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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Mini-Review Article

Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs): The Role of Checkpoint Inhibitors

Author(s): Giulia Arrivi and Nicola Fazio*

Volume 22, Issue 8, 2022

Published on: 21 April, 2022

Page: [629 - 638] Pages: 10

DOI: 10.2174/1568009622666220114124335

Price: $65

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Abstract

Background: The treatment options for GEP-NENs include various drugs and are based on grading, morphology, and location of the primary.

Objective: The aim of our work is to investigate the clinical impact of new immune checkpoint inhibitors in order to define a new possible strategy of use within GEP-NENs.

Methods: A scientific literature search from 2015 to January 2020 was performed using PubMed and Embase: reviews and prospective or retrospective studies with a minimum of twenty patients were selected; conference proceedings were included.

Results: Several studies have been conducted to assess the role of immune checkpoint inhibitors in NENs, but nowadays, the current knowledge in this field is mainly based on phase I-II studies. Immunotherapy showed limited antitumor activity, but a higher response rate was reported in poor-differentiated neuroendocrine tumors. No specific biomarkers were identified for patient selection and response assessment.

Conclusion: Immunotherapy appears as a powerful possibility to help our patients, but nowadays, we see many gaps in this field. We must balance therapeutic possibilities offered by precision oncology with an understanding of the limitations of the application of testing and treatment in clinical practice. Future efforts should focus on research of the best patients to a candidate for immunotherapy in terms of disease characteristics and previous treatments and how to select them with accurate biomarkers.

Keywords: Gastroenteropancreatic, neuroendocrine, tumors, checkpoint inhibitors, immunotherapy, PD-L1.

