Skip to main content

Advertisement

SpringerLink
Log in

Immunotherapy in Neuroendocrine Neoplasms: Where Are We Now?

  • Neuroendocrine Cancers (M Cives, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Immune checkpoint inhibitors (ICIs) represent a breakthrough in the management of many hard-to-treat cancers over the past decade with demonstrable improvement in survival outcomes. We reviewed the state of the art of ICIs in neuroendocrine neoplasms (NENs). While ICIs have become part of the standard of care for the management of small cell lung cancer (SCLC), their role is still unclear in the management of extra-pulmonary (EP) poorly differentiated neuroendocrine carcinomas (NECs) as well as in the management of well-differentiated neuroendocrine tumors (NETs). Conflicting results derived from the various studies in NETs and EP NECs therefore for specific settings, such as the lung NETs, or therapeutic regimen, e.g., combo vs single agent, for ICIs benefit. Therefore, at the moment, no ICIs approach is justified for NETs and EP NECs in clinical practice. Future investigations should be designed with the aim to overcome the several limitations of the current trials, e.g., lacking of a central pathology review or heterogeneity of the cohorts, in order to reduce the risk of biases. Future trials combining ICIs with other biological agents are welcome. This review aims to provide a comprehensive overview of the biological rationale and evolving clinical applications of the use of ICIs in the management of NENs (both well-differentiated and poorly differentiated groups).

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Fazio N, Abdel-Rahman O, Spada F, Galdy S, De Dosso S, Capdevila J, et al. RAF signaling in neuroendocrine neoplasms: from bench to bedside. Cancer Treat Rev. 2014;40(8):974–9.

    Article  CAS  Google Scholar 

  2. Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–71.

    Article  CAS  Google Scholar 

  3. Abdel-Rahman O, Fouad M. Everolimus-based combination for the treatment of advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): biological rationale and critical review of published data. Tumour Biol. 2015;36(2):467–78.

    Article  CAS  Google Scholar 

  4. Abdel-Rahman O, Fouad M. Bevacizumab-based combination therapy for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a systematic review of the literature. J Cancer Res Clin Oncol. 2015;141(2):295–305.

    Article  CAS  Google Scholar 

  5. 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.

    Article  Google Scholar 

  6. Horinouchi H, Yamamoto N, Fujiwara Y, Sekine I, Nokihara H, Kubota K, et al. Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. Investigational new drugs. 2015;33(4):881–9.

    Article  CAS  Google Scholar 

  7. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. The Lancet Oncology. 2012;13(5):459–65.

    Article  CAS  Google Scholar 

  8. Aglietta M, Barone C, Sawyer MB, Moore MJ, Miller WH Jr, Bagala C, et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 2014;25(9):1750–5.

    Article  CAS  Google Scholar 

  9. McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33(18):2013–20.

    Article  CAS  Google Scholar 

  10. McNeel DG, Smith HA, Eickhoff JC, Lang JM, Staab MJ, Wilding G, et al. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer immunology, immunotherapy : CII. 2012;61(7):1137–47.

    Article  CAS  Google Scholar 

  11. Momtaz P, Postow MA. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmacogenomics and personalized medicine. 2014;7:357–65.

    PubMed  PubMed Central  Google Scholar 

  12. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. The Journal of experimental medicine. 2000;192(7):1027–34.

    Article  CAS  Google Scholar 

  13. Mehnert JM, Bergsland E, O’Neil BH, Santoro A, Schellens JHM, Cohen RB, et al. 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.

    Article  CAS  Google Scholar 

  14. Strosberg J, Mizuno N, Doi T, Grande E, Delord J-P, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. Clinical Cancer Research. 2020;26(9):2124–30.

    Article  CAS  Google Scholar 

  15. Yao J, Strosberg J, Fazio N, Pavel M, Ruszniewski P, Bergsland E, et al. 1308O 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). Annals of Oncology. 2018;29(suppl_8):mdy293. 001.

    Google Scholar 

  16. Zhang P, Lu M, Li J, Shen L. 1309O Efficacy and safety of PD-1 blockade with JS001 in patients with advanced neuroendocrine neoplasms: a non-randomized, open-label, phase Ib trial. Annals of Oncology. 2018;29(suppl_8):mdy293. 002.

    Google Scholar 

  17. Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, et al. 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):2290–6.

    Article  CAS  Google Scholar 

  18. Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, et al. Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clin Cancer Res. 2020;26(17):4454–9.

    Article  CAS  Google Scholar 

  19. Capdevila J, Teule A, Lopez C,. et al. A multi-cohort phase II study of durvalumab plus tremelimumab for the treatment of patients (pts) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic or lung origin: The DUNE trial (GETNE 1601). Annals of Oncology (2020) 31 (suppl_4): S711-S724. 10.1016/annonc/annonc281

  20. Kim C, Liu SV, Subramaniam DS, Torres T, Loda M, Esposito G, et al. Phase I study of the (177)Lu-DOTA(0)-Tyr(3)-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung. J Immunother Cancer. 2020;8(2).

