e15124 Background: Current comparisons of targeted treatments for advanced neuroendocrine neoplasms (NENs)-specifically surufatinib, sunitinib, and everolimus—are lacking. This study aims to assess their efficacy and safety in a real-world setting. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs prescribed surufatinib, sunitinib or everolimus between July 2020 and April 2023. The primary outcome was median progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR) and adverse events (AE). Results: A total of 123, 56 and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib or everolimus were enrolled. In pancreatic NENs (pNEN), surufatinib demonstrated superior efficacy over sunitinib and everolimus combined (mPFS: 8.67 vs 6.37 months, P=0.02; ORR: 17.1% vs 8.3%). Specifically, surufatinib outperformed sunitinib (mPFS: 8.67 vs 6.40 months, P=0.04; ORR: 17.1% vs 10.9%) and everolimus (mPFS: 8.67 vs 5.37 months, P=0.05; ORR: 17.1% vs 3.8%) individually. In extrapancreatic NENs (epNEN), surufatinib showed enhanced efficacy compared to everolimus (mPFS: 9.47 vs 6.70 months, P=0.15; ORR: 8.3% vs 5.3%). On multivariate Cox analysis, male, functional status, Ki67 index>20%, previous SSA and germline mutation, poor differentiation, liver metastasis, multi treatment lines were identified as negative effect (P<0.05) for PFS in pNEN and epNEN patients respectively. The most common adverse events (AEs) were hypertension (12.2%) in surufatinib-treated patients, manageable with medication. Sunitinib led to decreased neutrophil counts (10.7%), and everolimus was associated with anemia (4.4%). Conclusions: Utilizing real-world data, this study reveals surufatinib significantly enhances progression-free survival (PFS) over sunitinib and everolimus in advanced neuroendocrine neoplasms (NENs), guiding future targeted treatment choices.