ESMO 2014-EVEROLIMUS IMPROVES SURVIVAL IN PANCREATIC NETs

In a phase III trial, treatment with everolimus (Afinitor) resulted in a median overall survival of over 3 and a half years in patients with well-differentiated and progressive pancreatic neuroendocrine tumors, representing a clinically meaningful although not statistically significant improvement. The findings were presented at the ESMO 2014 Congress in Madrid (Abstract 1132O).

RADIANT-3 Trial

RADIANT-3, a phase III prospective, double-blind, randomized, parallel-group, placebo-controlled, multicenter study, involved 410 patients with advanced-, low-, or intermediate-grade pancreatic neuroendocrine tumors. Patients were randomly assigned to receive either everolimus at 10 mg once daily or daily placebo, both in conjunction with best supportive care. The primary endpoint was progression-free survival, and the key secondary endpoints were overall survival and the safety and tolerability of everolimus.

Patients on placebo whose disease progressed during the core phase were allowed to cross over to open-label everolimus. In addition, when all patients were unblinded at the end of the core phase, those initially assigned to placebo were offered to switch to open-label everolimus and those in the everolimus arm could transition to open-label everolimus. All patients initially randomized to placebo were included in the placebo arm results, even if they crossed over to everolimus therapy.

Results from the primary analysis of this study, previously reported by Yao et al in The New England Journal of Medicine, demonstrated that everolimus more than doubled median progression-free survival vs placebo (11.0 vs 4.6 months).

Overall Survival Results

The current data represent an analysis of the mature overall survival results. Median overall survival was 44.02 months (95% confidence interval [CI] = 35.61–51.75) in the everolimus treatment arm compared with 37.68 months (95% CI = 29.14–45.77) in the placebo arm; the 6.34-month difference between the two arms was not statistically significant (hazard ratio [HR] = 0.94,  95% CI = 0.73–1.20; P= .300). However, the investigators noted that a high crossover of patients from placebo to everolimus (85%) may have contributed to the long median overall survival in the placebo arm and may have confounded the ability to detect a difference in the overall survival results.

The safety profile was consistent with that observed for everolimus in advanced pancreatic neuroendocrine tumors, and no unexpected or new safety concerns were identified at the time of this analysis. The most commonly reported (> 40%) adverse events for everolimus compared to placebo during the core phase of 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%). The most common (≥ 40%) adverse events reported with everolimus during this follow-up phase were stomatitis (46.7%), diarrhea (43.6%), and rash (40.0%).

"The median overall survival of 44 months for everolimus is unprecedented in controlled clinical trials for advanced progressive pancreatic neuroendocrine tumors," said lead investigator James Yao, MD, of The University of Texas MD Anderson Cancer Center, Houston. "The results affirm the importance of targeting key pathways involved in tumor growth, such as the mTOR pathway in advanced pancreatic neuroendocrine tumors."

Dr. Yao has served as a consultant and has received research funding from Novartis. For full disclosures of the study authors, view the study abstract at www.esmo.org.