DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

James Yao; Emily Bergsland; Rahul Aggarwal; Ana Aparicio; Himisha Beltran; Judy S Crabtree; Christine L Hann; Toni Ibrahim; Lauren A Byers; Hironobu Sasano; John Umejiego; Marianne Pavel

doi:10.1093/oncolo/oyac161

. 2022 Aug 19;27(11):940–951. doi: 10.1093/oncolo/oyac161

DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

James Yao ^1,^2,^✉, Emily Bergsland ^2,², Rahul Aggarwal ³, Ana Aparicio ⁴, Himisha Beltran ⁵, Judy S Crabtree ⁶, Christine L Hann ⁷, Toni Ibrahim ⁸, Lauren A Byers ⁹, Hironobu Sasano ¹⁰, John Umejiego ¹¹, Marianne Pavel ¹²

PMCID: PMC9632312 PMID: 35983951

Abstract

Introduction

Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis.

Methods

This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs.

Discussion

DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN.

Conclusions

Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

Keywords: neuroendocrine tumors, neuroendocrine carcinoma, DLL3 protein, human, molecular targeted therapy

This review describes neuroendocrine neoplasms (NEN) classification, incidence, pathogenesis, and current management, focusing on delta-like ligand 3 (DLL3) in NEN progression and prognosis. Therapeutic targeting of DLL3 is addressed, and ongoing studies of DLL3-targeting therapies are summarized.

Implications for Practice.

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors, most commonly located in the gastrointestinal tract, lung, bronchi, thymus, and pancreas. NENs are classified as well-differentiated neuroendocrine tumors (NET) or poorly differentiated neuroendocrine carcinomas (NEC). Targeted therapies, chemotherapy, and immune therapies have demonstrated clinical activity in NEN, but further improvements in response duration and survival are needed. Delta-like ligand 3 (DLL3) is overexpressed in many NENs, implicated in tumor progression, and associated with poor clinical outcomes, especially in patients with NEC. DLL3-targeting therapies are currently under clinical investigation, with promising antitumor activity demonstrated to date.

Introduction

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors defined by National Comprehensive Cancer Network criteria as having traits of both endocrine and nervous system tissues, and World Health Organization criteria as being of epithelial or neuronal/neuroectodermal origin.^1,2 NEN can form in almost every organ, but most commonly arise in the gastrointestinal tract, lung, bronchi, thymus, and pancreas.^3-5 They are typically characterized by neurosecretory granules as well as histology and immunoprofiles/protein expression profiles, depending on differentiation.^2,5 NEN are classified as well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC).^2,6 This review describes NEN classification, incidence, pathogenesis, and current management, focusing on delta-like ligand 3 (DLL3) in NEN progression and prognosis. Therapeutic targeting of DLL3 is addressed, and ongoing studies of DLL3-targeting therapies are summarized.

Small-cell lung cancer (SCLC) is a poorly differentiated NEC, which is often discussed separately from other NEN because of differences in epidemiology, genetics, treatment, and prognosis.¹ The disease state section of this review focuses on NEN other than SCLC, providing some discussion of SCLC when included in a given analysis. The sections on DLL3 prevalence and DLL3-targeting therapies specifically include SCLC, as much of the understanding of DLL3 as a therapeutic target originated in SCLC, thus providing context for targeting DLL3 in NEN.

Methods

The authors performed a narrative review of relevant academic English language literature. Levels of evidence were not assessed. The review is limited to published data and data presented at scientific congresses.

Overview of NEN

Classification

NET and NEC are biologically distinct, with different morphological characteristics, risk factors, genetics, and clinical aggressiveness.^2,5 Essential features discriminating NET and NEC are histological tumor differentiation and grade, assessed by mitotic count and Ki-67 proliferation index (Table 1).^1,2,6-15 NET are well differentiated and can range from low- to high-grade tumors. Grade 1 (G1) NET are defined as well-differentiated low-grade tumors; G2 NET are well-differentiated intermediate-grade tumors; G3 NET, most frequently occurring in the pancreas, are well-differentiated high-grade tumors with >20% proliferative activity or high mitotic rate.¹ NEC are poorly differentiated and high-grade by definition. NEC are either large-cell (LCNEC) or small-cell NEC.

Table 1.

