Skip to main content

Advertisement

SpringerLink
Log in

Drug Development in Neuroendocrine Tumors: What Is on the Horizon?

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

Opinion statement

Neuroendocrine neoplasms (NENs) constitute a heterogenous group of malignancies. Translational research into NEN cell biology is the cornerstone for drug development strategies in this field. Somatostatin receptor type 2 (SSTR2) expression is the hallmark of well-differentiated neuroendocrine tumors (NETs). Somatostatin analogs and peptide receptor radionuclide therapy (PRRT) form the basis of anti-SSTR2 treatment onto new combination strategies, antibody-drug conjugates and bispecific antibodies. Classical pathways involved in NET development (PI3K-Akt-mTOR and antiangiogenics) are reviewed but new potential targets for NET treatment will be explored. Epigenetic drugs have shown clinical activity in monotherapy and preclinical combination strategies are more than attractive. Immunotherapy has shown opposite results in different NEN settings. Although the NOTCH pathway has been targeted with disappointing results, new strategies are being developed. Finally, after years of solid preclinical evidence on different genetically engineered oncolytic viruses, clinical trials for refractory NET patients are now ongoing.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References and Recommended Reading

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

  1. Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia. 2017;19(12):991–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocrine Reviews. 2004;25(3):458–511.

    Article  CAS  PubMed  Google Scholar 

  3. • Pavel M, Öberg K, Falconi M, Krenning E, Sundin A, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(5) Article in press. European guidelines for the diagnosis, treatment, and follow-up of NETs. They will provide the basis of the current treatments available in the clinical practice (outside clinical trials) for NET patients.

  4. Herrera-Martínez AD, Hofland J, Hofland LJ, Brabander T, Ferry EFALM, et al. Targeted systemic treatment of neuroendocrine tumors: current options and future perspectives. Drugs. 2019;79:21–42.

    Article  PubMed  CAS  Google Scholar 

  5. Torniai M, Scortichini L, Tronconi F, Rubini C, Morgese F, et al. Systemic treatment for lung carcinoids: from bench to bedside. Clin Trans Med. 2019;8:22.

    Article  Google Scholar 

  6. Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol. 2010;16(24):2963–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, 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. 27(28):4656–63.

  8. Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati D, Ronicke E, 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 (PROMID): results of long-term survival. Neuroendocrinology. 2017;104:26–32.

    Article  CAS  PubMed  Google Scholar 

  9. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, et al. Lanreotide in Metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33.

    Article  PubMed  CAS  Google Scholar 

  10. Caplin ME, Pavel M, Cwikła JB, Phan AT, Raderer M, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocrine-Related Cancer. 2016;23:191–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chan DL, Ferone D, Albertelli M, Pavlakis N, Segelov E, Singh S. Escalated-dose somatostatin analogues for antiproliferative effect in GEPNETS: a systematic review. Endocrine. 2017;57(3):366–75.

    Article  CAS  PubMed  Google Scholar 

  12. Ruszniewski P, Ćwikła J, Lombard-Bohas C, Borbath I, Shah T, et al. Baseline characteristics from CLARINET FORTE: evaluating lanreotide autogel (LAN) 120 mg every 14 days in patients with progressive pancreatic or midgut neuroendocrine tumours during a standard first-line LAN regimen. Ann Oncol. 2019;30(suppl_5):v564–73.

    Google Scholar 

  13. Pavel M, Ćwikła JB, Lombard-Bohas C, Borbath I, Shah T, et al. Efficacy and safety of lanreotide autogel (LAN) 120 mg every 14 days in progressive pancreatic or midgut neuroendocrine tumours (NETs): CLARINET FORTE study results. ESMO 2020 Virtual Congress. Mini Oral Communication.

  14. Lepage C, Phelip JM, Lievre A, Le Malicot K, Tougeron D, et al. Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours (NETs). REMINET: an international double-blind, placebo-controlled randomized phase II. ESMO Virtual Congress 2020. Presented as a Poster.

  15. Cakir M, Dworakowska D, Grossman A. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1–molecular pathways. J Cell Mol Medc. 2010;14:2570–84.

