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Everolimus Improves Outcomes in Pancreatic Neuroendocrine Tumors

Silas Inman @silasinman
Published: Friday, Oct 10, 2014

Dr. James C. Yao

James C. Yao, MD

Treatment with the mTOR inhibitor everolimus (Afinitor) improved overall survival (OS) by 6.34 months over placebo for patients with pancreatic neuroendocrine tumors (pNET), according to updated results from the phase III RADIANT-3 trial. However, this improvement in survival was not deemed statistically significant, as a result of 85% of patients in the placebo arm crossing over to receive treatment with open-label everolimus, lead investigator James C. Yao, MD, explained in an interview with OncLive at the 2014 NANETS Symposium.

The FDA approved everolimus for the treatment of patients with unresectable, locally advanced or metastatic pNET on May 5, 2011, based on the progression-free survival (PFS) findings from the RADIANT-3 study. At that time, the median PFS with everolimus was 11.0 months compared with 4.6 months with placebo (HR = 0.35; P <.001).

"We saw an approximate 6-month benefit in terms of progression-free survival and we saw a similar 6-month benefit in terms of overall survival, although, clearly, that difference was not statistically significant because of the high rate of crossover," said Yao, from the University of Texas MD Anderson Cancer Center. "The 44-month overall survival seen in the everolimus arm is the longest ever to have been reported in a randomized trial in pancreatic neuroendocrine tumors."

In the phase III study, patients with progressive advanced, low- or intermediate-grade pNETs were randomized in a 1:1 ratio to best supportive care plus 10-mg daily everolimus (n = 207) or placebo (n = 203). Following progression and the unblinding of the study, patients in the placebo arm crossed over to open-label everolimus. The primary endpoint of the study was PFS, with OS as a secondary outcome measure. The P value boundary for statistical significance for OS was .0249.

In the updated analysis, the median OS was 44.02 months with everolimus versus 37.68 months with placebo (HR = 0.94; 95% CI, 0.73-1.20; P = 0.3). The OS rate at 48 months was 46.9% with everolimus and 41.3% with placebo. At 60 months, the OS rate was 34.7% versus 35.5% for everolimus and placebo, respectively. Patients initially randomized to everolimus received treatment for an average of 67.1 weeks compared with 44 weeks for those who crossed over from placebo.

"The study really turned into, from an OS perspective, a comparison of early treatment versus late treatment," Yao stated.

The most commonly reported adverse events with everolimus versus placebo prior to unblinding the study were stomatitis (53.9% vs 13.3%), rash (52.5% vs 15.8%), diarrhea (48.0% vs 23.6%), and fatigue (44.6% vs 26.6%). In the open-label portion of the study, the most common side effects with everolimus were stomatitis (46.7%), diarrhea (43.6%), and rash (40.0%).

Additionally, everolimus was associated with an increased rate of pneumonitis (12% vs 0%) and interstitial lung disease (2% vs 0%). The most common grade 3/4 adverse events with everolimus were anemia, hyperglycemia, stomatitis, thrombocytopenia, diarrhea, hypophosphatemia, and neutropenia.

"The development of some of these side effects, for example stomatitis, was associated with better outcomes," Yao said. "The development of stomatitis within 8 weeks of starting treatment in the pNET population was associated with a hazard ratio of 0.7 compared with those who received the drug but did not develop stomatitis. So, some of these side effects are actually associated with a longer PFS."

In a study presented at the 2014 ASCO Annual Meeting, data from seven randomized, double-blind, phase III studies exploring everolimus analyzed the incidence of stomatitis and its relationship with efficacy. An association between stomatitis and PFS was observed in patients treated in the RADIANT-3 trial, suggesting 31.3% better outcomes for patients who developed the side effect (HR = 0.687; 95% CI, 0.465-1.014).

"I think the take-home message there is that, while canker sores can be a troublesome side effect for this class of drugs, appropriate management could be well worth it," Yao said. "These patients tend to have a greater amount of benefit."


References

Yao J, Pavel M, Lombar-Bohas C, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: final overall survival results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (Radiant-3). Presented at: the annual meeting of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 1132O.

Rugo HS, Yao JC, Hortobagyi GN, et al. Meta-analysis of stomatitis incidence in everolimus clinical studies and its relationship with efficacy. J Clin Oncol. 2014;32(5s):suppl;abstract 645.

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