Characteristics, classification, and grading criteria for NEN.^1,2,6-15 Adapted from Nagtegaal et al.⁶

	NET, G1	NET, G2	NET, G3^a	NEC, SCNEC	NEC, LCNEC	MiNEN
Grade	Low	Intermediate	High	High^b	High^b	Variable^c
Mitotic rate,^d mitoses/2 mm²	<2	2-20	>20	>20	>20	Variable^c
Ki-67 index,^e %	<3	3-20	>20	>20	>20	Variable^c
Differentiation	Well differentiated	Well differentiated	Well differentiated	Poorly differentiated	Poorly differentiated	Well or poorly differentiated^c
Additional characteristics	Produce secretory granules with high levels of neuroendocrine markers, and are characterized by well-developed “organoid” arrangements or neuroendocrine shape with nesting, trabecular, or gyriform/serpentine growth pattern			Characterized by a sheetlike proliferation pattern, with cells that have irregular nuclei, high mitotic features, fewer cytoplasmic secretory granules, and low levels of neuroendocrine markers		Mixed neuroendocrine and non-neuroendocrine histology
Commonly associated mutations	MEN1, DAXX, PTEN, and ATRX, and mTOR family member signaling pathway mutations are observed in pancreatic NETs; NOTCH1 is absent or poorly expressed Some sporadic pancreatic NETs have been shown to harbor germline mutations in the DNA repair genes MUTYH, CHEK2, and BRCA2			TP53 or RB1 mutations May also have KRAS and SMAD4 mutations BRAF mutations in colorectal NEC		NOTCH1 and Hes1 expression is reduced or absent in the neuroendocrine cells, but both expressed in the adenomatous component The most frequent alterations occurred in TP53, RB1, PTEN, APC, PIK3CA, KRAS, BRAF, and MYC

Open in a new tab

Only includes gastrointestinal and pancreatic NETs.

Poorly differentiated NEC are not formally graded, but are considered high-grade by definition.

In most MiNENs, both the neuroendocrine and non-neuroendocrine components are poorly differentiated, and the neuroendocrine component has proliferation indices in the same range as other NECs; this MiNEN category allows for one or both components to be well differentiated; when feasible, each component should therefore be graded separately.

Mitotic rates are to be expressed as the number of mitoses/2 mm² as determined by counting in 50 fields of 0.2 mm² (i.e., in a total area of 10 mm²).

The Ki-67 proliferation index value is determined by counting at least 500 cells in the regions of highest labelling (hot-spots), which are identified at scanning magnification; the final grade is based on whichever of the 2 proliferation indexes places the neoplasm in the higher-grade category.

Abbreviations: DLL3, delta-like ligand 3; LCNEC, large-cell neuroendocrine carcinoma; MiNEN, mixed neuroendocrine–non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; SCNEC, small-cell neuroendocrine carcinoma.

Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN) also occur, having an aggressive course, with the non-neuroendocrine component frequently displaying as an adenocarcinoma or squamous cell carcinoma.^7,9 In most MiNEN, the neuroendocrine and non-neuroendocrine components are poorly differentiated; the neuroendocrine component proliferates at rates similar to other NEC.^1,6

Treatment-emergent NEN describes those non-neuroendocrine cancers, such as prostate and lung cancers, that develop neuroendocrine features following treatment.² NEN are rarely present at initial diagnosis, but targeted therapy may be associated with neuroendocrine transformation.^16-18 Treatment-emergent neuroendocrine prostate cancers (NEPC) are most similar morphologically and genomically to poorly differentiated NEC and are typically characterized by small cells with prominent nuclei and rapid proliferation (small-cell carcinoma).^17,19,20 The limited cytoplasm contains eosinophilic granules, hyperchromatic nucleus, and salt-and-pepper chromatin.^17,21 Mixed histologies also can be observed.

Incidence

The 2012 US incidence of neuroendocrine tumors was estimated at 6.98 cases/100 000 people based on an analysis of data from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry.³ Common sites of NET vary according to race or ethnic group.^4,22 Based on SEER data, Asian/Pacific Island and American Indian/Alaskan Native patients had a lower incidence of NET than White patients; African American patients had a higher incidence across all sites.⁴ Similarly, age-adjusted incidence rates of NET, particularly small intestinal and rectal, were significantly higher in the SEER African American population than in the SEER/Norwegian Registry of Cancer White population.²² Based on SEER data, Asian/Pacific Island and American Indian/Alaskan Native patients had a lower incidence of NEC than White and African American patients.

