"Present and future of immunotherapy in Neuroendocrine Tumors"

Abstract

Immunotherapy, so promising in many neoplasms, still does not have a precise role in the treatment of neuroendocrine neoplasms (NENs). In this article, we provide an overview on the current knowledge about immunotherapy with immune checkpoint inhibitors (ICIs) applied to NENs, evaluating future perspectives in this setting of tumors.Evidence so far available for ICIs in gastroenteropancreatic (GEP)-NENs is definitively not as robust as for other tumors such as Small Cell Lung Cancer or Merkel Cell Carcinoma. In fact, with regard to the well-differentiated forms of NENs (NETs), the results obtained nowadays have been disappointing. However, the near future, might reserve interesting results for ICIs in GEP-NEN from a total of nine different ICI drugs, used throughout 19 randomised controlled trials. Such numbers highlight the growing attention gathering around NENs and ICIs, in response to the need of stronger evidences supporting such therapy.For the future, the most important aspect will be to study strategies that can make NETs more susceptible to response to ICI and, thus, enhance the effectiveness of these treatments. Therefore, the combination of conventional therapy, target therapy and immunotherapy deserve attention and warrant to be explored. A sequential chemotherapy, possibly inducing an increase in tumor mutational burden and tested before immunotherapy, could be a hypothesis deserving more consideration. A radiation treatment that increases tumor-infiltrating lymphocytes, could be another approach to explore before ICIs in NENs. Equally essential will be the identification of biomarkers useful for selecting patients potentially responsive to this type of treatment.

Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs)

“…12 Combination therapies that enhance tumor susceptibility to immune-checkpoint inhibitors are currently being studied; however, current data have been disappointing in well-differentiated NETs. 14 There is a clear unmet medical need for effective treatment options for NETs, given the increasing incidence, poor prognosis, and advanced stage at diagnosis. In addition, studies are needed to determine the optimal sequence of current therapies and the impact of combinations of therapies on efficacy and safety.…”

“… 12 Combination therapies that enhance tumor susceptibility to immune-checkpoint inhibitors are currently being studied; however, current data have been disappointing in well-differentiated NETs. 14 …”

Medikamentöse Systemtherapie bei Neuroendokrinen Neoplasien des GastroEnteropankreatischen Systems

“…NET zeigen häufig einen niedrigen Tumor Mutational Burden (TMB) als potenziell negativen Prädiktor für eine Immuntherapie [60]. Bei NET G1/G2 des GEP-Systems zeigten Studien mit Pembrolizumab, Spartalizumab und Durvalumab plus Tremelimumab weitgehend negative Studienergebnisse [40,[60][61][62]. In der Monotherapie zeigte Toripalimab bisher das vielversprechendste Ergebnis [62]…”

Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver?

“…A comprehensive list of all agents being approved for human use and their indications is provided in Table 1. Given the broad spectrum of the efficacy and the favourable safety profile, ICIs are currently under evaluation in patients with NENs [16][17][18][19][20][21][22]. Of note, a minority of LCs express PD-L1 [23,24], and PD-L1 expression is sometimes associated with metastatic potential [23] and poorer survival [24,25].…”