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[1]
Nagtegaal, I.D.; Odze, R.D.; Klimstra, D.; Paradis, V.; Rugge, M.; Schirmacher, P.; Washington, K.M.; Carneiro, F.; Cree, I.A. WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology, 2020, 76(2), 182-188.
[http://dx.doi.org/10.1111/his.13975] [PMID: 31433515]
[2]
Maggard, M.A.; O’Connell, J.B.; Ko, C.Y. Updated population-based review of carcinoid tumors. Ann. Surg., 2004, 240(1), 117-122.
[http://dx.doi.org/10.1097/01.sla.0000129342.67174.67] [PMID: 15213627]
[3]
Dasari, A.; Shen, C.; Halperin, D.; Zhao, B.; Zhou, S.; Xu, Y.; Shih, T.; Yao, J.C. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol., 2017, 3(10), 1335-1342.
[http://dx.doi.org/10.1001/jamaoncol.2017.0589] [PMID: 28448665]
[4]
Dasari, A.; Mehta, K.; Byers, L.A.; Sorbye, H.; Yao, J.C. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer, 2018, 124(4), 807-815.
[http://dx.doi.org/10.1002/cncr.31124] [PMID: 29211313]
[5]
Rinke, A.; Müller, H.H.; Schade-Brittinger, C.; Klose, K.J.; Barth, P.; Wied, M.; Mayer, C.; Aminossadati, B.; Pape, U.F.; Bläker, M.; Harder, J.; Arnold, C.; Gress, T.; Arnold, R. PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J. Clin. Oncol., 2009, 27(28), 4656-4663.
[http://dx.doi.org/10.1200/JCO.2009.22.8510] [PMID: 19704057]
[6]
Caplin, M.E.; Pavel, M.; Ćwikła, J.B.; Phan, A.T.; Raderer, M.; Sedláčková, E.; Cadiot, G.; Wolin, E.M.; Capdevila, J.; Wall, L.; Rindi, G.; Langley, A.; Martinez, S.; Blumberg, J.; Ruszniewski, P. CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N. Engl. J. Med., 2014, 371(3), 224-233.
[http://dx.doi.org/10.1056/NEJMoa1316158] [PMID: 25014687]
[7]
Yao, J.C.; Shah, M.H.; Ito, T.; Bohas, C.L.; Wolin, E.M.; Van Cutsem, E.; Hobday, T.J.; Okusaka, T.; Capdevila, J.; de Vries, E.G.E.; Tomassetti, P.; Pavel, M.E.; Hoosen, S.; Haas, T.; Lincy, J.; Lebwohl, D.; Öberg, K. RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med., 2011, 364(6), 514-523.
[http://dx.doi.org/10.1056/NEJMoa1009290] [PMID: 21306238]
[8]
Raymond, E.; Dahan, L.; Raoul, J-L.; Bang, Y-J.; Borbath, I.; Lombard-Bohas, C.; Valle, J.; Metrakos, P.; Smith, D.; Vinik, A.; Chen, J-S.; Hörsch, D.; Hammel, P.; Wiedenmann, B.; Van Cutsem, E.; Patyna, S.; Lu, D.R.; Blanckmeister, C.; Chao, R.; Ruszniewski, P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med., 2011, 364(6), 501-513.
[http://dx.doi.org/10.1056/NEJMoa1003825] [PMID: 21306237]
[9]
Strosberg, J.; El-Haddad, G.; Wolin, E.; Hendifar, A.; Yao, J.; Chasen, B.; Mittra, E.; Kunz, P.L.; Kulke, M.H.; Jacene, H.; Bushnell, D.; O’Dorisio, T.M.; Baum, R.P.; Kulkarni, H.R.; Caplin, M.; Lebtahi, R.; Hobday, T.; Delpassand, E.; Van Cutsem, E.; Benson, A.; Srirajaskanthan, R.; Pavel, M.; Mora, J.; Berlin, J.; Grande, E.; Reed, N.; Seregni, E.; Öberg, K.; Lopera Sierra, M.; Santoro, P.; Thevenet, T.; Erion, J.L.; Ruszniewski, P.; Kwekkeboom, D.; Krenning, E. NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N. Engl. J. Med., 2017, 376(2), 125-135.
[http://dx.doi.org/10.1056/NEJMoa1607427] [PMID: 28076709]
[10]
Rinke, A.; Wittenberg, M.; Schade-Brittinger, C.; Aminossadati, B.; Ronicke, E.; Gress, T.M.; Müller, H.H.; Arnold, R.; Mössner, J.; Novotny, A.; Mönig, H.; Haag, G.M.; Pace, A.; Fischer, R.; Blitzer, M.; Wiedenmann, B.; Weber, M.M.; Koop, I. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide lar in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results of long-term survival. Neuroendocrinology, 2016, 104(1), 26-32.