NEN most commonly arises from gastroenteropancreatic (GEP) structures. A SEER study of GEP NECs found that 38% were in the colon, rectum, or anus, while 23% started in the pancreas. A SEER study of GEP NETs found the rectum to be the most common primary site followed by the small intestine and pancreas, while studies from Asia and Europe found different rank orders.²³

NEN are experienced by men and women at similar rates.²⁴ However, primary NEN locations vary significantly by sex, with females more likely to have primary tumors in the lung, stomach, appendix, or cecum and males in the thymus, duodenum, pancreas, jejunum/ileum, or rectum.⁴

Pathogenesis

Most NEN arise sporadically, typically as unifocal tumors, but 5-30% have an inherited component and are typically multifocal.^1,25,26 NET and NEC can be distinguished by the genomic landscape in addition to histological features. Mutations associated with >7% of pancreatic NET include MEN1, DAXX, ATRX, PTEN, and genes in the mTOR signaling pathway.^2,27 Clinically sporadic pancreatic NET have also been shown to be associated with germline mutations in DNA repair genes MUTYH, CHEK2, and BRCA2.^11,12,14 Recurrent mutations for well-differentiated NETs of other sites have not been well defined, although significant enrichments in APC, TP53, KRAS, or BRAF in NEC compared to G3 NET have been suggested as potential classifiers.²⁸ Large-scale chromosomal instability is common, with chromatin-remodeling genes and subunits of the SWI/SNF complex mutated in 40% and >20% of pulmonary NETs, respectively.²⁹ Specific patterns of chromosomal gain and loss appear to have independent prognostic values in NET subtypes.³⁰ Mutations associated with NEC include TP53 or RB1 mutations, with KRAS and SMAD4 mutations also identified.^2,6,11BRAF mutations have been identified in colorectal NEN.¹⁵ In gastroenteropancreatic NEC and SCLC, molecular subtypes based on differential expression of ASCL1, NEUROD1, POU2F3, and other genes have been described.^31-33 De novo neuroendocrine bladder cancers are strongly associated with mutations characteristic of neuroendocrine or small-cell cancers, such as SOX2, EZH2, and RB/p53 pathway mutations.³⁴

In addition to the expression of NEN-associated markers, treatment-emergent NEPC is associated with decreased androgen receptor and/or prostate-specific antigen (PSA) expression.^16,17,21,35 Transformed NEPC shares genomic features with prostate adenocarcinoma. RB1 and TP53 mutations are associated with the risk of transformation in prostate cancers and in a unique subset of EGFR-mutant lung cancers, with attenuated androgen receptor signaling through a reduction in androgen receptor splice variant 7 in castration-resistant NEPC.^36,37 Preliminary evidence suggests lower rates of TMPRES-ERG gene fusions in NEPC than prostate adenocarcinoma.³⁷ Mutations and/or copy number loss in DNA repair pathway genes were almost exclusive to treatment-emergent NEPC versus non–treatment-emergent tumors.¹⁶ Transformation of metastatic castration-resistant prostate cancer (CRPC) to treatment-emergent small-cell NEPC was associated with RB1 inactivation.³⁸

Evolution and Prognosis

NET can evolve from G1 to G3 and eventually toward poorly differentiated NEC.^39-41 Prognosis in patients with NEN varies by tumor type, stage and grade, and age at diagnosis. Generally, a worse prognosis is associated with tumors originating in the lung; those with liver, brain, or bone metastasis; higher grade/stage of tumor; and older age at diagnosis.^3,42-44 Gastroenteropancreatic NET and NEC have differences in terms of prognosis; patients with gastroenteropancreatic NEC commonly develop distant metastasis, are characterized by rapid tumor growth, and have lower survival than patients with gastroenteropancreatic NET.⁴⁵

Treatment-emergent NEC is associated with shorter survival and limited response to therapies.^16,18 Treatment-emergent NEPC was associated with shorter median overall survival (OS) and progression-free survival (PFS) than mixed histology disease³⁵ or metastatic CRPC.²¹

Current Management

Recommended treatments for NEN vary by subtype, stage/differentiation, and biologic characteristics.^1,42,46 Herein, systemic therapies for advanced disease are described.

Somatostatin analogues have been used for symptomatic management of NETs^47,48 and their antiproliferative effects.^46,49,50 Octreotide and lanreotide, targeting somatostatin receptors (SSTR) 2 and 5, prolonged time to tumor progression or PFS in patients with well-differentiated midgut, hindgut, pancreatic, and G1/2 enteropancreatic NETs^49,50; however, OS was not improved in long-term trials.^50,51 In addition, lanreotide prolonged PFS and objective response rate (ORR) in patients with advanced bronchopulmonary NET.⁵² The radiolabeled somatostatin analog, lutetium ¹⁷⁷Lu dotatate (LUTATHERA), is approved for SSTR-positive gastroenteropancreatic NETs.⁵³¹⁷⁷Lu dotatate plus standard-dose octreotide improved ORR (18%) and PFS compared to high-dose long-acting octreotide in patients with advanced midgut NETs after progression on somatostatin analogues, but not OS.^54,55 Low or weak SSTR expression in many NEC⁵⁶ and transient responses in SSTR-positive tumors could present challenges for ¹⁷⁷Lu dotatate. The multi-tyrosine kinase inhibitor (TKI) sunitinib targets VEGFR 1-3 and is approved in patients with advanced, well-differentiated pancreatic NETs, providing improved PFS and an ORR of 9%.^57,58 A more recent TKI, surufatinib, was associated with improved PFS in extrapancreatic and pancreatic NETs.^57,59-62