    Article  CAS  Google Scholar 

  16. Johnson ML, Meyer T, Halperin DM, Fojo AT, Cook N, et al. First in human phase 1/2a study of PEN-221 somatostatin analog (SSA)-DM1 conjugate for patients (PTS) with advanced neuroendocrine tumor (NET) or small cell lung cancer (SCLC): phase 1 results. J Clin Oncol. 2018;36(15_suppl):4097.

    Article  Google Scholar 

  17. Si Y, Kim S, Ou J, Lu Y, Ernst P, et al. Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy. Cancer Gene Ther. 2020. https://doi.org/10.1038/s41417-020-0196-5.

  18. El-Rayes B, Pant S, Villalobos V, et al. Preliminary safety, PK/PD, and antitumor activity of XmAb18087, an SSTR2 x CD3 bispecific antibody, in patients with advanced neuroendocrine tumors. Poster presented at: North American Neuroendocrine Tumor Society 2020 Annual Symposium.

  19. • Brabander T, Nonnekens J, Hofland J. The next generation of peptide receptor radionuclide therapy. Endocr Relat Cancer. 2019;26:C7–C11 Review about possible treatment strategies to improve PRRT treatment in NETs from all point of views.

    Article  CAS  PubMed  Google Scholar 

  20. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. NEJM. 2017;376:125–35.

    Article  CAS  PubMed  Google Scholar 

  21. Braat AJ, Bruijnen R, van Rooij R, Braat M, Wessels FJ, et al. Additional holmium-166 radioembolisation after lutetium-177-dotatate in patients with neuroendocrine tumour liver metastases (HEPAR PLuS): a single-centre, single-arm, open-label, phase 2 study. Lancet Oncol. 2020. https://doi.org/10.1016/S1470-2045(20)30027-9.

  22. Hirmas N, Jadaan R, Al-Ibraheem A. Peptide receptor radionuclide therapy and the treatment of gastroentero-pancreatic neuroendocrine tumors: current findings and future perspectives. Nucl Med Mol Imaging. 2018;52(3):190–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yordanova A, Ahrens H, Feldmann G, Brossart P, Gaertner FC, et al. Peptide receptor radionuclide therapy combined with chemotherapy in patients with neuroendocrine tumors. Clin Nucl Med. 2019;44(5):e329–35.

    Article  PubMed  Google Scholar 

  25. Pavlakis N, Ransom DT, Wyld D, Sjoquist KM, Asher R, et al. First results for Australasian Gastrointestinal Trials Group (AGITG) control net study: phase II study of 177Lu-octreotate peptide receptor radionuclide therapy (LuTate PRRT) +/- capecitabine, temozolomide (CAPTEM) for midgut neuroendocrine tumors (mNETs). JCO. 2020;38(4):604.

    Article  Google Scholar 

  26. Jin XF, Auernhammer CJ, Ilhan H, Lindner S, Nölting S, et al. Combination of 5-fluorouracil with epigenetic modifiers induces radiosensitization, somatostatin receptor 2 expression, and radioligand binding in neuroendocrine tumor cells in vitro. J Nucl Med. 2019;60(9):1240–6.

    Article  CAS  PubMed  Google Scholar 

  27. Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355(6330):1152–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, et al. 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):2124–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cullinane C, Waldeck K, Kirby L, Rogers BE, Eu P, et al. Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP. Sci Rep. 2020;10:10196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Waddington CH. The epigenotype. Endeavour. 1942;1:18–20.

    Google Scholar 

  31. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27(5):351–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bates SE. Epigenetic therapies for cancer. N Engl J Med. 2020;383:650–63.

    Article  CAS  PubMed  Google Scholar 

  33. Stalberg P, Westin G, Thirlwell C. Genetics and epigenetics in small intestinal neuroendocrine tumours. J Intern Med. 2016;280:584–94.

    Article  CAS  PubMed  Google Scholar 

  34. Karpathakis ADH, Dibra H, Pipinikas C, Feber A, Morris T, et al. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumour. Clin Cancer Res. 2015;12:250–8.

