Role of immunotherapy in gastro-enteropancreatic neuroendocrine neoplasms (gep-nens): Current advances and future directions.

Neuroendocrine neoplasms (NENs) are heterogeneous tumours originating from neuroendocrine cells (Pearse & Polak, Gut, 1971, 12,783). They were once considered as rare tumours, although their annual incidence has increased significantly and now exceeds seven cases in 100 000 in the USA (Dasari, et al., JAMA oncology, 2017, 3, 1335). They are a group of highly diverse neoplasms and can be classified into the spectrum of well-differentiated neuroendocrine tumours to poorly differentiated neuroendocrine carcinomas. This is entirely based on the tumour differentiation and grade (low, intermediate, high), which is determined by the Ki-67/mitotic index. The lower grades (G1/2) of the well-differentiated group are characterised by a relative indolent clinical course and the ability to secrete a variety of peptide hormones (Kloppel, Visceral medicine, 2017, 33, 324). Higher grades and poorly differentiated tumours tend to be more aggressive and have limited therapeutic options (Sorbye et al., Neuroendocrinology, 2019, 108, 54). In the modern era of immuno-oncology, immune checkpoint inhibitors (ICPIs) that target programmed cell death 1 (pembrolizumab, nivolumab), programmed cell death-ligand1 (avelumab, atezolizumab and durvalumab) or cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) have revolutionised the management of many solid tumours. In patients with gastro-enteropancreatic (GEP)-NENs, there is a limited data regarding the role of ICPIs either as a single agent or in combination regimens. Here, we review the current advances for ICPIs and where they fit in the management of GEP-NENs.