The PI3K/Akt/mTOR pathway plays a critical role in NEN pathogenesis, and clinical trials of inhibitors that target this signaling axis support the promise of this approach.⁶³ Everolimus is an approved therapy in adults with progressive gastrointestinal, pancreatic, and lung NETs, based on RADIANT-3 and -4 trials demonstrating PFS prolongation.^64-66 In RADIANT-2, everolimus plus octreotide improved median PFS, narrowly missing statistical significance versus placebo plus octreotide.^67,68 Currently, temozolomide-based chemotherapy and streptozotocin/5-FU are among the most well-established therapies for pancreatic well-differentiated NET and are associated with higher ORR than targeted agents.^69,70 Platinum-based chemotherapy is standard-of-care for poorly differentiated NEC, but second- and third-line treatment options are limited and generally associated with short duration of response.^51,71 Second-line options typically include the reintroduction of platinum chemotherapy and etoposide, irinotecan-based treatment (FOLFIRI),⁷² and oxaliplatin-based treatments (FOLFOX).⁷³ The efficacy of second-line regimens is variable in G3 NET,^40,74 although functional imaging and timing of G3 NET diagnosis may aid in treatment selection.⁴¹ FOLFOX has shown activity in poorly differentiated G3 NEC after cisplatinum-based chemotherapy.⁷³ Platinum-based therapy provided a better response in patients with NEC than in those with G3 NET; however, the duration of PFS (~5 months) and OS (~9 months) in NEC remained poor.^71,75

Nivolumab in combination with ipilimumab may be considered in patients with progressive G3 NET and NEC,¹ with response rates up to 31-44% among patients with high-grade NEN,^76,77 and 33% in patients with atypical bronchial carcinoid.⁷⁶ In contrast, objective response was 0% in low-/intermediate-grade non-pancreatic NEN tumors.⁷⁷ In high-grade NEC independent of the primary organ site, objective response was reported in 5/19 (26%) patients, with a clinical benefit rate of 32%.⁷⁸ More recently, lower response rates were observed in a larger study in gastroenteropancreatic NEC and lung LCNEC (8 weeks: 14.9%).⁷⁹ It remains unclear which patients benefit from immunotherapy.

Despite some improvement in outcomes, an unmet need exists for novel therapies with increased response durability and survival, particularly in highly proliferating G3 NEN with poor prognosis.

DLL3 Signaling in NEN Tumorigenesis

Tumorigenesis of Notch1, DLL3 in NEN

The Notch pathway is a highly conserved cell signaling pathway that is implicated in malignant transformation, cell proliferation, cycle arrest, and apoptosis, epithelial to mesenchymal transition, and suppression of neuroendocrine differentiation.⁸⁰ The Notch signaling pathway is initiated by the binding of one of five ligands (Jagged 1 [Jag 1], Jag 2, DLL1, DLL3, DLL4) with one of four receptors (Notch 1-4).^80-82 The DLL family of proteins interact with EGF repeats on Notch receptors on cell membranes, triggering Notch signaling.^11,83 In canonical Notch signaling, ligand binding results in the intracellular cleavage of the receptor by metalloproteases, and the Notch intracellular domain then translocates into the nucleus and modulates transcription of Notch-responsive genes.⁸² Notch signaling can be oncogenic or tumor suppressive depending on the cellular context. DLL1 has a tumor-suppressive role in lung cancer and is poorly expressed in the bone marrow of patients with lung cancer. In contrast, DLL1 has an oncogenic role in breast cancer, and its overexpression is associated with a poorer prognosis. DLL4 has an oncogenic role in a range of cancers.^11,83 DLL3 is a noncanonical inhibitory ligand of the Notch receptor that is involved in NEC/NET tumorigenesis.⁸⁰ DLL3 is thought to inhibit Notch signaling in cis; it does not bind or activate Notch receptors when presented in trans.⁸⁴ In normal tissues, DLL3 is generally expressed at low levels (if at all) and confined to the cytoplasm.^85-88 It regulates Notch signaling by preventing the localization of Notch receptors to the cell surface and redirecting them to the endosomes for degradation.⁸⁵