    Google Scholar 

  35. Scarpa A, Chang DK, Nones K, Corbo V, Patch A, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71.

    Article  CAS  PubMed  Google Scholar 

  36. • Refardt J, Klomp I, van Koetsveld PM, Dogan-Oruc F, de Herder WW, et al. DNA methyltransferase inhibitor hydralazine induces upregulation of somatostatin type 2 receptors in human neuroendocrine tumor cells. Neuroendocrinology. 2020;110:1–312.

    Google Scholar 

  37. • Klomp MJ, Dalm SU, van Koetsveld PM, Dogan-Oruç F, De Jong M, et al. Histone deacetylase inhibitor treatment increases SST2 expression on neuroendocrine tumor cells. Neuroendocrinology. 2020;110:1–312 These two articles are evidence that epigenetic drugs may re-differentiate NETs, re-expressing SST2 receptor.

    Google Scholar 

  38. Lynch JT, Harris WJ, Somervaille TC. LSD1 inhibition: a therapeutic strategy in cancer? Expert Opin Ther Targets. 2012;16(12):1239–49.

    Article  CAS  PubMed  Google Scholar 

  39. Hollebecque A, de Bono JS, Salvagni S, Plummer R, Niccoli P, et al. CC-90011 in patients (Pts) with advanced solid tumors (STs) and relapsed/refractory non-Hodgkin lymphoma (R/R NHL): updated results of a phase I study. Ann Oncol. 2020;31(suppl_1):S8–S10.

    Google Scholar 

  40. Solárová Z, Mojžiš J, Solár P. Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (review). Int J Oncol. 2015;46:907–26.

    PubMed  Google Scholar 

  41. Lundsten S, Spiegelberg D, Raval NR, Nestor M. The radiosensitizer onalespib increases complete remission in 177Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts. Eur J Nucl Med Mol Imaging. 2020;47(4):980–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lines KE, Stevenson M, Filippakopoulos P, Müller S, Lockstone HE. Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors. Oncogenesis. 2017;6:e332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Turner HE, Harris AL, Melmed S, Wass JH. Angiogenesis in endocrine tumors. Endocr Rev. 2003;24:600–32.

    Article  CAS  PubMed  Google Scholar 

  44. Halperin DM, Kulke MH, Yao JC. A tale of two tumors: treating pancreatic and extrapancreatic neuroendocrine tumors. Ann Rev Med. 2015;66:1–16.

    Article  CAS  PubMed  Google Scholar 

  45. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, et al. Sunitinib Malate for the treatment of pancreatic neuroendocrine tumors. NEJM. 2011;364:501–13.

    Article  CAS  PubMed  Google Scholar 

  46. Xu J, Shen L, Bai C, Wang W, Li J, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;S1470-2045(20):30493–9.

    Google Scholar 

  47. Xu J, Shen L, , Zhou Z, Li J, Bai, et al. Efficacy and safety of surufatinib in patients with well-differentiated advanced extrapancreatic neuroendocrine tumors (NETs): results from the randomized phase III study (SANET-ep). Ann Oncol (2019) 30 (suppl_5): v851-v934.

    Google Scholar 

  48. Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, 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  PubMed  PubMed Central  Google Scholar 

  49. Grande E, Capdevila J, Castellano D, Teulé A, Durán I, et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Annals of Oncology. 2015;26:1987–93.

    Article  CAS  PubMed  Google Scholar 

  50. Strosberg JR, Cives M, Hwang J, Weber T, Nickerson M, et al. A phase II study of axitinib in advanced neuroendocrine tumors. Endocr Relat Cancer. 2016;23(5):411–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Capdevila J, Fazio N, Lopez C, Teule A, Valle JW, et al. Final results of the TALENT trial (GETNE1509): a prospective multicohort phase II study of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs). J Clin Oncol. 2019;37(15_suppl):4106.

    Article  Google Scholar 

  52. Chan JA, Faris JE, Murphy JE, Blaszkowsky LS, Kwak EL, 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 

  53. US National Library of Medicine ClinicalTrials.gov. www.clinicaltrials.gov

  54. Grande E, Espinosa P, Serrano R, Jimenez-Fonseca P, Alonso-Gordoa T, et al. RESUNET (GETNE-2016-01): a phase II study to evaluate the efficacy and safety of the rechallenge with sunitinib in G1/G2 pancreatic neuroendocrine tumors (pNET). A Spanish Task Force Group in Neuroendocrine and Endocrine Tumors (GETNE) study. ESMO Virtual Congress 2020. Presented as a Poster.

