PD-L1 – inhibitors in neuroendocrine neoplasia

Abstract

Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.

Immune Checkpoint Inhibitors: New Weapons Against Medullary Thyroid Cancer?

“…The therapeutic potential of FDA-approved atezolizumab, avelumab, ipilimumab and pembrolizumab has also been investigated in NENs other than MTC (39,40), thereby confirming a strong interest for ICI therapy in this subset of tumors.…”

Neuroendocrine Carcinoma of the Larynx and Pharynx: A Clinical and Histopathological Study

“…As an alternative, PD-1/PD-L1 checkpoint inhibitors, which are playing an increasingly important role in the treatment of metastatic squamous cell carcinoma of the head and neck, also appear to show some activity in a PD NEC, particularly when used in combination [ 18 , 31 , 32 , 33 , 34 ]. The PD-L1 expression in our patients and in the study by Bahr et al was negligible [ 35 ]; however, as demonstrated by Ozdirk et al in a small series of neuroendocrine neoplasms of different origin but also in other histological types, patients with negative or low PD-L1 expression on tumor cells may still derive some clinical benefit from anti-PD-L1 treatment [ 34 , 36 ]. Additional information is expected from studies exploring potential therapeutic strategies based on shared genomic alterations of NECs irrespective of their sites of origin [ 37 ].…”

“…In this context, further studies on the relationship between the Ki-67 labeling index and the mitosis number are warranted. In addition, a better response to the immune-checkpoint blockade was found to be associated with a higher proliferation rate [ 34 ].…”

Evaluation of PD-L1 expression in a large set of gastroenteropancreatic neuroendocrine tumours and correlation with clinicopathological data

“…Several anti-PD-1 antibodies such as cemiplimab, dostarlimab, nivolumab, and pembrolizumab and anti-PD-L1 antibodies such as atezolizumab, avelumab, and durvalumab have been approved, and many other inhibitors are under development, for the treatment of cancers including non-small cell lung cancer (NSCLC); head and neck squamous cell carcinoma; oesophagus, gut, colorectal, and renal clear cell carcinoma; bladder cancer; melanoma; Merkel cell carcinoma; and Hodgkin's lymphoma [9] , [10] , [11] , [12] . Trials examining the efficacy of these antibodies for GEP-NENs either alone or in combination with other therapies, however, have produced mixed results [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] . The inconsistencies may be due to the small numbers of patients included in the trials or to the substantial differences between studies in grading, localisation, and other clinicopathological characteristics of the tumours.…”