DLL3 and Notch in Development of NEN

DLL3 expression is regulated by achaete-scute complex homolog 1 (ASCL1),⁸³ a transcription factor that dictates neuroendocrine cell fate and whose expression correlates with tumor-initiating cell capacity.⁸⁹ Upregulation of ASCL1 in RB1-mutated high-grade pulmonary NEC (SCLC and LCNEC) was associated with DLL3 overexpression compared with normal tissues. ASCL1 expression in SCLC is associated with DLL3 but negatively associated with Notch expression.⁹⁰ DLL3 is expressed on the surface of tumor cells, in addition to having cytoplasmic localization.^86-88 By modulating Notch1, DLL3 promotes migration and invasion in SCLC.⁹¹ Conversely, Notch pathway activation was associated with low neuroendocrine differentiation and increased intrinsic tumor immunity in SCLC cells.⁹² Both ASCL1 and DLL3 are highly expressed in NEPC. These were among the most differentially expressed Notch signaling genes in NEPC cells compared with adenocarcinoma, localized prostate adenocarcinoma, or benign cells.⁹³ Additionally, upregulated DLL3 expression in patients with gastrointestinal or bladder/urinary tract NECs was strongly associated with ASCL1 expression.⁹⁴ Notch2 and DLL3 were upregulated in patients with invasive versus non-invasive growth hormone–producing pituitary adenoma (P < .05).⁹⁵

DLL3 and Inflammatory Biomarkers in NEN

The relationship between DLL3 expression and tumor immune environment may be complex. In consecutive surgically resected lung NEN, neoplasms with high DLL3 expression were often high-grade and more often displayed a moderate-to-severe inflammatory infiltrate than their low-expressing counterparts (65.6% vs. 27.7%).⁹⁷ This inflamed state may suggest that T-cell-based therapies could have improved efficacy in these tumors. On the other hand, studies in SCLC found that DLL3 levels varied between transcriptional subtypes and were lowest in a subtype characterized by expression of numerous immune checkpoints and human leukocyte antigens, designated the SCLC-inflamed subtype (SCLC-I).^32,33 The authors found that this inflamed subtype was associated with better responses to immune checkpoint blockade (ICB), raising the question of whether the patient populations benefiting from ICB and DLL3-targeted therapies will be non-overlapping. A gene expression analysis in neuroendocrine bladder cancer (NEBC) found DLL3 expression to correlate with neuronal differentiation genes and high response rates in patients treated with atezolizumab.³⁴ Surprisingly, immune pathway gene expression signatures normally enriched in tumors sensitive to immune checkpoint blockade were suppressed in these NEBCs. In total, these examples in differing neuroendocrine tumors highlight the need for further study of the immune system in DLL3-positive NEN. Future studies will be needed to determine if DLL3 expression correlates with expression of inflammatory biomarkers, if DLL3 has a role in immune infiltration into NENs, and whether DLL3 expression is prognostic for ICB response.

DLL3 Expression in NEN

Across nonneoplastic tissues, DLL3 expression is generally absent or low and confined to the cytoplasm.^86,96 Numerous studies have established DLL3 mRNA and protein expression as features of NEN across several anatomic sites. DLL3 is particularly highly expressed in high-grade NETs and NECs, including on the tumor cell surface (described below). Representative prevalence of DLL3 by immunohistochemical (IHC) analysis according to NEN type and site is shown in Fig. 1^89,93,97-109; representative DLL3 staining with lung NEN and NEPC as examples is shown in Fig. 2.^97,104

Figure 1. — Representative DLL3 prevalence (ie, >1% DLL3-expressing cells) by immunohistochemistry in NEN tumors.^89,93,97-109

*Prevalence of high DLL3 expression (ie, ≥50% of DLL3-expressing cells). ^†Strongly positive for DLL3.

Abbreviations: Adeno, adenocarcinoma; CRPC, castration-resistant prostate cancer; DLL3, delta-like ligand 3; LCNEC, large-cell neuroendocrine cancer; NEPC, neuroendocrine prostate cancer; NEN, neuroendocrine neoplasms.

Figure 2. — DLL3 immunohistochemical staining by the site of origin, including (**A-D**) Lung NET (reproduced with permission from Drs Ali, Di Stefano, Poma, Ricci, Proietti, Davini, Lucchi, Melfi, and Fontanini from their original publication in *Front Oncol*⁹⁷), and (**E-F**) NEPC. Representative images showing variable percentages of DLL3 immunohistochemical staining in lung NET: (A) typical carcinoid DLL3 negative; (B) a case of atypical carcinoid showing combined cytoplasmic and membranous staining with moderate intensity; (C) Large-cell NEC with strong and diffuse DLL3 staining; (D) high (>50% positive tumor cells) immunohistochemical expression level of DLL3 in a small-cell lung carcinoma specimen (magnification, ×20) using rabbit anti-DLL3 antibody (clone SP347; Ventana Medical Systems, Inc. Tucson, AZ, USA); (E) adenocarcinoma with neuroendocrine component (H-score of 65, 80% positive cells) and (F) NEPC (H-score of 150, 90% positive cells) using rabbit anti-DLL3 antibody (clone SP347).^97,104

Abbreviations: DLL3, delta-like ligand 3; NEC, neuroendocrine carcinoma; NEPC, neuroendocrine prostate cancer; NET, neuroendocrine tumor.

