ASCO GI Coverage: Everolimus Associated With Significant PFS Improvement in Patients With PNETs

Data from a large randomized trial showed that treatment with the targeted agent everolimus was associated with a 65% improvement in progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (PNETs). Patients treated with everolimus had a median PFS of 11 months versus 4.6 months for patients who received best supportive care. Four times as many patients in the everolimus arm were alive and free of disease progression at 18 months.

"These data support the use of everolimus as a standard of care for patients with progressive advanced pancreatic neuroendocrine tumors," said Manisha H. Shah, MD, an oncologist at Ohio State University, at the Gastrointestinal Cancers Symposium. A member of the mammalian target of rapamycin (mTOR) inhibitor class, everolimus is involved in the regulation of a variety of activities in carcinogenesis. Dysregulation of the mTOR pathway in PNET is associated with poor prognosis.

Everolimus demonstrated activity in 2 phase II studies of advanced PNET (J Clin Oncol. 2008;26:3063-3072; Ann Surg Oncol. 2007;14:3492-3500), which provides a rationale for an international phase III trial. Investigators randomized 410 patients to best supportive care plus either everolimus or placebo. Treating physicians had the discretion to give patients concurrent somatostatin analog therapy. Tumor status was assessed every 12 weeks by CT or MRI scan, and the primary endpoint was PFS.

The greater than 6-month difference in PFS with everolimus translated into a 65% reduction in the hazard ratio compared with placebo (P <.0001). The magnitude of the difference in PFS increased over time, increasing from 69% after 3 months (84% vs 56%) to almost 75% after 18 months (34% vs 9%).

Shah reported that 10 everolimus patients had partial responses and 151 patients had stable disease, resulting in a disease control rate of 77.7%. In contrast, 4 patients in the placebo group had partial responses and 103 had stable disease for a disease control rate of 52.7% (P <.0001 vs everolimus). She noted that 148 patients in the placebo group crossed over to everolimus after progression.

The most common adverse events (all grades) in the everolimus group were stomatitis (64%), rash (49%), diarrhea (34%), fatigue (31%), infection (23%), nausea (20%), decreased appetite (20%), and headache (19%). Grade 3/4 adverse events were uncommon. About half of the patients in both groups had prior treatment with a somatostatin analog and about 40% of each group received treatment concurrently with randomized therapy. Shah noted that subgroup analysis showed that treatment with a somatostatin analog had no impact on the benefit conferred by everolimus.

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Shah MH, Ito T, Lombard-Bohas C, et al. Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3). Paper presented at: 2011 Gastrointestinal Cancers Symposium; January 2011; San Francisco, CA.

Published in Oncology & Biotech News. February 2011.