Background: In the RADIANT-3 trial, everolimus, an oral inhibitor of mTOR, significantly prolonged progression-free survival (PFS) in pts with advanced pNET (ESMO 2010, Abstract #LBA9). Updated safety and exploratory biomarker analyses from this trial are presented. Methods: Pts with progressive, advanced low- or intermediate-grade pNET were randomized to everolimus 10 mg/d orally (n=207) or placebo (n=203); both arms received best supportive care. The primary endpoint was PFS (RECIST v1.0). Results: Median PFS by investigator assessment with everolimus was 11.0 mo vs with 4.6 mo with placebo (HR=0.35; 95% CI, 0.27-0.45; p<0.0001), resulting in a 65% reduction in the risk for progression. Everolimus compared with placebo resulted in a rapid and significant (p<0.001) reduction in baseline biomarkers, including chromogranin A, neuron-specific enolase, gastrin, and glucagon. Treatment arms were well balanced with respect to on-study somatostatin analog (SSA) use (39%, everolimus arm; 40%, placebo arm). An improvement in median PFS was observed with everolimus vs placebo in pts who received on-study SSA (11.4 mo vs 3.9 mo; HR=0.40; 95% CI, 0.29-0.56) and those without on-study SSA (10.8 mo vs 4.6 mo; HR=0.35; 95% CI, 0.24-0.50). Median safety follow-up is now 20.1 mo. Most common drug-related adverse events (AEs) with everolimus vs 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 3-4 AEs were anemia (5.9% vs 0%), hyperglycemia (5.9% vs 2.5%), stomatitis (4.9% vs 0%), and thrombocytopenia (3.9% vs 0%). Conclusions: In the RADIANT-3 trial, the largest randomized controlled trial ever completed in pts with progressive advanced pNET, everolimus provided a significant increase in median PFS, irrespective of SSA use, and significant reductions in tumor and secretory biomarkers. Oral stomatitis represented the most common drug-related AE; however, grade 3-4 somatitis was rare. These emerging data, including longer follow-up safety data, support the use of everolimus as a standard of care for pts with progressive, advanced pNET.