Background: We previously presented data of this phase II study showing that the combination of Everolimus and Octreotide LAR for advanced neuroendocrine tumors (NETs), in the first line setting, is an active and safe treatment. At a median follow-up period of 277 days, the median time to progression (TTP) and the overall survival (OS) have not been reached (ASCO 2013 Abs. 4136). Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Patients with advanced well differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic (GEP) tract and of the lung, received Octreotide LAR 30 mg every 28 days in combination with Everolimus 10 mg per day, continuously. The primary endpoint was objective response rate (ORR). Currently we performed an analysis of “long responder” patients and of OS and TTP after 4 years. Results: A total of 50 patients (58% males) were enrolled; 36 (72%) of these patients have received treatment for more than 1 year. The median exposure to study drugs is 118 weeks (range 47-242). Currently 4 patients are still taking advantage from the above mentioned treatment. The primary tumor site was: liver 2 pts, pancreas 11 pts, small intestine 8 pts, lung 7 pts and unknown in 8 pts About 70% of these patients had no carcinoid Syndrome and 50% received surgery at the primary tumor site. The ORR was: CR 1 pt, PR 8 (22%) pts, SD 27 (75%) pts. The median TTP is 38 months (95% CI 19 – n.d.). The median OS has not been reached. Conclusions: Everolimus in combination with octreotide LAR has shown to be active in advanced NETs. The current analysis showed a further prolongation of TTP, and a long exposure to the study drug without major side effects in the long term. The treatment with two drugs has induced objective responses , but also long duration SD. Acknowledgements: Italian Trials in Medical Oncology (I.T.M.O.) group, Giacinto Facchetti Foundation and Novartis.