Systemic therapies for gastroenteropancreatic neuroendocrine carcinomas: Current paradigm and future avenues

Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are aggressive, poorly differentiated neoplasms representing the most common subtype of extra-pulmonary neuroendocrine carcinomas. Despite increasing recognition, they remain biologically and therapeutically elusive, with limited understanding of their molecular drivers and few established treatment paradigms. Most patients present with advanced disease, making systemic therapy the cornerstone of management. Platinum-based chemotherapy remains the standard first-line approach, though outcomes are suboptimal and consensus is lacking regarding maintenance strategies and second-line options. Later lines of therapy are ineffective, and survival is short after progression on first-line therapy. In this review, we synthesize current evidence on systemic therapies for GEP-NECs, highlighting clinical trials of cytotoxic agents, immune checkpoint inhibitors, molecularly targeted therapies, and novel modalities such as bispecific T-cell engagers. We also discuss the role of molecular profiling and emerging biomarkers in guiding therapy, with an emphasis on precision-driven approaches for this highly heterogeneous and challenging group of malignancies.