# Interventional Clinical Trials in Metastatic Pulmonary Large-Cell Neuroendocrine Carcinoma: A Systematic Review of Prospective, Interventional Trials

## TL;DR

This review highlights the lack of effective treatments for advanced lung cancer called large-cell neuroendocrine carcinoma and calls for better research and collaboration.

## Contribution

The study systematically reviews limited clinical trial data on metastatic LCNEC and emphasizes the need for innovative trial designs and molecular profiling.

## Key findings

- Only four non-randomized clinical trials on metastatic LCNEC were identified, all with modest clinical outcomes.
- Platinum-based chemotherapy was most commonly tested, with median progression-free survival under six months.
- Immunotherapy was evaluated in only one study, and overall survival rarely exceeded one year.

## Abstract

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare and aggressive form of lung cancer, accounting for approximately 3% of cases. Despite its clinical relevance, the optimal treatment strategy for advanced or metastatic LCNEC remains unclear. We conducted a systematic review of prospective interventional clinical trials to evaluate the available therapeutic evidence. Only four non-randomized studies met inclusion criteria. Most trials investigated platinum-based chemotherapy in the first-line setting, while immunotherapy was evaluated in only one study. Clinical outcomes were modest, with progression-free survival typically shorter than six months and overall survival rarely exceeding one year. The limited number of trials, small sample sizes, and methodological variability highlight a significant evidence gap. These findings emphasize the urgent need for international collaboration, innovative clinical trial designs, and integration of molecular profiling to improve treatment strategies and enable personalized care for patients with lung LCNEC.

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.