Skip to main content
SpringerLink
Log in

Emerging Systemic Therapies for Neuroendocrine Tumors

  • Chapter
  • First Online:
Neuroendocrine Tumors

  • 515 Accesses

Abstract

Neuroendocrine tumors (NETs) are a group of heterogeneous neoplasms arising from the diffuse neuroendocrine system. The incidence and prevalence of NETs have been steadily rising. The therapeutic landscape in NETs has changed significantly over recent years with the addition of several systemic therapy options. Advances in clinical and basic science research in the field have paved the way for development of a number of novel systemic therapies for management of advanced NETs, while studies to refine the use of approved agents continue. The novel therapy options include targeted therapies, immunotherapy agents, cytotoxic chemotherapies, radionuclide therapies, liver-directed therapies, and combination of these agents. This chapter reviews the currently available and emerging systemic therapies for the management of NETs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72.

    PubMed  Google Scholar 

  2. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–42.

    Article  Google Scholar 

  3. Shah MH, Goldner WS, Halfdanarson TR, Bergsland E, Berlin JD, Halperin D, et al. NCCN guidelines insights: neuroendocrine and adrenal tumors, version 2.2018. J Natl Compr Cancer Netw. 2018;16(6):693–702.

    Article  CAS  Google Scholar 

  4. Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13.

    Article  CAS  Google Scholar 

  5. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet (London, England). 2016;387(10022):968–77.

    Article  CAS  Google Scholar 

  6. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.

    Article  CAS  Google Scholar 

  7. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.

    Article  CAS  Google Scholar 

  8. Rinke A, Müller H-H, Schade-Brittinger C, Klose K-J, Barth P, Wied M, et al. 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):4656–63.

    Article  CAS  Google Scholar 

  9. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33.

    Article  Google Scholar 

  10. Kulke MH, Hörsch D, Caplin ME, Anthony LB, Bergsland E, Öberg K, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2016;35(1):14–23.

    Article  Google Scholar 

  11. Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991;68(2):227–32.

    Article  CAS  Google Scholar 

  12. Chong CR, Wirth LJ, Nishino M, Chen AB, Sholl LM, Kulke MH, et al. Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. Lung Cancer. 2014;86(2):241–6.

    Article  Google Scholar 

  13. Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30(14):1692–8.

    Article  CAS  Google Scholar 

  14. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22(23):4762–71.

    Article  CAS  Google Scholar 

  15. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005;23(22):4897–904.

    Article  CAS  Google Scholar 

  16. Kunz PL, Catalano PJ, Nimeiri H, Fisher GA, Longacre TA, Suarez CJ, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: a trial of the ECOG-ACRIN Cancer Research Group (E2211). J Clin Oncol. 2018;36(15 suppl):4004.

    Article  Google Scholar 

  17. Eads JR, Catalano PJ, Fisher GA, Klimstra DS, Zhang Z, Rubin D, et al. Randomized phase II study of cisplatin and etoposide versus temozolomide and capecitabine in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas (GEPNEC): a trial of the ECOG-ACRIN Cancer Research Group (EA2142). J Clin Oncol. 2016;34(15 suppl):TPS4149-TPS.

    Google Scholar 

  18. Gupta M, Choi M, Ramirez RA, Attwood K, Mukherjee S, Iyer RV. Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/folinic acid (FA) in refractory advanced high-grade neuroendocrine cancer (HG-NEC) of gastroenteropancreatic (GEP) or unknown origin. J Clin Oncol. 2020;38(4 suppl):TPS636-TPS.

    Google Scholar 

  19. Chan JA, Faris JE, Murphy JE, Blaszkowsky LS, Kwak EL, McCleary NJ, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET). J Clin Oncol. 2017;35(4 suppl):228.

    Article  Google Scholar 

  20. Xu J, Li J, Bai C, Xu N, Zhou Z, Li Z, et al. Surufatinib in advanced well-differentiated neuroendocrine tumors: a multicenter, single-arm, open-label, phase Ib/II trial. Clin Cancer Res. 2019;25(12):3486.

    CAS  PubMed  Google Scholar 

  21. CHI-MED. Chi-Med announces that Surufatinib Phase III SANET-p Study has already achieved its primary endpoint in advanced pancreatic neuroendocrine tumors in China and will stop early 2020. Available from: https://www.globenewswire.com/news-release/2020/01/20/1972348/0/en/Chi-Med-Announces-that-Surufatinib-Phase-III-SANET-p-Study-Has-Already-Achieved-its-Primary-Endpoint-in-Advanced-Pancreatic-Neuroendocrine-Tumors-in-China-and-Will-Stop-Early.html.

