Immune Checkpoint Inhibitors in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Nicola Fazio and Anna La Salvia
Endocrine Reviews, First published online October 29, 2025, bnaf037
https://doi.org/10.1210/endrev/bnaf037

Abstract

High-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (HG-NENs) comprise both highly proliferating well-differentiated NENs, called grade 3 neuroendocrine (NE) tumors, and poorly differentiated NENs (also named neuroendocrine carcinomas). The clinical management of these neoplasms poses unique challenges, and, while platinum plus etoposide is the first-line therapy in advanced setting of neuroendocrine carcinomas, this is not the optimal regimen in G3 neuroendocrine tumors in which other chemotherapy schemes, targeted agents, and somatostatin analogs have shown to be active. However, overall response rates and clinical benefit are not satisfactory. Interestingly, HG-NENs may be a more suitable target for immune checkpoints inhibitors (ICIs) than low-grade NENs, because of their higher tumor mutational burden, increased PD-1 expression, probable increased PD-L1 expression, and higher immune infiltration of tumor microenvironment. With these assumptions, few clinical trials have investigated the efficacy and safety of ICIs in HG-NEN. With our work, we aimed to provide a comprehensive overview of the available literature data about ICIs’ role in HG GEP NENs, by analyzing the critical points regarding study population, study design, study results, and potential useful biomarkers for selecting HG-GEP-NEN patients for ICI therapy.

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