Abstract
Patients with metastatic or advanced pancreatic neuroendocrine tumors (NETs) carry
poorer prognoses relative to patients with other NETs due to bulkier and often, more
proliferative baseline disease. Patients with these tumors also possess more approved
treatment options relative to patients with other NETs, making therapeutic sequencing
nuanced. As such, defining optimal therapeutic sequencing and developing more potent
cytoreductive treatments for patients are significant areas of research need in the
field. Herein this review, we discuss the current systemic therapy landscape, our
approach to therapeutic sequencing in the clinic and ongoing studies seeking to define
optimal sequencing of systemic therapies, and novel therapeutics in development, for
patients with pancreatic NETs. We limit the scope of this latter topic to agents with
preclinical or clinical rationale over the last 8 years to provide a contemporary
view of the drug development landscape and focus primarily on new types of peptide
receptor radionuclide therapy, anti-vascular endothelial growth factor receptor tyrosine
kinase inhibitors and anti-vascular endothelial growth receptor tyrosine kinase inhibitor
plus immunotherapy combinations.
Keywords
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References
- Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumors in the united states.JAMA Netw Open. 2021; 4e2124750
- Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the united states.JAMA Oncol. 2017; 3: 1335-1342
- Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment.Chin J Cancer. 2013; 32: 312-324
- Digestive well-differentiated grade 3 neuroendocrine tumors: current management and future directions.Cancers (Basel). 2021; : 13
- Lanreotide in metastatic enteropancreatic neuroendocrine tumors.N Engl J Med. 2014; 371: 1556-1557
- Everolimus for advanced pancreatic neuroendocrine tumors.N Engl J Med. 2011; 364: 514-523
- Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.N Engl J Med. 2011; 364: 501-513
- N.-T., phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors.N Engl J Med. 2017; 376: 125-135
- Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors.Clin Cancer Res. 2017; 23: 4617-4624
- Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Oncol. 2020; 21: 1489-1499
- 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).Journal of Clinical Oncology. 2018; 36 (-4004): 4004
- Chemotherapy in neuroendocrine tumors.Cancers (Basel). 2021; 13
- Comparison of design, eligibility, and outcomes of neuroendocrine neoplasm trials initiated from 2000 to 2009 vs 2010 to 2020.JAMA Netw Open. 2021; 4e2131744
- Medical management of gastroenteropancreatic neuroendocrine tumors.Surg Oncol Clin N Am. 2020; 29: 293-316
- Comparison of the therapeutic response to treatment with a 177Lu-Labeled somatostatin receptor agonist and antagonist in preclinical models.J Nucl Med. 2016; 57: 260-265
- Somatostatin and other Peptide receptors as tools for tumor diagnosis and treatment.Neuroendocrinology. 2004; 80: 51-56
- Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches.Clin Cancer Res. 2013; 19: 2842-2849
- 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: 4656-4663
- Progression-free survival (PFS) with lanreotide autogel/depot (LAN) in enteropancreatic NETs patients: The CLARINET extension study.Journal of Clinical Oncology. 2014; 32 (-4107): 4107
- Tumor response in the CLARINET study of lanreotide depot vs. placebo in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).Journal of Clinical Oncology. 2016; 34 (-434): 434
- Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results.Eur J Cancer. 2021; 157: 403-414
- The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study.Ann Oncol. 2001; 12: 941-945
- Yttrium-90 DOTATOC: first clinical results.Eur J Nucl Med. 1999; 26: 1439-1447
- Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience.Semin Nucl Med. 2002; 32: 110-122
- Long-term efficacy, survival, and safety of.[Clin Cancer Res. 2017; 23: 4617-4624
- Targeted α-Emitter therapy of neuroendocrine tumors.Semin Nucl Med. 2020; 50: 171-176
- (177)Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors.Expert Rev Gastroenterol Hepatol. 2019; 13: 1023-1031
- Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors.Journal of Clinical Oncology. 2021; 39 (-4112): 4112
- Symptomatic and radiological response to 177Lu-DOTATATE for the treatment of functioning pancreatic neuroendocrine tumors.J Clin Endocrinol Metab. 2019; 104: 1336-1344
- Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours.Eur J Nucl Med Mol Imaging. 2014; 41: 925-933
- Afinitor (everolimus) [package insert].Novartis Pharmaceuticals Corporation, East Hanover, NJ2018 (2018)
- Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway.J Clin Oncol. 2010; 28: 245-255
- Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study.J Clin Oncol. 2016; 34: 3906-3913
- Sutent (sunitinib malate) [package insert].Pfizer Labs, New York, NY2011 (2011)
- Molecular basis for sunitinib efficacy and future clinical development.Nat Rev Drug Discov. 2007; 6: 734-745
- New strategies for advanced neuroendocrine tumors in the era of targeted therapy.Clin Cancer Res. 2012; 18: 1830-1836
- In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.Clin Cancer Res. 2003; 9: 327-337
- Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer.J Clin Oncol. 2006; 24: 25-35
- Activity of sunitinib in patients with advanced neuroendocrine tumors.J Clin Oncol. 2008; 26: 3403-3410
- O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors.Clin Cancer Res. 2009; 15: 338-345
- Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas.J Clin Oncol. 2004; 22: 4762-4771
- Temozolomide alone or combined with capecitabine for the treatment of advanced pancreatic neuroendocrine tumor.Neuroendocrinology. 2020; 110: 83-91
- First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas.Cancer. 2011; 117: 268-275
- Efficacy and toxicity analysis of capecitabine and temozolomide in neuroendocrine neoplasms.J Natl Compr Canc Netw. 2021; 20: 29-36
- High risk of myelodysplastic syndrome and acute myeloid leukemia after 177Lu-octreotate PRRT in NET patients heavily pretreated with alkylating chemotherapy.Endocr Relat Cancer. 2016; 23: L17-L23
- Efficacy of FOLFOX in patients with aggressive pancreatic neuroendocrine tumors after prior capecitabine/temozolomide.Oncologist. 2021; 26: 115-119
- Oxaliplatin and 5-Fluorouracil in advanced well-differentiated digestive neuroendocrine tumors: a multicenter national retrospective study from the french group of endocrine tumors.Neuroendocrinology. 2021; 112: 537-546
- A clinical score for neuroendocrine tumor patients under consideration for Lu-177-DOTATATE therapy.Endocr Relat Cancer. 2021; 28: 203-212
- External validation of a clinical score for patients with neuroendocrine tumors under consideration for peptide receptor radionuclide therapy.JAMA Netw Open. 2022; 5e2144170
- Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings.Semin Nucl Med. 2002; 32: 133-140
- Tumor response after [(90)Y-DOTA(0),Tyr(3)]octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size.J Nucl Med. 2001; 42: 1841-1846
- PRRT genomic signature in blood for prediction of (177)Lu-octreotate efficacy.Eur J Nucl Med Mol Imaging. 2018; 45: 1155-1169
- (2)(1)(3)Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience.Eur J Nucl Med Mol Imaging. 2014; 41: 2106-2119
- Targeted alpha-emitter therapy with (212)Pb-DOTAMTATE for the treatment of metastatic SSTR-expressing neuroendocrine tumors: first-in-human, dose-escalation clinical trial.J Nucl Med. 2022; (Online only publication: jnumed.121.263230)
- Broadening horizons with (225)Ac-DOTATATE targeted alpha therapy for gastroenteropancreatic neuroendocrine tumour patients stable or refractory to (177)Lu-DOTATATE PRRT: first clinical experience on the efficacy and safety.Eur J Nucl Med Mol Imaging. 2020; 47: 934-946
- Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors.Ther Adv Med Oncol. 2021; 1317588359211018047
- Phase I trial of well-differentiated neuroendocrine tumors (NETs) with radiolabeled somatostatin antagonist (177)Lu-Satoreotide tetraxetan.Clin Cancer Res. 2019; 25: 6939-6947
- The next generation of peptide receptor radionuclide therapy.Endocr Relat Cancer. 2019; 26: C7-C11
- Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib.Theranostics. 2016; 6: 1821-1832
- Activation of DNA-PK by ionizing radiation is mediated by protein phosphatase 6.PLoS One. 2009; 4: e4395
- ETCTN 10450: a Phase 1 Trial of Peposertib and Lutetium Lu 177 Dotatate in Well- differentiated Somatostatin Receptor- positive Neuroendocrine Tumors.in: NANETS 2021 Symposium Abstracts. 2021
- Ribonucleotide reductase inhibitors: a new look at an old target for radiosensitization.Front Oncol. 2011; 1: 56
- Etctn 10388: A phase I trial of triapine and lutetium Lu 177 dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).Journal of Clinical Oncology. 2020; 38 (-TPS4660): TPS4660
- Surufatinib: first approval.Drugs. 2021; 81: 727-732
- Interim analysis results of surufatinib in U.S. patients with neuroendocrine tumors (NETs).Journal of Clinical Oncology. 2021; 39 (-4114): 4114
- Emerging treatment options for gastroenteropancreatic neuroendocrine tumors.J Clin Med. 2020; 9
Limited H M, BeiGene, surufatinib in combination with tislelizumab in subjects with advanced solid tumors. https://ClinicalTrials.gov/show/NCT04579757: 2021.
- Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET).Journal of Clinical Oncology. 2017; 35 (-228): 228
Testing cabozantinib in patients with advanced pancreatic neuroendocrine and carcinoid tumors. https://ClinicalTrials.gov/show/NCT03375320. 2022
- Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the phase II TALENT trial (GETNE1509).J Clin Oncol. 2021; 39: 2304-2312
- Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study.Clin Cancer Res. 2020; 26: 2124-2130
- Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms.Endocr Relat Cancer. 2021; (ERC-20-0382.R1)
- Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019; 380: 1116-1127
- Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med. 2020; 382: 1894-1905
- A phase II trial of atezolizumab and bevacizumab in patients with advanced, progressive neuroendocrine tumors (NETs).Journal of Clinical Oncology. 2020; 38 (-619): 619
Phase II study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors. https://ClinicalTrials.gov/show/NCT03290079. 2022
- Targeting the somatostatin receptor 2 with the miniaturized drug conjugate, PEN-221: a potent and novel therapeutic for the treatment of small cell lung cancer.Mol Cancer Ther. 2019; 18: 1926-1936
- Discovery of an SSTR2-Targeting maytansinoid conjugate (PEN-221) with potent activity in vitro and in vivo.J Med Chem. 2019; 62: 2708-2719
- 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.Journal of Clinical Oncology. 2018; 36 (-4097): 4097
- The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results.Journal of Clinical Oncology. 2021; 39 (-4110): 4110
- The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types.Cancer. 2020; 126: 3192-3201
A study of XmAb®18087 in subjects with NET and GIST. https://ClinicalTrials.gov/show/NCT03411915. 2022
el-Rayes S P, V Villalobos, A Hendifar, et al. Preliminary safety, PK/PD, and antitumor activity of XmAb18087, an SSTR2 x CD3 bispecific antibody, in patients with advanced neuroendocrine tumors. NANETS 2020 Symposium Abstracts2020.
- Molecular signatures and their clinical utility in pancreatic neuroendocrine tumors.Front Endocrinol (Lausanne). 2020; 11575620
- Belzutifan: first approval.Drugs. 2021; 81: 1921-1927
- Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC).Journal of Clinical Oncology. 2021; 39 (-4555): 4555
Belzutifan/MK-6482 for the treatment of advanced pheochromocytoma/paraganglioma (PPGL) or pancreatic neuroendocrine tumor (pNET) (MK-6482-015). https://ClinicalTrials.gov/show/NCT04924075. 2022
- Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6.Clin Cancer Res. 2012; 18: 4612-4620
- Cyclin-dependent kinases 4/6 inhibitors in neuroendocrine neoplasms: from bench to bedside.Curr Oncol Rep. 2022;
- Cell cycle protein expression in neuroendocrine tumors: ssociation of CDK4/CDK6, CCND1, and phosphorylated retinoblastoma protein with proliferative index.Pancreas. 2017; 46: 1347-1353
- The PALBONET trial: a phase II study of palbociclib in metastatic grade 1 and 2 pancreatic neuroendocrine tumors (GETNE-1407).Oncologist. 2020; 25: 745-e1265
- The novel cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) alone and in dual-targeting approaches demonstrates antitumoral efficacy in neuroendocrine tumors in vitro.Neuroendocrinology. 2018; 106: 58-73
- A pilot study of the cyclin dependent kinases 4, 6 inhibitor ribociclib in patients with foregut neuroendocrine tumors.in: NANETS 2018 Symposium Abstracts. 2018
Article info
Publication history
Published online: August 28, 2022
Accepted:
August 2,
2022
Received in revised form:
July 21,
2022
Received:
April 19,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