DLL3 protein expression by IHC analysis is most consistently defined as negative (<1% positive tumor cells), positive (>1%), low expressing (<50%), or high expressing (>50%).^{97,98,101,102,110-112} H scores (range 0-300), combining the percentage of DLL3-expressing cells and signal intensity, quantify DLL3 expression.^93,101 However, variability in quantification between studies is likely partially due to the use of different assays or cutoffs. In addition to tissue-based detection methods, blood-based biomarkers are being developed, such as specific neuroendocrine-related transcripts or circulating tumor cells, which could enable earlier and easier identification of patients most likely to respond to targeted therapies.^93,113-115

Prevalence in NET

High DLL3 expression is frequently observed in high-grade NEN and less frequently in low-grade, well-differentiated NET.⁹⁷ Of 155 patients with lung NET, high DLL3 was observed in 12.2% of typical and 24.4% of atypical carcinoids (ie, low-grade tumors).⁹⁷ In 47 patients with gastroenteropancreatic NENs, DLL3 was detected in 76.9% of NECs, whereas DLL3 was absent in the 5 patients with G3 NET.¹⁰²

Prevalence in NEC

Pulmonary NEC and SCLC

DLL3 expression has been investigated extensively in SCLC. High DLL3 protein expression with localization to the cytoplasm and/or membrane was demonstrated by IHC analysis in patients with SCLC.⁹⁶ Others reported DLL3 staining primarily in the Golgi apparatus and plasma membrane.¹¹¹ High DLL3 expression was observed in the majority of patients with extensive-stage SCLC.^90,116 Chinese patients with SCLC also had significantly higher DLL3 expression in SCLC tissue compared with matched para-noncancerous tissues.¹¹⁷ Analyses from clinical trial populations demonstrate that DLL3 is expressed in >75% of SCLC.^110,118,119

LCNEC is associated with high DLL3 expression.¹²⁰ In patients with LCNEC, 26/70 (37.1%) were DLL3 positive. The disease was stage I in 15 and 26 DLL3-positive and negative patients, respectively; stage II in 4 and 11; and stage III in 7 and 7 patients.¹⁰⁹ By IHC analysis, DLL3 expression was observed in 82% of 45 patients with SCLC, LCNEC, or neuroendocrine carcinoma with mixed histology.⁹⁹ A high percentage (75%) of stage IV LCNEC shows DLL3 expression, with the majority being cytoplasmic.⁹⁸ Similarly, IHC analysis of 73 patients revealed high DLL3 expression in 54% of patients with LCNEC and 75% with SCLC.⁹⁷

NEPC

DLL3 is expressed in NEPC.^93,104 DLL3 was expressed in most patients with castration-resistant NEPC (n = 36/47 [76.6%]), but only a subset of those with CRPC adenocarcinoma (n = 7/56 [12.5%]).⁹³ Another study using 21 NEPC tumor samples reported 16 (76%) were DLL3-positive.¹⁰⁴

Other NEC

DLL3 expression was demonstrated in gastroenteropancreatic, bladder, and cervical NEN.^34,102,103 In a retrospective study of 47 patients, DLL3 was expressed on 76.9% of poorly differentiated gastroenteropancreatic NEC; DLL3 expression correlated with RB1 loss (P < .001), a negative Ga-PET/CT scan (P = .001), and an unfavorable clinical outcome.¹⁰²

In transcriptomic and protein analyses of 63 patients with small-cell bladder cancer, 79% had increased small-cell component (>50%), and DLL3 and CD56 protein expression (>1% of tumor cells) was 68% and 81%, respectively, in 53 patients with available samples.¹⁰³ Similarly, samples from patients with neuroendocrine bladder cancer showed strong enrichment with biomarkers characteristic of neuroendocrine or small-cell malignancies, including DLL3.³⁴ In patients with NEC of the cervix, DLL3 expression was found in 81% and was inversely correlated or mutually exclusive with other commonly observed mutations.¹⁰⁵ DLL3 expression was upregulated in 49% of patients with extra-pulmonary NEC (gastrointestinal tract, n = 4; bladder, n = 7).⁹⁴ Almost all patients with Merkel cell carcinoma (MCC; ~90%) had DLL3 expression, with over half having ≥50% tumor cells positive for DLL3 expression.^100,101

DLL3 overexpression was also observed in patients with growth hormone−producing pituitary adenoma, with DLL3 more highly expressed in invasive versus non-invasive tumors.⁹⁵ Similarly, in medullary thyroid carcinoma, DLL3 expression correlated with stromal desmoplasia and lymph node metastases, and may indicate aggressive disease.¹⁰⁸ In DLL3-high tumors, protein distribution was primarily membranous; localization in DLL3-low tumors was primarily cytoplasmic.