  22. CHI-MED. Chi-Med to discuss surufatinib Phase III and U.S. phase I/Ib efficacy and safety data. Presented at the 2019 ESMO Annual Meeting 2019. Available from: https://www.chi-med.com/2019-esmo-annual-meeting/.

  23. CHI-MED. Chi-Med announces surufatinib granted U.S. FDA Fast Track Designations for the treatment of both pancreatic and non-pancreatic neuroendocrine tumors 2020. Available from: https://www.chi-med.com/surufatinib-granted-us-fda-fast-track-designations/.

  24. Capdevila J, Fazio N, López-López C, Teule A, Valle JW, Tafuto S, et al. Progression-free survival (PFS) and subgroups analyses of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs): updated results from the phase II TALENT trial (GETNE 1509). J Clin Oncol. 2019;37(4 suppl):332.

    Article  Google Scholar 

  25. Iyer RV, Konda B, Owen DH, Attwood K, Sarker S, Suffren S-A, et al. Multicenter phase 2 study of nintedanib in patients (pts) with advanced progressing carcinoid tumors. J Clin Oncol. 2018;36(15 suppl):4105.

    Article  Google Scholar 

  26. Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 2015;16(6):695–703.

    Article  CAS  Google Scholar 

  27. Bergsland EK, Mahoney MR, Asmis TR, Hall N, Kumthekar P, Maitland ML, et al. Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) (Alliance A021202). J Clin Oncol. 2019;37(15 suppl):4005.

    Article  Google Scholar 

  28. Singh J, Shipley D, Cultrera J, Chua C, Cohn AL, Soriano AO, et al. Phase 2 study of carfilzomib for the treatment of patients with advanced neuroendocrine cancers. J Clin Oncol. 2018;36(4 suppl):382.

    Google Scholar 

  29. Al-Toubah T, Schell MJ, Cives M, Zhou JM, Soares HP, Strosberg JR. A phase II study of Ibrutinib in advanced neuroendocrine neoplasms. Neuroendocrinology. 2020;110(5):377–83.

    Article  CAS  Google Scholar 

  30. Mehnert JM, Bergsland E, O’Neil BH, Santoro A, Schellens JHM, Cohen RB, Doi T, Ott PA, Pishvaian MJ, Puzanov I, Aung KL, Hsu C, Le Tourneau C, Hollebecque A, Élez E, Tamura K, Gould M, Yang P, Stein K, Piha-Paul SA. Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Cancer. 2020;126(13):3021–30. https://doi.org/10.1002/cncr.32883. Epub 2020 Apr 22. PMID: 32320048.

  31. Strosberg JR, Mizuno N, Doi T, Grande E, Delord J-P, Shapira-Frommer R, et al. Pembrolizumab treatment of advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(4 suppl):190.

    Google Scholar 

  32. Mulvey C, Raj NP, Chan JA, Aggarwal RR, Cinar P, Hope TA, et al. Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: results of part A (pembrolizumab alone). J Clin Oncol. 2019;37(4 suppl):363.

    Google Scholar 

  33. Vijayvergia N, Dasari A, Ross EA, Dotan E, Halperin DM, Astsaturov IA, et al. Pembrolizumab (P) monotherapy in patients with previously treated metastatic high grade neuroendocrine neoplasms (HG-NENs). J Clin Oncol. 2018;36(15 suppl):4104.

    Google Scholar 

  34. Yao JC SJ, Fazio N, Pavel ME, Ruszniewski P, Bergsland E, et al. 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 prior treatment (Tx). Ann Oncol. 2018;29(suppl 8):viii467–8.

    Google Scholar 

  35. Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, Fontaine A, Shah MH, Kasi A, Baghdadi TA, Matrana M, Gatalica Z, Korn WM, Hayward J, McLeod C, Chen HX, Sharon E, Mayerson E, Ryan CW, Plets M, Blanke CD, 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):2290–96. https://doi.org/10.1158/1078-0432.CCR-19-3356. Epub 2020 Jan 22. PMID: 31969335; PMCID: PMC7231627.

  36. Mandriani B, Cives M, Pellé E, Quaresmini D, Ramello M, Strosberg J, Abate-Daga D, Silvestris F. Presented at NANETS 2019 Annual Symposium and Meeting; Boston, Massachusetts 2019.

    Google Scholar 

  37. Foundation NTR. Developing novel treatments for NETs using CAR T-Cell Technology 2020. Available from: https://netrf.org/research/study-explores-car-t-cell-therapy-for-neuroendocrine-tumors/.