  55. Grande E, Lopez C, Alonso Gordoa T, Benavent M, Capdevila J, et al. SUNitinib with EVOfosfamide (TH-302) for G1/G2 metastatic pancreatic neuroendocrine tumours (pNETs) naïve for systemic treatment. The SUNEVO phase II trial of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumours (GETNE). Ann Oncol. 2019;30(suppl_5):v564–73.

    Google Scholar 

  56. Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013;123:2502–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lamberti G, Brighi N, Maggio I, Manuzzi L, Peterle C, et al. The role of mTOR in neuroendocrine tumors: future cornerstone of a winning strategy? Int J Mol Sci. 2018;19(3):747.

    Article  PubMed Central  CAS  Google Scholar 

  58. Wulbrand U, Remmert G, Zöfel P, Wied M, Arnold R, et al. mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours. Eur J Clin Invest. 2000;30(8):729–39.

    Article  CAS  PubMed  Google Scholar 

  59. Strosberg JR, Chan JA, Ryan DP, Meyerhardt JA, Fuchs CS, et al. A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2013;20(3):383–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dasari A, Phan A, Gupta S, Rashid A, Yeung SC, et al. Phase I study of the anti-IGF-1R monoclonal antibody, cixutumumab in combination with everolimus and octreotide LAR in advanced low to intermediate grade neuroendocrine tumors. Endocr Relat Cancer. 2015;22(3):431–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, et al. Safety profiles of anti-CTLA-4 and anti- PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473–86.

    Article  CAS  PubMed  Google Scholar 

  62. D’Angelo SP, Russell J, Lebbé C, Chmielowski B, Gambichler T, et al. Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol. 2018;4(9):e180077.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374:2542–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    Article  CAS  PubMed  Google Scholar 

  65. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, 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. Lancet. 2019;394(10212):1929–39.

    Article  CAS  PubMed  Google Scholar 

  66. Maggio I, Manuzzi L, Lamberti G, Ricci AD, Tober N, et al. Landscape and future perspectives of immunotherapy in neuroendocrine neoplasia. Cancers. 2020;12:832.

    Article  CAS  PubMed Central  Google Scholar 

  67. da Silva A, Bowden M, Zhang S, Masugi Y, Thorner AR, et al. Characterization of the neuroendocrine tumor immune microenvironment. Pancreas. 2018;47(9):1123–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Xing J, Ying H, Li J, Gao Y, Sun Z, et al. Immune checkpoint markers in neuroendocrine carcinoma of the digestive system. Front Oncol. 2020;10:132.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yao JC, Strosberg J, Fazio N, Pavel ME, Ruszniewski P, 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(Supplement 8):viii467–78.

    Article  Google Scholar 

  70. Mehnert JM, Bergsland E, O’Neil BH, Santoro A, Schellens JH, 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  PubMed  Google Scholar 

  71. Lu M, Zhang P, Zhang Y, Li Z, Gong J, et al. Efficacy, safety and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ib trial. Clin Cancer Res. 2020;26:2337–45.

    Article  CAS  PubMed  Google Scholar 

  72. Fottner C, Apostolidis L, Ferrata M, Krug S, Michl P, 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). Neuroendocrinology. 2020;110:1–312.

    Google Scholar 

  73. Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, 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;26:2290–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Capdevila J, Teule A, López C, García-Carbonero R, Benavent M, 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). ESMO 2020 Virtual Congress. Presented as Oral Communication.

  75. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, et al. 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):1353–65.

    Article  CAS  PubMed  Google Scholar 

  76. Halperin DM, Liu S, Dasari A, Fogelman DR, Bhosale P, et al. A phase II trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs). J Clin Oncol. 2020;38:619.

    Article  Google Scholar 

  77. Crabtree JS, Singleton CS, Miele L. Notch signaling in neuroendocrine tumors. Front Oncol. 2016;6:94.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wang MM. Notch signaling and Notch signaling modifiers. Int J Biochem Cell Biol. 2011;43(11):1550–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liverani C, Bongiovanni A , Mercatali L , Pieri F , Spadazzi C, et al. The prognostic role of DLL3 expression in high-grade gastroenteropancreatic neuroendocrine neoplasms. ESMO Virtual Congress 2020. Presented as a Poster.