Clinical Implications of DLL3 in NEN

High DLL3 expression is primarily associated with various NEC and extensive-/late-stage disease and is negatively correlated with survival in most studies.^{102,111,112,116,120} Recent analysis of 155 samples of lung NENs found high DLL3 expression was more common in patients who smoked (current/former) and was associated with peripheral tumors.⁹⁷ High DLL3 expression was associated with lower OS (P = .001) and disease-free survival (DFS; P < .01). DLL3 expression correlated with other features associated with high-grade NEC (ie, high mitosis number, Ki-67 index, and necrosis). In 76 patients with growth hormone−producing pituitary adenoma, low DLL3 expression was associated with significantly longer DFS compared with high DLL3 expression (P = .027).⁹⁵ In patients with small-cell bladder cancer, low protein expression of both CD56 (≤30%) and DLL3 (≤10%) was associated with a longer median OS (103.4 vs. 18.4 months, P = .01) and PFS (92.2 vs. 11.4 months, P = .02) relative to patients with high expression of either biomarker.¹⁰³ In contrast, multivariate analysis in a preliminary study in archival lung NET (SCLC, n = 22; LCNEC, n = 6) found low ASCL1 and DLL3 expression presented high risk of death (OR=3.79; P = .05).¹²¹

However, DLL3 expression has not always been reported as a prognostic indicator.¹¹¹ In patients with SCLC, there was no difference in PFS (242.0 vs. 165.0 days, P = .900) or OS (160.0 vs. 250.0 days, P = .975) according to DLL3 expression.¹¹⁶ Similarly, in a retrospective study of samples from 43 Chinese patients with SCLC, DLL3 expression was not associated with reduced DFS or OS.¹¹⁷ In addition, analysis of 45 high-grade lung NET did not reveal any correlation between DLL3 expression and OS.⁹⁹

Current therapies have a limited duration of response in G3 NET or NEC. Among patients with DLL3-positive surgically resected LCNEC, no difference was found in 5-year OS and relapse-free survival (RFS) between patients treated with versus without adjuvant chemotherapy (5-year OS, 58.3% vs. 35.7%, P = .36; 5-year RFS, 41.7% vs. 35.7%, P = .74). In contrast, in those with DLL3-negative tumors, a significantly greater 5-year OS and RFS was observed for patients treated with versus without adjuvant chemotherapy (5-year OS, 90.0% vs. 26.9%, P < .01; 5-year RFS, 80.0% vs. 21.7%, P < .01).¹⁰⁹

DLL3-Targeting Therapies

Several different DLL3-targeting modalities are being pursued, including antibody-drug conjugates (ADC), T-cell engagers, and chimeric antigen receptor (CAR) T cells. Preclinical and clinical experience with some of these agents is summarized here.

Despite its development being terminated, Rova-T, an ADC consisting of a DLL3-targeting monoclonal antibody, cathepsin-cleavable linker, and pyrrolobenzodiazepine (PBD) warhead, demonstrated the potential of targeting DLL3.⁸⁶ Preclinical efficacy of Rova-T in combination with the mTOR inhibitor everolimus was demonstrated in pancreatic and bronchial NEN cell lines.¹²² The first-in-human clinical trial of Rova-T in recurrent SCLC found an overall ORR of 18% in evaluable patients and 38% in patients with high DLL3 expression despite often severe side effects attributable to the PBD warhead.¹¹⁰ However, in the phase II TRINITY study, Rova-T did not demonstrate differential benefits in DLL3-positive disease versus the overall population.¹¹⁹

A phase I/II study of Rova-T was conducted in 101 patients with NEN (pulmonary and extrapulmonary LCNEC, n = 13; high-grade gastroenteropancreatic NEC, n = 36; NEPC, n = 21; pooled other NEC/NET, n = 31) and 99 patients with other solid tumors (melanoma, n = 20; medullary thyroid cancer, n = 13; glioblastoma, n = 23; other solid tumors, n = 43). Overall, confirmed responses were reported for 10% of patients treated at 0.3 mg/kg, including 13% with NEC/NET; the median PFS and OS were 4.1 (95% CI, 2.8-4.8) and 7.1 (95% CI, 5.6-9.7) months, respectively. Median PFS and OS were 4.3 (95% CI, 2.7-6.1) and 7.4 (95% CI, 5.6-13.1) months in patients with high DLL3 expression, and 3.3 (95% CI, 2.4-4.8) and 7.1 (95% CI, 4.3-9.9) months among patients with low DLL3 expression.¹²³ Similarly, treatment with Rova-T did not provide benefit compared with topotecan in the second-line setting for SCLC or as maintenance after induction etoposide/platinum in the first-line setting.^124,125