[http://dx.doi.org/10.1159/000443612] [PMID: 26731483]
[11]
Caplin, M.E.; Pavel, M.; Phan, A.T.; Ćwikła, J.B.; Sedláčková, E.; Thanh, X.M.T.; Wolin, E.M.; Ruszniewski, P. Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: Final results of the CLARINET open-label extension study. Endocrine, 2021, 71(2), 502-513.
[http://dx.doi.org/10.1007/s12020-020-02475-2] [PMID: 33052555]
[12]
Strosberg, J.R.; Fine, R.L.; Choi, J.; Nasir, A.; Coppola, D.; Chen, D.T.; Helm, J.; Kvols, L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer, 2011, 117(2), 268-275.
[http://dx.doi.org/10.1002/cncr.25425] [PMID: 20824724]
[13]
Spada, F.; Maisonneuve, P.; Fumagalli, C.; Marconcini, R.; Gelsomino, F.; Antonuzzo, L.; Campana, D.; Puliafito, I.; Rossi, G.; Faviana, P.; Messerini, L.; Barberis, M.; Fazio, N. Temozolomide alone or in combination with capecitabine in patients with advanced neuroendocrine neoplasms: An Italian multicenter real- world analysis. Endocrine, 2021, 72(1), 268-278.
[http://dx.doi.org/10.1007/s12020-020-02421-2] [PMID: 32700133]
[14]
Spada, F.; Antonuzzo, L.; Marconcini, R.; Radice, D.; Antonuzzo, A.; Ricci, S.; Di Costanzo, F.; Fontana, A.; Gelsomino, F.; Luppi, G.; Nobili, E.; Galdy, S.; Cella, C.A.; Sonzogni, A.; Pisa, E.; Barberis, M.; Fazio, N. Oxaliplatin-based chemotherapy in advanced neuroendocrine tumors: Clinical outcomes and preliminary correlation with biological factors. Neuroendocrinology, 2016, 103(6), 806-814.
[http://dx.doi.org/10.1159/000444087] [PMID: 26789262]
[15]
Frizziero, M.; Spada, F.; Lamarca, A.; Kordatou, Z.; Barriuso, J.; Nuttall, C.; McNamara, M.G.; Hubner, R.A.; Mansoor, W.; Manoharan, P.; Fazio, N.; Valle, J.W. Carboplatin in combination with oral or intravenous etoposide for extra-pulmonary, poorly-differentiated neuroendocrine carcinomas. Neuroendocrinology, 2019, 109(2), 100-112.
[http://dx.doi.org/10.1159/000497336] [PMID: 30703770]
[16]
Elvebakken, H.; Perren, A.; Scoazec, J-Y.; Tang, L.H.; Federspiel, B.; Klimstra, D.S.; Vestermark, L.W.; Ali, A.S.; Zlobec, I.; Myklebust, T.Å.; Hjortland, G.O.; Langer, S.W.; Gronbæk, H.; Knigge, U.; Tiensuu Janson, E.; Sorbye, H. A consensus developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations. Neuroendocrinology, 2021, 111(9), 883-894.
[http://dx.doi.org/10.1159/000511905] [PMID: 33002892]
[17]
Hallet, J.; Law, C.H.L.; Cukier, M.; Saskin, R.; Liu, N.; Singh, S. Exploring the rising incidence of neuroendocrine tumors: A population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer, 2015, 121(4), 589-597.
[http://dx.doi.org/10.1002/cncr.29099] [PMID: 25312765]
[18]
Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; Akerley, W.; van den Eertwegh, A.J.M.; Lutzky, J.; Lorigan, P.; Vaubel, J.M.; Linette, G.P.; Hogg, D.; Ottensmeier, C.H.; Lebbé, C.; Peschel, C.; Quirt, I.; Clark, J.I.; Wolchok, J.D.; Weber, J.S.; Tian, J.; Yellin, M.J.; Nichol, G.M.; Hoos, A.; Urba, W.J. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med., 2010, 363(8), 711-723.
[http://dx.doi.org/10.1056/NEJMoa1003466] [PMID: 20525992]
[19]
Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; Ferrucci, P.F.; Smylie, M.; Hill, A.; Hogg, D.; Marquez-Rodas, I.; Jiang, J.; Rizzo, J.; Larkin, J.; Wolchok, J.D. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol., 2018, 19(11), 1480-1492.
[http://dx.doi.org/10.1016/S1470-2045(18)30700-9] [PMID: 30361170]
[20]
Balar, A.V.; Castellano, D.; O’Donnell, P.H.; Grivas, P.; Vuky, J.; Powles, T.; Plimack, E.R.; Hahn, N.M.; de Wit, R.; Pang, L.; Savage, M.J.; Perini, R.F.; Keefe, S.M.; Bajorin, D.; Bellmunt, J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol., 2017, 18(11), 1483-1492.
[http://dx.doi.org/10.1016/S1470-2045(17)30616-2] [PMID: 28967485]
[21]
Vuky, J.; Balar, A.V.; Castellano, D.; O’Donnell, P.H.; Grivas, P.; Bellmunt, J.; Powles, T.; Bajorin, D.; Hahn, N.M.; Savage, M.J.; Fang, X.; Godwin, J.L.; Frenkl, T.L.; Homet Moreno, B.; de Wit, R.; Plimack, E.R. Long-term outcomes in KEYNOTE-052: Phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J. Clin. Oncol., 2020, 38(23), 2658-2666.
[http://dx.doi.org/10.1200/JCO.19.01213] [PMID: 32552471]
[22]
Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; O’Brien, M.; Rao, S.; Hotta, K.; Leiby, M.A.; Lubiniecki, G.M.; Shentu, Y.; Rangwala, R.; Brahmer, J.R. KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med., 2016, 375(19), 1823-1833.
[http://dx.doi.org/10.1056/NEJMoa1606774] [PMID: 27718847]
[23]
Kölby, L.; Persson, G.; Franzén, S.; Ahrén, B. Randomized clinical trial of the effect of interferon α on survival in patients with disseminated midgut carcinoid tumours. Br. J. Surg., 2003, 90(6), 687-693.
[http://dx.doi.org/10.1002/bjs.4149] [PMID: 12808615]
[24]
Detjen, K.M.; Welzel, M.; Farwig, K.; Brembeck, F.H.; Kaiser, A.; Riecken, E.O.; Wiedenmann, B.; Rosewicz, S. Molecular mechanism of interferon alfa-mediated growth inhibition in human neuroendocrine tumor cells. Gastroenterology, 2000, 118(4), 735-748.
[http://dx.doi.org/10.1016/S0016-5085(00)70143-0] [PMID: 10734025]
[25]
Katz, S.C.; Donkor, C.; Glasgow, K.; Pillarisetty, V.G.; Gönen, M.; Espat, N.J.; Klimstra, D.S.; D’Angelica, M.I.; Allen, P.J.; Jarnagin, W.; Dematteo, R.P.; Brennan, M.F.; Tang, L.H. T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases. HPB (Oxford), 2010, 12(10), 674-683.
[http://dx.doi.org/10.1111/j.1477-2574.2010.00231.x] [PMID: 21083792]
[26]
Vikman, S.; Sommaggio, R.; De La Torre, M.; Oberg, K.; Essand, M.; Giandomenico, V.; Loskog, A.; Totterman, T.H. Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue. Acta Oncol., 2009, 48(3), 391-400.
[http://dx.doi.org/10.1080/02841860802438495] [PMID: 18855160]
[27]
Ameri, P.; Ferone, D. Diffuse endocrine system, neuroendocrine tumors and immunity: what’s new? Neuroendocrinology, 2012, 95(4), 267-276.
[http://dx.doi.org/10.1159/000334612] [PMID: 22248635]
[28]
Bösch, F.; Brüwer, K.; Altendorf-Hofmann, A.; Auernhammer, C.J.; Spitzweg, C.; Westphalen, C.B.; Boeck, S.; Schubert-Fritschle, G.; Werner, J.; Heinemann, V.; Kirchner, T.; Angele, M.; Knösel, T. Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia. Endocr. Relat. Cancer, 2019, 26(3), 293-301.
[http://dx.doi.org/10.1530/ERC-18-0494] [PMID: 30608901]
[29]
Cives, M.; Strosberg, J.; Al Diffalha, S.; Coppola, D. Analysis of the immune landscape of small bowel neuroendocrine tumors. Endocr. Relat. Cancer, 2019, 26(1), 119-130.
[http://dx.doi.org/10.1530/ERC-18-0189] [PMID: 30400003]
[30]
