Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcinoma and small cell lung cancer. Results: From 12/2017-11/2018 a total of 29 pts (20 male, 69%), were enrolled (16 NEC G3 and 11 moderately differentiated NETG3). Mean age was 59.2±10.2 ys (range 33-75), median follow up 16.5 weeks (3-48). Median Ki67 was 60% (range 20-95%). Site of origin included pancreas (12), genito-urinary tract (4), stomach-esophagus (3), colo-rectum (3), lung (2), ear-nose-throat (2), papilla of Vater (1). In an interim analysis the DCR (stable disease or partial remission according to irRECIST) after 8 weeks was 32% (4 SD, 2 PR). In responders, mean duration of disease control was 20 (±13.8) weeks, with 4 pts. showing stable disease or partial remission ≥6 months. Median OS was 4.2 months (range 1- >12). Treatment-related adverse events occurred in 11 of 29 pts (38%) and were mainly mild to moderate (CTCAE-grade 1 [52%], 2 [44%] and 3 [4%]) and included fatigue (n=6; 20.6%), diarrhea (n=4; 13.7%), fever/chills after infusion (n=4; 13.7%), loss of appetite and nausea (n=4; 13.7%), skin rash (n=1; 3%), deterioration of preexisting psoriasis (n=1; 3%) and abdominal pain (n=1; 3%). Conclusions: Immune checkpoint blockade with avelumab in pretreated high grade NEN shows relevant activity in a subset of patients with excellent tolerability. Clinical trial information: NCT03352934