  80. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Morgensztern D, Besse B, Greillier L, Santana-Davila R, Ready N, et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin Cancer Res. 2019;25(23):6958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. https://news.abbvie.com/news/press-releases/abbvie-discontinues-rovalpituzumab-tesirine-rova-t-research-and-development-program.htm

  83. Hipp S, Voynov V, Drobits-Handl B, Giragossian C, Trapani F, et al. A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020.

  84. Cooke K, Estrada J, Zhan J, Werner J, Caenepeel S, et al. Antitumor activity of AMG757, a half-life extended (HLE) bispecific T-cell engager (BiTE®) immune therapy targeting DLL3, in human PDX and orthotopic mouse models of small cell lung cancer (SCLC). Cancer Res. 2020;80(16 Suppl):Abstract nr 4558.

    Article  Google Scholar 

  85. Chen X, Amar N, Zhu Y, Wang C, Xia C, et al. Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth. J Immunother Cancer. 2020;8(1):e000785.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Campos SK, Barry MA. Current advances and future challenges in adenoviral vector biology and targeting. Curr Gene Ther. 2007;7:189–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Waehler R, Russell SJ, Curiel DT. Engineering targeted viral vectors for gene therapy. Nat Rev Genet. 2007;8:573–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Leja L, Yu D, Nilsson B, Gedda L, Zieba A, et al. Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells. Gene Therapy. 2011;18:1052–62.

    Article  CAS  PubMed  Google Scholar 

  89. Seubert CM, Stritzker J, Hess M, Donat U, Sturm JB, et al. Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a b-galactosidase-activatable prodrug seco-analog of duocarmycin SA. Cancer Gene Therapy. 2011;18:42–52.

    Article  CAS  PubMed  Google Scholar 

  90. Puhlmann M, Brown CK, Gnant M, Huang J, Libutti SK, et al. Vaccinia as a vector for tumor-directed gene therapy: biodistribution of a thymidine kinase-deleted mutant. Cancer Gene Therapy. 2000;7:66–73.

    Article  CAS  PubMed  Google Scholar 

  91. Kloker LD, Berchtold S, Smirnow I, Beil J, Krieg A, et al. Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms. BMC Cancer. 2020;20:628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Matsushima H, Kaibori M, Hatta M, Ishizaki M, Nakatake R, et al. Efficacy of a third-generation oncolytic herpes simplex virus in neuroendocrine tumor xenograft models. Oncotarget. 2019;10(67):7132–41.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gastrointestinal and Endocrine Tumor Unit, Medical Oncology Department, Vall Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Pg Vall d’Hebron, 119-129 08035, Barcelona, Spain

    Alejandro Garcia-Alvarez MD, Jorge Hernando Cubero MD, PhD & Jaume Capdevila MD, PhD

Authors
  1. Alejandro Garcia-Alvarez MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge Hernando Cubero MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaume Capdevila MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alejandro Garcia-Alvarez MD.

Ethics declarations

Conflict of Interest

Alejandro Garcia-Alvarez declares that he has no conflict of interest.

Jorge Hernandro Cubero has received compensation for service on speakers' bureaus from Eisai, Ipsen, Novartis, Roche, Pfizer, Angelini Pharma, and Advanced Accelerator Applications.

Jaume Capdevila has received research funding from Eisai, AstraZeneca, Advanced Accelerator Applications, Ipsen, Pfizer, and Novartis; has received compensation from Bayer, Eisai, Advanced Accelerator Applications, Ipsen, Pfizer, Merck Serono, Sanofi, Amgen, and Novartis for service as a consultant/guest lecturer.

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

Garcia-Alvarez, A., Hernando Cubero, J. & Capdevila, J. Drug Development in Neuroendocrine Tumors: What Is on the Horizon?. Curr. Treat. Options in Oncol. 22, 43 (2021). https://doi.org/10.1007/s11864-021-00834-3

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11864-021-00834-3

Keywords

Search

Navigation