding that “treatment with sunitinib offers a new and effective option for treating pancreatic NETs.”
In a statement to the press, Mace Rothenberg, MD, senior vice president of clinical development and medical affairs for Pfizer’s Oncology Business Unit, said, “This trial advances our understanding of the use of novel targeted therapies in a patient population with limited treatment options.” Based on the findings of this study, Pfizer has filed supplemental applications for a new indication for Sutent in the treatment of pancreatic NETs with the regulatory authorities in the United States, Europe, and Canada.
Raymond E, Niccoli-Sire P, Bang Y, et al. Updated results of the phase III trial of sunitinib versus placebo for treatment of advanced pancreatic neuroendocrine tumors. Abstract 127. Presented at: 2010 Gastrointestinal Cancers Symposium. January 22, 2010; Orlando, FL.