da Silva, A.; Bowden, M.; Zhang, S.; Masugi, Y.; Thorner, A.R.; Herbert, Z.T.; Zhou, C.W.; Brais, L.; Chan, J.A.; Hodi, F.S.; Rodig, S.; Ogino, S.; Kulke, M.H. Characterization of the neuroendocrine tumor immune microenvironment. Pancreas, 2018, 47(9), 1123-1129.
[http://dx.doi.org/10.1097/MPA.0000000000001150] [PMID: 30153220]
[31]
Ono, K.; Shiozawa, E.; Ohike, N.; Fujii, T.; Shibata, H.; Kitajima, T.; Fujimasa, K.; Okamoto, N.; Kawaguchi, Y.; Nagumo, T.; Tazawa, S.; Homma, M.; Yamochi-Onizuka, T.; Norose, T.; Yoshida, H.; Murakami, M.; Tate, G.; Takimoto, M. Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136 patients. Oncol. Lett., 2018, 15(2), 2123-2130.
[http://dx.doi.org/10.3892/ol.2017.7569] [PMID: 29434915]
[32]
Cavalcanti, E.; Armentano, R.; Valentini, A.M.; Chieppa, M.; Caruso, M.L. Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death Dis., 2017, 8(8), e3004.
[http://dx.doi.org/10.1038/cddis.2017.401] [PMID: 28837143]
[33]
Kim, S.T.; Ha, S.Y.; Lee, S.; Ahn, S.; Lee, J.; Park, S.H.; Park, J.O.; Lim, H.Y.; Kang, W.K.; Kim, K.M.; Park, Y.S. The impact of PD-L1 expression in patients with metastatic GEP-NETs. J. Cancer, 2016, 7(5), 484-489.
[http://dx.doi.org/10.7150/jca.13711] [PMID: 26958083]
[34]
Lamarca, A.; Nonaka, D.; Breitwieser, W.; Ashton, G.; Barriuso, J.; McNamara, M.G.; Moghadam, S.; Rogan, J.; Mansoor, W.; Hubner, R.A.; Clark, C.; Chakrabarty, B.; Valle, J.W. PD-L1 expression and presence of TILs in small intestinal neuroendocrine tumours. Oncotarget, 2018, 9(19), 14922-14938.
[http://dx.doi.org/10.18632/oncotarget.24464] [PMID: 29599916]
[35]
Arnason, T.; Sapp, H.L.; Rayson, D.; Barnes, P.J.; Drewniak, M.; Nassar, B.A.; Huang, W.Y. Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors. Arch. Pathol. Lab. Med., 2011, 135(12), 1539-1544.
[http://dx.doi.org/10.5858/arpa.2010-0560-OA] [PMID: 22129180]
[36]
Sahnane, N.; Furlan, D.; Monti, M.; Romualdi, C.; Vanoli, A.; Vicari, E.; Solcia, E.; Capella, C.; Sessa, F.; La Rosa, S. Microsatellite unstable gastrointestinal neuroendocrine carcinomas: A new clinicopathologic entity. Endocr. Relat. Cancer, 2015, 22(1), 35-45.
[http://dx.doi.org/10.1530/ERC-14-0410] [PMID: 25465415]
[37]
Salem, M.E.; Puccini, A.; Grothey, A.; Raghavan, D.; Goldberg, R.M.; Xiu, J.; Korn, W.M.; Weinberg, B.A.; Hwang, J.J.; Shields, A.F.; Marshall, J.L.; Philip, P.A.; Lenz, H.J. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol. Cancer Res., 2018, 16(5), 805-812.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0735] [PMID: 29523759]
[38]
Mehnert, J.M.; Rugo, H.S.; O’Neil, B.H.; Santoro, A.; Schellens, J.H.M.; Cohen, R.B.; Doi, T.; Ott, P.A.; Pishvaian, M.J.; Puzanov, I.; Aung, K.L.; Hsu, C.; Le Tourneau, C.; Soria, J-C.; Elez, E.; Tamura, K.; Gould, M.; Zhao, G.; Stein, K.; Piha-Paul, S.A. Pembrolizumab for patients with PD-L1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Ann. Oncol., 2017, 28, v142.
[http://dx.doi.org/10.1093/annonc/mdx368]
[39]
Dolled-Filhart, M.; Locke, D.; Murphy, T.; Lynch, F.; Yearley, J.H.; Frisman, D.; Pierce, R.; Weiner, R.; Wu, D.; Emancipator, K. Development of a prototype immunohistochemistry assay to measure programmed death ligand-1 expression in tumor tissue. Arch. Pathol. Lab. Med., 2016, 140(11), 1259-1266.
[http://dx.doi.org/10.5858/arpa.2015-0544-OA] [PMID: 27788043]
[40]
