The results affirm the importance of targeting key pathways involved in tumor growth, such as the mTOR pathway in advanced [pancreatic neuroendocrine tumors].
—James C. Yao, MD
Final results from the RADIANT-3 trial showed a 6-month difference in overall survival favoring everolimus (Afinitor) plus best supportive care over placebo plus best supportive care in patients with well-differentiated advanced and progressive pancreatic neuroendocrine tumors.1 Although the difference between the two arms was not statistically significant, investigators said it was clinically relevant and noteworthy.
“I think we are making some progress in pancreatic neuroendocrine tumors. The median overall survival of 44 months for everolimus is unprecedented in controlled clinical trials for advanced progressive pancreatic neuroendocrine tumors. The results affirm the importance of targeting key pathways involved in tumor growth, such as the mTOR pathway in advanced pancreatic neuroendocrine tumors,” stated lead author James C. Yao, MD, Professor in the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, in his presentation at the European Society for Medical Oncology (ESMO) 2014 Congress.
“The diagnosis of pancreatic neuroendocrine tumor is increasing,” Dr. Yao said. “Advanced pancreatic neuroendocrine tumor is incurable with a very poor prognosis. In 2011, everolimus and sunitinib [Sutent] were approved for this indication. Before that, only one drug was available and therapeutic options were limited.”
RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors) was a pivotal phase III, randomized, placebo-controlled clinical trial that enrolled 410 patients from 18 countries. For the primary endpoint, median progression-free survival was 11 months with everolimus vs 4.6 months with placebo, a highly significant 65% reduction in risk of disease progression favoring everolimus (P < .001).
“These data were presented previously, showing a 2.4-fold improvement in median progression-free survival,” he emphasized.
At the ESMO Congress, Dr. Yao presented final overall survival and safety data for the first time.
The study included patients whose tumors had well-differentiated histology. Patients were stratified according to prior chemotherapy and World Health Organization performance status and randomly assigned to placebo or everolimus. Placebo recipients were allowed to cross over to open-label everolimus at the end of the double-blind period or after disease progression.
An intent-to-treat analysis found that median overall survival was 44 months for those initially assigned to everolimus and 37.7 months for those on placebo. The high crossover rate from placebo to everolimus (85%) in the trial made it likely that a conventional intent-to-treat overall survival analysis would underestimate the survival benefit in the everolimus group, Dr. Yao explained.
The investigators used a rank-preserving structural failure time estimate to adjust for survival time while on everolimus in patients who crossed over from the placebo arm. This analysis showed a survival benefit with everolimus (survival rates of 82.6% vs 74.9% at 12 months and 67.7% vs 55.6% at 24 months).
No new safety concerns were reported in the final analysis. During the double-blind phase of the trial, stomatitis was reported in 54% of the everolimus group vs 13% of the placebo group. Other adverse events that occurred in at least 40% of patients receiving everolimus during the core phase of the trial were rash (53% vs 16%, respectively), diarrhea (48% vs 23.6%), and fatigue (44.6% vs 26.6%). ■
Disclosure: Dr. Yao has served as a consultant to and has received research funding from Novartis. For full disclosures of the study authors, visit www.esmo.org.
1. Yao J, Pavel M, Lombard-Bohas C, et al: Everolimus (EVE) for the treatment of advanced pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results of a randomized, double-blind, placebo (PBO)-controlled, multicenter phase III trial (RADIANT-3). ESMO 2014 Congress. Abstract 1132O. Presented September 27, 2014.
Formal discussant of the RADIANT-3 trial at the European Society for Medical Oncology (ESMO) Congress, Alexandria Phan, MD, of Houston Methodist Cancer Center, agreed that the crossover to open-label everolimus (Afinitor) by placebo patients probably muddied the waters in the survival estimate....