Abstract
Background/Objectives: Pulmonary neuroendocrine neoplasms comprise a heterogeneous group of epithelial lung tumors characterized by varying degrees of differentiation and biological aggressiveness. Among high-grade types, large cell neuroendocrine carcinoma (LCNEC) is an uncommon but clinically significant entity, representing approximately 3% of lung cancers, with the optimal first-line therapeutic approach remaining uncertain. Our aim was to evaluate the available prospective therapeutic evidence in patients with advanced or metastatic pulmonary LCNEC, defining the current evidence and identifying key gaps to inform future research. Methods: A systematic literature search was conducted using PubMed, Scopus, and Web of Science (last update: 9 August 2025). Endpoints included the evaluation of clinical outcomes from interventional trials and safety. Results: Overall, 2139 records were identified through the database search and handsearching. After removal of duplicates and non-eligible records, only 4 prospective, non-randomized studies were eligible for the systematic review. Due to the risk of bias and substantial methodological variability, a meta-analysis could not be reliably performed. Three trials investigated first-line platinum-based chemotherapy regimens, while only one study evaluated immunotherapy in lung LCNEC. Overall clinical outcomes were modest, with benefits appearing limited in duration, with median PFS consistently <6 months and median OS rarely exceeding one year. Conclusions: The findings of this review underscore a persistent and substantial evidence gap in the management of advanced pulmonary LCNEC. Closing this gap will require coordinated international collaborations and innovative trial designs, including molecular analysis as a driver for patient management. Without such efforts, the prospect of personalized medicine for lung LCNEC will remain far from reality.