Pembrolizumab (P) monotherapy in patients with previously treated metastatic high grade neuroendocrine neoplasms (HG-NENs).

Vijayvergia, Namrata; Dasari, Arvind; Ross, Eric A.; Dotan, Efrat; Halperin, Daniel M.; Astsaturov, Igor; Hall, Michael J.; Ross, Nicole; McClean, Daniel; Denlinger, Crystal S.; Cohen, Steven J.; Engstrom, Paul F.

doi:10.1200/jco.2018.36.15_suppl.4104

Cited by 15 publications

(8 citation statements)

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“…Regarding NEC, just recently Vijayvergia et al reported data from 21 patients with metastatic high-grade neuroendocrine neoplasms (Ki-67 > 20%) that were treated with pembrolizumab after failure of a first line platinum/etoposide doublet (NCT02939651). Pembrolizumab, though generally well-tolerated, showed limited activity as a single agent in this study (Disease Control Rate 19%, PFS 9.14 weeks, OS 15.4 weeks [ 45 ] ). Similar results were found by Mulvey et al, who analyzed the efficacy of pembrolizumab in 14 patients with extrapulmonary poorly differentiated neuroendocrine carcinomas with progression on first-line chemotherapy (NCT03136055).…”

Section: Review Of the Literature And Discussion Of Resultsmentioning

confidence: 99%

PD-L1 – inhibitors in neuroendocrine neoplasia

et al. 2021

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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.

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Section: Review Of the Literature And Discussion Of Resultsmentioning

confidence: 99%

PD-L1 – inhibitors in neuroendocrine neoplasia

et al. 2021

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“…Two studies have presented preliminary results of pembrolizumab monotherapy in previously treated patients with extrapulmonary poorly differentiated NEC (NCT 03136055 and NCT02939651); treatment was well tolerated, but initial results concluded that pembrolizumab in monotherapy was not effective in these biomarker-unselected populations of patients with EP-NEC (poorly differentiated), arising in different organs (Vijayvergia et al 2018, Mulvey et al 2019.…”

Section: New Therapeutic Perspectivesmentioning

confidence: 99%

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

McNamara

Scoazec

Walter

2020

Endocrine-Related Cancer

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Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.

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“…Based on these observations and the fact that treatment options in both gastroenteropancreatic (GEP) neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC) are limited [ 4 , 5 ], checkpoint inhibitors were also evaluated for NET and NEC in early clinical trials. However, in GEP-NET and NEC only low response rates to anti-PD1 monotherapies were observed [ 6 , 7 , 8 ]. Combined PD-L1 and CTLA4 blockade demonstrated a 44% overall response rate in patients with nonpancreatic NEC, while in G1/G2 NET objective responses were infrequent [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment

Busse

Mochmann

Spenke

et al. 2020

Cancers

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Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation.

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Pembrolizumab (P) monotherapy in patients with previously treated metastatic high grade neuroendocrine neoplasms (HG-NENs).

Abstract: Study supported by Merck Investigator Studies Program Grant * Only Grade 1-2 toxicities occurring in >10% patients are depicted Possibly or probably related to study drug

Cited by 15 publications

References 1 publication

PD-L1 – inhibitors in neuroendocrine neoplasia

PD-L1 – inhibitors in neuroendocrine neoplasia

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment

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