Strosberg, J.; Mizuno, N.; Doi, T.; Grande, E.; Delord, J.P.; Shapira-Frommer, R.; Bergsland, E.; Shah, M.; Fakih, M.; Takahashi, S.; Piha-Paul, S.A.; O’Neil, B.; Thomas, S.; Lolkema, M.P.; Chen, M.; Ibrahim, N.; Norwood, K.; Hadoux, J. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: Results from the phase II KEYNOTE-158 study. Clin. Cancer Res., 2020, 26(9), 2124-2130.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-3014] [PMID: 31980466]
[41]
Yao, J.C.; Strosberg, J.; Fazio, N.; Pavel, M.E.; Ruszniewski, P.; Bergsland, E.; Li, D.; Tafuto, S.; Raj, N.; Campana, D.; Hijioka, S.; Raderer, M.; Guimbaud, R.; Gajate, P.; Pusceddu, S.; Reising, A.; Degtyarev, E.; Mookerjee, B.; Aimone, P.; Singh, S. Activity & Safety of Spartalizumab (PDR001) in Patients (Pts) with advanced Neuroendocrine Tumors (NET) of Pancreatic (Pan), Gastrointestinal (GI), or Thoracic (T) origin, & Gastroenteropancreatic Neuroendocrine Carcinoma (GEP NEC) who have progressed on. Ann. Oncol., 2018, 29(Supple_8), VIII467-68.
[http://dx.doi.org/10.1093/annonc/mdy293.001]
[42]
Fottner, C.; Apostolidis, L.; Ferrata, M.; Krug, S.; Michl, P.; Schad, A.; Roth, W.; Jaeger, D.; Galle, P.R.; Weber, M.M. A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC). J. Clin. Oncol., 2019, 37(Supple_15), 4103.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.4103]
[43]
Patel, S.P.; Othus, M.; Chae, Y.K.; Giles, F.J.; Hansel, D.E.; Singh, P.P.; Fontaine, A.; Shah, M.H.; Kasi, A.; Baghdadi, T.A.; Matrana, M.; Gatalica, Z.; Korn, W.M.; Hayward, J.; McLeod, C.; Chen, H.X.; Sharon, E.; Mayerson, E.; Ryan, C.W.; Plets, M.; Blanke, C.D.; Kurzrock, R. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. Clin. Cancer Res., 2020, 26(10), 2290-2296.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-3356] [PMID: 31969335]
[44]
Klein, O.; Kee, D.; Markman, B.; Chang Lee, R.; Michael, M.; Mileshkin, L. R.; Scott, C. L.; Linklater, R.; Menon, S.; Tebbutt, N. C.; Palmer, J.; Behren, A.; Cebon, J. S. A phase II clinical trial of ipilimumab/nivolumab combination immunotherapy in patients with rare upper gastrointestinal, neuroendocrine, and gynecological malignancies. J. Clin. Oncol., 2019, 37(Supple_15), 2570.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.2570]
[45]
Matos Garcia, I.; Grande, E.; Garcia-Carbonero, R.; Lopez, C.; Teule, A.; Capdevila, J. A multicohort phase II study of durvalumab plus tremelimumab for the treatment of Patients (PTS) with Advanced Neuroendocrine Neoplasms (NENs) of Gastroenteropancreatic (GEP) or lung origin (the DUNE Trial-GETNE1601-). J. Clin. Oncol., 2017, 35(Supple_15)
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.TPS4146]
[46]
Halperin, D.M.; Liu, S.; Dasari, A.; Fogelman, D.R.; Bhosale, P.; Mahvash, A.; Dervin, S.; Estrella, J.; Cortazar, P.; Maru, D.M.; Mckenna, E.F.; Wistuba, I.I.; Schulze, K.; Futreal, P.A.; Darbonne, W.C.; Yun, C.; Hwu, P.; Yao, J.C. A phase ii trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs). J. Clin. Oncol., 2020, 38(Supp-4)
[http://dx.doi.org/10.1200/JCO.2020.38.4_suppl.619]
[47]
Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; Leming, P.D.; Spigel, D.R.; Antonia, S.J.; Horn, L.; Drake, C.G.; Pardoll, D.M.; Chen, L.; Sharfman, W.H.; Anders, R.A.; Taube, J.M.; McMiller, T.L.; Xu, H.; Korman, A.J.; Jure-Kunkel, M.; Agrawal, S.; McDonald, D.; Kollia, G.D.; Gupta, A.; Wigginton, J.M.; Sznol, M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med., 2012, 366(26), 2443-2454.
