SUNITINIB FOR PANGREATIC NET

January 25, 2010 (Orlando, Florida) — In the final analysis of an international randomized phase 3 trial, the multikinase inhibitor sunitinib (Sutent, Pfizer) significantly prolonged both survival and progression-free survival in patients with advanced pancreatic neuroendocrine tumors (NET), investigators reported here at the 2010 Gastrointestinal Cancers Symposium.

The meeting is sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society for Surgical Oncology.

The study looked at 340 patients with advanced, progressive, well-differentiated pancreatic NETs. They were randomly assigned to continuous sunitinib 37.5 mg/d or placebo, along with best supportive care.

The median progression-free survival, which was the study's primary end point, was 11.4 months in the sunitinib group and 5.5 months in the placebo group, for a 58% reduction in risk (P < .001).

"With sunitinib, we improved progression-free survival by doubling it to 11.4 months, with a highly significant P value," said principal investigator Eric Raymond, MD, professor of medical oncology at Beaujon University Hospital in Clichy, France.

"Events occurred in 34.9% of the sunitinib arm versus 60% of the placebo arm," he noted, "meaning that the probability of being event-free at 6 months was 71.3% with sunitinib and 43% with placebo."

The overall response rate was 9.3% with sunitinib and 0% with placebo, with a median duration of response of 8.1 months with the drug. Stable disease rates were 34.9% and 24.7%, respectively.

The low response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria is in keeping with the finding from many other studies that this class of agents might be "destroying the inner tumor but not reducing the tumor's diameter," Dr. Raymond said. "The RECIST criteria underestimate the effect of this class of agents."

"After 1 cycle, we often saw hypodensity of the tumor on imaging, which translated into sustained tumor stabilization," he added. "Stable disease was a common feature of sunitinib treatment." Some of the patients in the trial are still stable after 2.5 years, he said in an interview.

Overall survival was a secondary end point, with sunitinib offering a survival probability of 92.6% and placebo offering a survival probability of 85.2%. This represented a statistically significant 59% reduction in risk (P = .0204), Dr. Raymond reported.

At a median follow-up of approximately 11 months, 9 patients in the sunitinib group had died, as had 21 in the placebo group.

"The study was stopped early because the number of events in the placebo arm was much higher, especially deaths," he said.

Preliminary results from this trial and the fact that the study was halted because of the benefit seen were reported by Medscape Oncology last year.

The phase 3 study findings have served as the basis for recent filings of supplemental applications for sunitinib in the treatment of NETs with the regulatory authorities in the United States, Europe, and Canada, according to the manufacturer, Pfizer.

Adverse Events Generally Tolerable

Adverse events were similar to those observed in other sunitinib studies. The most prominent events were diarrhea, nausea, vomiting, asthenia, hand-foot syndrome, and fatigue. Grade 3/4 events were uncommon, although they were slightly increased in the sunitinib group, most commonly neutropenia (12.0%), hypertension (9.6%), hand-foot syndrome (6%), and leukopenia (6%). Grade 5 treatment-related events occurred in 1 patient in each group (cardiac failure with sunitinib and dehydration with placebo).

"The adverse events were generally tolerable and manageable by dose interruption, dose reduction, and/or standard medical therapy," he added.

Asked to comment on the study, Jordan Berlin, MD, clinical director of gastrointestinal oncology at Vanderbilt's Ingram Cancer Center in Nashville, Tennessee, told Medscape Oncology that "this trial offers more than just an encouraging benefit in terms of time to progression and survival. What is most exciting is the proof of principle, that a targeted agent has a major effect in NET, and also that we can do these studies in this patient population."

He explained that NETs are not only rare, but that patients are a heterogeneous group that can be challenging to evaluate in a randomized phase 3 trial. "Some people have thought a phase 3 trial was not practical in this group."

The authors of the study report receiving support from Pfizer, the manufacturer of sunitinib. Dr. Berlin also reports receiving research support from Pfizer.

2010 Gastrointestinal Cancers Symposium (GICS): Abstract 127. Presented January 22–24, 2010.