Background: Everolimus has shown antitumor activity in patients (pts) with advanced pancreatic neuroendocrine tumors (NETs). We aimed to assess efficacy and safety of everolimus in combination with octreotide long-acting repeatable (LAR) in patients with well differentiated NETs of gastroenteropancreatic and of lung origin. Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Pts with advanced well differentiated, previously untreated NETs of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg every 28 days in conjunction with everolimus 10 mg per day continuously. The primary endpoint was objective response rate (ORR). Results: A total of 50 pts (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%) and jejunum and duodenum in 2 (4%) of pts. 13 (26%) pts had carcinoid syndrome. The ORR, calculated on the ITT population, was 20.0% (95% CI 8.9-31.1): 2 patients (4%) had a complete response (CR), 8 (16%) a partial response (PR). Thirty-six patients (72%) achieved stable disease (SD). All CR and all PR as well as 91.7% of SD had a duration ≥ 6 months. Clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, the median time to progression (TTP) was 16.3 months (95% CI 10.7-20.1). Overall survival could not be assessed. Treatment-related adverse events (AEs) were mostly of grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, while grade 3 AEs included skin rash in 1 case, stomatitis in 4 cases (8%) and diarrhea in 11 cases (22%). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs and, in this study, not only in primary pancreatic tumors. Compared to other clinical trials with everolimus in NETs, the observed ORR in this study was higher. Aknowledgements: The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) group and Novartis Pharma for the support provided. Clinical trial information: 2008-007153-13.