Background: In the RADIANT-2 trial, everolimus, an oral inhibitor of mTOR, plus octreotide (E+O) demonstrated a clinically meaningful increase in median progression-free survival (PFS) vs placebo + octreotide LAR (P+O) in patients with advanced low- or intermediate-grade NET and a history of carcinoid syndrome (ESMO 2010 Abstract #LBA8). Updated safety and exploratory biomarker analyses from this trial are presented. Methods: Patients (n=429) received everolimus 10 mg/d + octreotide LAR 30 mg IM q 28 days (n=216) or placebo + octreotide LAR (n=213). The primary endpoint was PFS per adjudicated central review (RECIST v1.0). Results: Median PFS (95% CI) with everolimus was 16.4 (13.7-21.2) mo vs 11.3 (8.4-14.6) mo with placebo (HR=0.77; 95% CI, 0.59-1.00; P=0.026), resulting in an increase of 5.1 mo. Benefit with E+O was observed across all prespecified subgroups (age, sex, PS, tumor grade, primary site, prior somatostatin analog, prior chemotherapy). Biomarker analyses showed baseline CgA to be a significant prognostic marker (HR=0.43; 95% CI, 0.32-0.59; P<0.001). Median PFS for those with elevated (>2x ULN) CgA was 13.9 (11.3-17.1) mo for E+O and 8.4 (7.7-11.1) mo for P+O (HR=0.66; 95% CI, 0.48-0.89; P=0.003). For those with nonelevated CgA, median PFS was 31.3 (19.3-NA) mo for E+O and 20.1 (13.04-NA) for P+O (HR=0.74; 95% CI, 0.42-1.28; P=0.14). Mixed-model analysis demonstrated that E+O led to greater fold reductions of both serum CgA (P=0.004) and urinary 5-HIAA (P<0.0001) vs P+O. Median safety follow-up is now 31.1 mo. Most frequent drug-related AEs (E+O vs P+O, %) were stomatitis (47.4 vs 10.9), rash (37.2 vs 12.3), and fatigue (31.6 vs 24.2) and were consistent with previous experience. Most frequent drug-related grade 3-4 AEs (E+O vs P+O, %) were fatigue (6.5 vs 2.8), diarrhea (6.0 vs 2.4), and hyperglycemia (5.1 vs 0.5). Conclusions: E+O has shown a clinically meaningful increase in median PFS and reduction in tumor and secretory biomarker levels with a favorable safety profile. These findings support the use of everolimus in patients with advanced NET and a history of secretory symptoms associated with carcinoid syndrome.