CHICAGO–In the RADIANT-3 trial, the largest randomized, double-blind, placebo-controlled, Phase 3 trial in patients with advanced pancreatic neuroendocrine tumors (pNET), everolimus, an oral inhibitor of mTOR, demonstrated a statistically and clinically significant median 6.4-month improvement in progression-free survival (PFS) and significant reductions in tumor and secretory biomarkers, according to data presented at the American Society of Clinical Oncology’s 2011 Annual Meeting.

Jonathan R. Strosberg, MD, of the H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, reported on updated safety and exploratory biomarker analyses from RADIANT-3. In the trial, patients with progressive, advanced low- or intermediate-grade (pNET were randomized to everolimus 10mg/day (n=207) or placebo (n=203); both arms received best supportive care. The primary endpoint was PFS measured by RECIST v1.0 (Response Evaluation Criteria in Solid Tumors).

Everolimus treatment improved PFS in patients with pNET, regardless of baseline biomarker levels. Median PFS by investigator assessment with everolimus was 11 months vs. 4.6 months with placebo (P<0.0001), resulting in a 65% reduction in the risk for progression.

At a median follow-up of 20.1 months, updated safety results were consistent with the primary analysis and the known safety profile of everolimus in patients with cancer. The most common nonhematologic drug-related adverse events (AEs) with everolimus as compared with placebo were stomatitis (52.9% vs. 12.3%), rash (48.5% vs. 10.3%), diarrhea (34.3% vs. 10.3%), and fatigue (32.4% vs. 14.3%). The most common grade 3 and 4 AEs observed with everolimus as compared with placebo were anemia (5.9% vs. 0%), hyperglycemia (5.9% vs. 2.5%), stomatitis (4.9% vs. 0%), and thrombocytopenia (4.0% vs. 0%).

In another analysis of RADIANT-3, Elisabeth G. E. De Vries, MD, University Medical Center Groningen, Groningen, The Netherlands, sought to characterize the reduction from baseline in key pNET biomarkers, including chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, and glucagon. To arrive at these findings, serum samples were collected and analyzed for CgA, NSE, gastrin, and glucagon at baseline and, if elevated above upper limits of normal, were repeated on Day 1 of each subsequent cycle.

Patients with elevated baseline values had biomarkers assessed for a median number of 10 cycles in the everolimus arm and four cycles in the placebo arm. Compared with placebo, everolimus use resulted in greater reductions of CgA, NSE, gastrin, and glucagon over time (P<0.0001 for all comparisons). During the first cycle, the fold decrease from baseline in the everolimus arm, compared with placebo, was 0.617/1.081=0.57 [0.45–0.73] for CgA; 0.478/0.951=0.50 [0.32–0.80] for NSE; 0.581/0.833=0.70 [0.52–0.94] for gastrin; and 0.679/1.034=0.66 [0.49–0.89] for glucagon. This positive treatment effect with everolimus was maintained over subsequent treatment cycles.

Dr. De Vries et al concluded that everolimus vs. placebo resulted in an early and sustained decreases in serum levels of CgA, NSE, gastrin, and glucagon. Elevated baseline CgA and NSE levels were associated with improvement of PFS in patients with pNET who received everolimus or placebo, suggesting that these biomarkers may be prognostic for outcome.

These results support the use of everolimus as a standard treatment option for patients with progressing low- or intermediate-grade advanced pNET. Everolimus was approved by the FDA in May 2011 for the treatment of progressive pNET that is unresectable, locally advanced, or metastatic.