Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

Abstract

Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Results: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Conclusion: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.

Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin

“…Indeed, PD-L1 staining segregates with NEC ≥55% (36.7%, p = 0.03) ( Table 1). Given the higher rate of mutations and the higher expression of PD-L1 observed in NEC ≥55% compared to NEC < 55%, these patients might be considered for immunotherapy, alone or in combination with targeted drugs and chemotherapy for management of these tumors [44]. Ferrata et al [45] have looked in more detail into PD-L1 expression in NENs of different primaries, stating that although PD-L1 expression is low in most of NETs, immunotherapeutic approaches are promising especially for high-grade NENs.…”

Microenvironment and tumor inflammatory features improve prognostic prediction in gastro‐entero‐pancreatic neuroendocrine neoplasms

“…On the other hand, advanced NENs remain poorly responsive to conventional (chemotherapy) or targeted approaches. Thus, there is an urgent need to identify new biological or molecular markers defining previously undetected subsets of advanced NEN patients who may be potentially responsive to innovative treatments such as immunotherapy .…”

“…Tumor and microenvironment immune profiling in the G3 subset allowed the identification of two groups: patients with reduced expression of HLA‐I T , associated with reduction of lymphoid markers, CD3 S and CD8 S and loss of PD‐L1 S (these patients have the worst prognosis and appear less suitable for immunotherapy (see supplementary material, Figure S3). On the other hand, patients with retention of expression of HLA‐I T and the presence of a lymphoid infiltrate (CD3 S , CD8 S , PD‐L1 S ) have a more favorable prognosis and could potentially be responsive to immunotherapy (see supplementary material, Figure S3) .…”

Merkel Cell Carcinoma of the Head and Neck Compared to Other Anatomical Sites in a Real-World Setting: Importance of Surgical Therapy for Facial Tumors

“…However, in 2017 the U.S. Food and Drug Administration (FDA) approval of the PD-L1 antibody avelumab could mark a turning point for patients. 38,39 Also, anti-PD-1 antibodies such as nivolumab or pembrolizumab prove efficacy in advanced MCC with objective response rate (ORR) of 56 to 73%. Notably, the ORR was observed regardless of MCC polyomavirus status or PD-L1 expression.…”