Immune checkpoint inhibitors in high-grade gastroenteropancreatic neuroendocrine neoplasms.

Abstract

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