  38. Lee S-H, Chu SY, Rashid R, Phung S, Leung IW, Muchhal US, et al. Abstract 3633: Anti-SSTR2 × anti-CD3 bispecific antibody induces potent killing of human tumor cells in vitro and in mice, and stimulates target-dependent T cell activation in monkeys: A potential immunotherapy for neuroendocrine tumors. Cancer Res. 2017;77(13 Supplement):3633.

    Google Scholar 

  39. Hanif A, Chander A, Attwood K, Fenstermaker R, Qiu J, Iyer RV. Evaluating survivin as a potential target in neuroendocrine tumors (NETs). J Clin Oncol. 2018;36(15 suppl):e16171.

    Article  Google Scholar 

  40. Pavel ME, Rinke A, Baum RP. COMPETE trial: peptide receptor radionuclide therapy (PRRT) with 177Lu-edotreotide vs. everolimus in progressive GEP-NET. Ann Oncol. 2018;29:viii478.

    Article  Google Scholar 

  41. Ginj M, Zhang H, Waser B, Cescato R, Wild D, Wang X, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103(44):16436–41.

    Article  CAS  Google Scholar 

  42. Reidy-Lagunes D, Pandit-Taskar N, O’Donoghue JA, Krebs S, Staton KD, Lyashchenko SK, et al. Phase I trial of well-differentiated neuroendocrine tumors (NETs) with radiolabeled somatostatin antagonist (177)Lu-satoreotide tetraxetan. Clin Cancer Res. 2019;25(23):6939–47.

    Article  Google Scholar 

  43. Nicolas G, Baum R, Herrmann K, Lassmann M, Hicks R, Navalkissoor S, Haug A, Oberwittler H, Wang T; Wild D, editor. Phase 1/2 open-label trial to assess the safety and preliminary efficacy of 177LuOPS201 as peptide receptor radionuclide therapy in patients with somatostatin receptor-positive, progressive neuroendocrine tumors. Presented at 10th Annual NANETS Symposium; 2017 October 19–21; Philadelphia, Pennsylvania.

    Google Scholar 

  44. Bodeker K, Bushnell D, Madsen M, Menda Y, Gaimari-Varner K, Graves S, O’Dorisio T, Dillon J, Chandrasekharan C. 131I MIBG and 90Y DOTATOC in a dosimetrically determined optimal combination for personalized therapy of selected patients with midgut neuroendocrine tumors: a first-in-man clinical trial. NANETS 2019 Symposium. 2019.

    Google Scholar 

  45. Kim C, Subramaniam DS, Liu SV, Giaccone G. Phase I/II trial of anti-PD-1 checkpoint inhibitor nivolumab and 177Lu-DOTA0-Tyr3-Octreotate for patients with extensive-stage small cell lung cancer. J Clin Oncol. 2018;36(15 suppl):TPS8589-TPS.

    Google Scholar 

  46. Bhave MA, Kircher SM, Kalyan A, Berlin J, Mulcahy MF, Cohen SJ, et al. A phase I/II study of the combination of temozolomide (TM) and pazopanib (PZ) in advanced pancreatic neuroendocrine tumors (PNETs) (NCT01465659). J Clin Oncol. 2018;36(15 suppl):4096.

    Google Scholar 

  47. Gutierrez ME, Giaccone G, Liu SV, Rajan A, Guha U, Halfdanarson TR, et al. Phase I, open-label, dose-escalation study of SNX-5422 plus everolimus in neuroendocrine tumors (NETs). Ann Oncol. 2016;27:vi138.

    Google Scholar 

  48. Dwight HO, Lai W, Ashima G, Ye Z, Sheryl-Ann S, Rajani J, et al. CLO20-054: A phase 2 trial of nivolumab and temozolomide in advanced neuroendocrine tumors (NETs): interim efficacy analysis. J Natl Compr Canc Netw. 2020;18(3.5):CLO20-054.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Medhavi Gupta, Gillian Prinzing & Renuka Iyer

Authors
  1. Medhavi Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gillian Prinzing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Renuka Iyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renuka Iyer .

Editor information

Editors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Jordan M. Cloyd

  2. Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Timothy M. Pawlik

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gupta, M., Prinzing, G., Iyer, R. (2021). Emerging Systemic Therapies for Neuroendocrine Tumors. In: Cloyd, J.M., Pawlik, T.M. (eds) Neuroendocrine Tumors. Springer, Cham. https://doi.org/10.1007/978-3-030-62241-1_20

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-62241-1_20

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-62240-4

  • Online ISBN: 978-3-030-62241-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation