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Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models. [Display omitted] • PDTOs of NETs and LCNEC from multiple sites were established • PDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumors • Drug assays reveal therapeutic vulnerabilities and biomarkers • Pulmonary NET PDTOs are dependent on EGF Dayton et al. established patient-derived tumor organoids (PDTOs) from neuroendocrine neoplasms including low-grade pulmonary neuroendocrine tumors. Multi-omic molecular analyses show that PDTOs retain parental tumor intra-tumoral heterogeneity. Phenotypic growth analyses reveal EGF dependency of a subset of pulmonary neuroendocrine tumors, indicating a therapeutic vulnerability in these tumors. [ABSTRACT FROM AUTHOR]