Immunotherapies for Well-differentiated Grade 3 Gastroenteropancreatic Neuroendocrine Tumors: A New Category in the World Health Organization Classification

According to the 2019 World Health Organization (WHO) classification, well-differentiated grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are a new category of cancer of the digestive system. G3 GEP-NET research and treatment are not as robust as those of lower grade (G1/2) NETs and poorly differentiated neuroendocrine carcinomas (NECs). Previously, the management of high-grade NETs was mainly based on NEC therapies, as high-grade NETs were classified as NECs under the previous WHO classification. Despite this, G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs, due to their distinct molecular pathogenesis and course of pathological grade transition. Patients with advanced G3 GEP-NETs, who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide, have limited treatment choices. Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors. Immunotherapies, either alone or in combination with other therapies, do not have a clear function in the treatment of G3 GEP-NETs. Currently, the majority of immunotherapy studies, both prospective and retrospective, do not reliably differentiate G3 GEP-NETs from NECs. By contrast, a significant number of studies include non-GEP neuroendocrine neoplasms (NENs). Therefore, there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor. The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.