  21. Halperin DM, Liu S, Dasari A, Fogelman DR, Bhosale P, Mahvash A, et al. A phase II trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs). American Society of Clinical Oncology. 2020.

  22. Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. The Lancet Oncology. 2016;17(7):883–95.

    Article  CAS  Google Scholar 

  23. Sequist L, Chiang A, Gilbert J, Gordon M, Conkling P, Thompson D, et al. Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC). Annals of Oncology. 2016;27(suppl_6).

  24. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. New England Journal of Medicine. 2018;379(23):2220–9.

    Article  CAS  Google Scholar 

  25. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. The Lancet. 2019;394(10212):1929–39.

    Article  CAS  Google Scholar 

  26. Sherman S, Rotem O, Zer A, Shochat T, Dudnik E. 1403P - Efficacy of immune check-point inhibitors (ICPi) in large cell neuroendocrine tumours of lung (LCNET). Annals of Oncology. 2019;30:v572–v3.

    Article  Google Scholar 

  27. Fottner C, Apostolidis L, Ferrata M, Krug S, Michl P, Schad A, et al. 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). Journal of Clinical Oncology. 2019;37(15_suppl):4103.

    Article  Google Scholar 

  28. Frumovitz M, Westin SN, Salvo G, Zarifa A, Xu M, Yap TA, et al. Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract. Gynecol Oncol. 2020.

  29. Vijayvergia N, Dasari A, Deng M, Litwin S, Al-Toubah T, Alpaugh RK, et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Br J Cancer. 2020;122(9):1309–14.

    Article  CAS  Google Scholar 

  30. 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). American Society of Clinical Oncology. 2019.

  31. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. New England Journal of Medicine. 2016;374(26):2542–52.

    Article  CAS  Google Scholar 

  32. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. The Lancet Oncology. 2016;17(10):1374–85.

    Article  CAS  Google Scholar 

  33. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncology. 2015:1–14.

  34. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Expert Opinion on Drug Safety. 2015;(ahead-of-print):1–12.

  35. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis. Future Oncology. 2015;(0).

  36. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Immunotherapy. 2015;7(11):1213–27.

    Article  CAS  Google Scholar 

  37. Abdel-Rahman O, Fouad M. Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Therapeutic advances in respiratory disease. 2016.

  38. Abdel-Rahman O, Helbling D, Schmidt J, Petrausch U, Giryes A, Mehrabi A, et al. Treatment-related death in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Clinical oncology (Royal College of Radiologists (Great Britain)). 2016.

  39. Abdel-Rahman O, Fouad M. A network meta-analysis of the risk of immune-related renal toxicity in cancer patients treated with immune checkpoint inhibitors. Immunotherapy. 2016;8(5):665–74.

    Article  CAS  Google Scholar 

  40. Abdel-Rahman O, Helbling D, Schmidt J, Petrausch U, Giryes A, Mehrabi A, et al. Treatment-associated fatigue in cancer patients treated with immune checkpoint inhibitors; a systematic review and meta-analysis. Clin Oncol (R Coll Radiol). 2016;28(10):e127–38.

    Article  CAS  Google Scholar 

  41. Abdel-Rahman O. Nonconventional patterns of benefit of solid tumors treated with PD-(L)1 inhibitors: a systematic review. Immunotherapy. 2017;9(12):995–1004.

    Article  CAS  Google Scholar 

  42. Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, et al. The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104(1):85–93.

    Article  CAS  Google Scholar 

  43. Elvebakken H, Perren A, Scoazec JY, Tang LH, Federspiel B, Klimstra DS, et al. A consensus developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations. Neuroendocrinology. 2020.

Download references

Author information

Authors and Affiliations

  1. Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti 435, 20141, Milan, Italy

    Nicola Fazio

  2. Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada

    Omar Abdel-Rahman

Authors
  1. Nicola Fazio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Omar Abdel-Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicola Fazio.

Ethics declarations

Conflict of Interest

Nicola Fazio has personal financial interests (Advisory board and public speaking: Novartis, Ipsen, Pfizer, Merck Serono, Advanced Accelerator Applications, MSD, Sanofi-Aventis, and Wren Laboratories Europe) and institutional financial interests (clinical trials (P.I., Steering committee): Novartis, Ipsen, Merck Serono, MSD, Pharmacyclics, Incyte, Halozyme, Roche, Astellas, Pfizer, FivePrime, and BeiGene). Omar Abdel-Rahman has no conflicts of interest

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuroendocrine Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fazio, N., Abdel-Rahman, O. Immunotherapy in Neuroendocrine Neoplasms: Where Are We Now?. Curr. Treat. Options in Oncol. 22, 19 (2021). https://doi.org/10.1007/s11864-021-00817-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11864-021-00817-4

Keywords

Search

Navigation