[http://dx.doi.org/10.1056/NEJMoa1200690] [PMID: 22658127]
[48]
Ott, P.A.; Bang, Y.J.; Piha-Paul, S.A.; Razak, A.R.A.; Bennouna, J.; Soria, J.C.; Rugo, H.S.; Cohen, R.B.; O’Neil, B.H.; Mehnert, J.M.; Lopez, J.; Doi, T.; van Brummelen, E.M.J.; Cristescu, R.; Yang, P.; Emancipator, K.; Stein, K.; Ayers, M.; Joe, A.K.; Lunceford, J.K. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J. Clin. Oncol., 2019, 37(4), 318-327.
[http://dx.doi.org/10.1200/JCO.2018.78.2276] [PMID: 30557521]
[49]
Sakuishi, K.; Apetoh, L.; Sullivan, J.M.; Blazar, B.R.; Kuchroo, V.K.; Anderson, A.C. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med., 2010, 207(10), 2187-2194.
[http://dx.doi.org/10.1084/jem.20100643] [PMID: 20819927]
[50]
Koyama, S.; Akbay, E.A.; Li, Y.Y.; Herter-Sprie, G.S.; Buczkowski, K.A.; Richards, W.G.; Gandhi, L.; Redig, A.J.; Rodig, S.J.; Asahina, H.; Jones, R.E.; Kulkarni, M.M.; Kuraguchi, M.; Palakurthi, S.; Fecci, P.E.; Johnson, B.E.; Janne, P.A.; Engelman, J.A.; Gangadharan, S.P.; Costa, D.B.; Freeman, G.J.; Bueno, R.; Hodi, F.S.; Dranoff, G.; Wong, K.K.; Hammerman, P.S. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun., 2016, 7, 10501.
[http://dx.doi.org/10.1038/ncomms10501] [PMID: 26883990]
[51]
Cristescu, R.; Mogg, R.; Ayers, M.; Albright, A.; Murphy, E.; Yearley, J.; Sher, X.; Liu, X. Q.; Lu, H.; Nebozhyn, M.; Zhang, C.; Lunceford, J. K.; Joe, A.; Cheng, J.; Webber, A. L.; Ibrahim, N.; Plimack, E. R.; Ott, P. A.; Seiwert, T. Y.; Ribas, A.; McClanahan, T. K.; Tomassini, J. E.; Loboda, A.; Kaufman, D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science, 2018, 362(6411), eaar3593.
[http://dx.doi.org/10.1126/science.aar3593]
[52]
Haddad, R.I.; Seiwert, T.Y.; Chow, L.Q.M.; Gupta, S.; Weiss, J.; Gluck, I.; Eder, J.P.; Burtness, B.; Tahara, M.; Keam, B.; Kang, H.; Muro, K.; Albright, A.; Huang, L.; Ayers, M.; Mogg, R.; Cristescu, R.; Cheng, J.D.; Mehra, R. Genomic determinants of response to pembrolizumab in Head and Neck Squamous Cell Carcinoma (HNSCC). J. Clin. Oncol., 2017, 35(Supple_15), 6009.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.6009]
[53]
Ayers, M.; Lunceford, J.; Nebozhyn, M.; Murphy, E.; Loboda, A.; Kaufman, D.R.; Albright, A.; Cheng, J.D.; Kang, S.P.; Shankaran, V.; Piha-Paul, S.A.; Yearley, J.; Seiwert, T.Y.; Ribas, A.; McClanahan, T.K. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest., 2017, 127(8), 2930-2940.
[http://dx.doi.org/10.1172/JCI91190] [PMID: 28650338]
[54]
Crocenzi, T.S.; El-Khoueiry, A.B.; Yau, T.C.; Melero, I.; Sangro, B.; Kudo, M.; Hsu, C.; Trojan, J.; Kim, T-Y.; Choo, S-P.; Meyer, T.; Kang, Y-K.; Yeo, W.; Chopra, A.; Baakili, A.; Dela Cruz, C.M.; Lang, L.; Neely, J.; Welling, T. Nivolumab (Nivo) in Sorafenib (Sor)-naive and -experienced Pts with advanced Hepatocellular Carcinoma (HCC): CheckMate 040 study. J. Clin. Oncol., 2017, 35(Supple_15), 4013.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.4013]
[55]
Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; Larkin, J.; Lorigan, P.; Neyns, B.; Blank, C.U.; Hamid, O.; Mateus, C.; Shapira-Frommer, R.; Kosh, M.; Zhou, H.; Ibrahim, N.; Ebbinghaus, S.; Ribas, A. KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med., 2015, 372(26), 2521-2532.
[http://dx.doi.org/10.1056/NEJMoa1503093] [PMID: 25891173]
[56]
Marabelle, A.; Fakih, M.; Lopez, J.; Shah, M.; Shapira-Frommer, R.; Nakagawa, K.; Chung, H.C.; Kindler, H.L.; Lopez-Martin, J.A.; Miller, W.H., Jr; Italiano, A.; Kao, S.; Piha-Paul, S.A.; Delord, J.P.; McWilliams, R.R.; Fabrizio, D.A.; Aurora-Garg, D.; Xu, L.; Jin, F.; Norwood, K.; Bang, Y.J. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol., 2020, 21(10), 1353-1365.
[http://dx.doi.org/10.1016/S1470-2045(20)30445-9] [PMID: 32919526]
[57]
Suzuki, E.; Kapoor, V.; Jassar, A.S.; Kaiser, L.R.; Albelda, S.M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res., 2005, 11(18), 6713-6721.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-0883] [PMID: 16166452]
[58]
Ohtsukasa, S.; Okabe, S.; Yamashita, H.; Iwai, T.; Sugihara, K. Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs. J. Cancer Res. Clin. Oncol., 2003, 129(12), 719-726.
[http://dx.doi.org/10.1007/s00432-003-0492-0] [PMID: 14564514]
[59]
Wan, S.; Pestka, S.; Jubin, R.G.; Lyu, Y.L.; Tsai, Y.C.; Liu, L.F. Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One, 2012, 7(3), e32542.
[http://dx.doi.org/10.1371/journal.pone.0032542] [PMID: 22396773]
[60]
Fazio, N.; Spada, F.; Giovannini, M. Chemotherapy in Gastroenteropancreatic (GEP) Neuroendocrine Carcinomas (NEC): A critical view. Cancer Treat. Rev., 2013, 39(3), 270-274.
[http://dx.doi.org/10.1016/j.ctrv.2012.06.009] [PMID: 22819619]
[61]
Antonia, S.J.; López-Martin, J.A.; Bendell, J.; Ott, P.A.; Taylor, M.; Eder, J.P.; Jäger, D.; Pietanza, M.C.; Le, D.T.; de Braud, F.; Morse, M.A.; Ascierto, P.A.; Horn, L.; Amin, A.; Pillai, R.N.; Evans, J.; Chau, I.; Bono, P.; Atmaca, A.; Sharma, P.; Harbison, C.T.; Lin, C.S.; Christensen, O.; Calvo, E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol., 2016, 17(7), 883-895.
[http://dx.doi.org/10.1016/S1470-2045(16)30098-5] [PMID: 27269741]
[62]
Horn, L.; Mansfield, A.S.; Szczęsna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; Reck, M.; Mok, T.; Lam, S.; Shames, D.S.; Liu, J.; Ding, B.; Lopez-Chavez, A.; Kabbinavar, F.; Lin, W.; Sandler, A.; Liu, S.V. IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med., 2018, 379(23), 2220-2229.
[http://dx.doi.org/10.1056/NEJMoa1809064] [PMID: 30280641]
[63]
Germano, G.; Lamba, S.; Rospo, G.; Barault, L.; Magrì, A.; Maione, F.; Russo, M.; Crisafulli, G.; Bartolini, A.; Lerda, G.; Siravegna, G.; Mussolin, B.; Frapolli, R.; Montone, M.; Morano, F.; de Braud, F.; Amirouchene-Angelozzi, N.; Marsoni, S.; D’Incalci, M.; Orlandi, A.; Giraudo, E.; Sartore-Bianchi, A.; Siena, S.; Pietrantonio, F.; Di Nicolantonio, F.; Bardelli, A. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature, 2017, 552(7683), 116-120.
[http://dx.doi.org/10.1038/nature24673] [PMID: 29186113]
[64]
Cao, Y.; Ma, Y.; Yu, J.; Sun, Y.; Sun, T.; Shao, Y.; Li, J.; Shen, L.; Lu, M. Favorable response to immunotherapy in a pancreatic neuroendocrine tumor with temozolomide-induced high tumor mutational burden. Cancer Commun. (Lond.), 2020, 40(12), 746-751.
[http://dx.doi.org/10.1002/cac2.12114] [PMID: 33230973]
[65]
Pembrolizumab in With Liver-Directed or Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors With Metastases. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03457948 (Accessed December 22, 2020).

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