Another DLL3-targeting ADC, SC-002, was designed to reduce the toxicity observed with Rova-T. In a phase Ia/Ib study in 35 patients with relapsed and/or refractory SCLC or LCNEC, 5 patients (14%) achieved a partial response as the best overall response; however, the toxicity profile of SC-002 prevented further development.¹²⁶

The toxicities of Rova-T and SC-002 were primarily attributed to the cytotoxic warhead, suggesting that DLL3 remained a compelling target. Indeed, the DLL3-targeting bispecific T-cell engager (BiTE) molecule tarlatamab (AMG 757) has shown promising clinical activity, and the DLL3-targeting T-cell–engaging agents BI 764532 and HPN328 are under clinical investigation (Table 2).

Table 2.

Select ongoing clinical trials of DLL3-targeting therapies

Treatment	Study ID	Tumor type	Target enrollment, n	Phase (status)
Tarlatamab	NCT03319940	SCLC	382	Phase I (recruiting)
	NCT04702737	NEPC	60	Phase I (recruiting)
	NCT04885998	SCLC	50	Phase I (recruiting)
	NCT05060016	SCLC	160	Phase II (recruiting)
BI 764532	NCT04429087	SCLC and other NEN	110	Phase I (recruiting)
HPN328	NCT04471727	SCLC and other high-grade NET	57	Phase I/II (recruiting)

Open in a new tab

NET, neuroendocrine tumor; NEPC, neuroendocrine prostate cancer; SCLC, small-cell lung cancer.

Tarlatamab engages and redirects T cells to kill DLL3-expressing SCLC and other NET cells in vitro,¹²⁷ and induces antitumor activity in patient-derived xenograft and orthotopic NET mouse models in vivo.⁸⁸ In a phase I SCLC study, tarlatamab showed preliminary antitumor activity with confirmed partial responses in 20% of patients, with a median response duration of 8.7 months.¹²⁸ Additional ongoing studies of tarlatamab in SCLC include a phase II study in third-line and beyond patients (NCT05060016) and a phase I study in combination with a PD-1 inhibitor (NCT04885998). Tarlatamab is also being evaluated in a phase I study of NEPC patients.¹⁰⁴

BI 764532 is a DLL3-targeting T-cell–engaging bispecific antibody shown to selectively bind DLL3 on tumor cells and CD3 on T cells, resulting in T-cell activation and directed lysis of SCLC cells in vitro.¹²⁹ Treatment with BI 764532 resulted in infiltration of T cells into tumor tissue and tumor regression in xenograft models. BI 764532 is being studied in phase I in patients with DLL3-expressing SCLC, LCNEC, or other NEC or small-cell carcinoma of any other origin.¹³⁰ HPN328 is a tri-specific T-cell–activating construct that consists of 3 binding domains, namely, CD3 on T cells, DLL3 on tumor cells, and human serum albumin to extend half-life.¹³¹ HPN328 mediated T-cell cytotoxicity against target cells in a dose- and DLL3-dependent manner. A phase I/II study in patients with DLL3-expressing SCLC or other high-grade NETs who have failed standard available therapy is currently recruiting patients.¹³² CAR T cells targeting DLL3, including AMG 119 (NCT03392064), are also in clinical development.

Conclusions

NEN are a heterogeneous group of tumors most commonly located in the gastrointestinal tract, lung, bronchi, thymus, and pancreas. They are classified based on histology and grading as well-differentiated NET or poorly differentiated NEC. Though targeted therapies, chemotherapy, and, to a limited extent, immunotherapies confer some clinical benefit to patients with NEN, a need remains to identify new treatments associated with more sustained responses and improved survival particularly for high-grade (G3) NET and NEC. The recognition that DLL3 is enriched in high-grade NENs and associated with worse clinical outcomes opens these challenging tumors up to the promise of DLL3-targeting agents, some of which have already demonstrated clinical antitumor activity.

Acknowledgments

The authors thank Miranda Tradewell, Erin P. O’Keefe, Lisa Denny, Lee Hohaia (ICON, Blue Bell, PA), and Eugene Gillespie (Amgen Inc.), whose work was funded by Amgen Inc., for medical writing assistance in the preparation of this manuscript.

Contributor Information

James Yao, Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Emily Bergsland, Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Rahul Aggarwal, Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Ana Aparicio, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Himisha Beltran, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Judy S Crabtree, Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Christine L Hann, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Toni Ibrahim, Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCSS Istituto Ortopedico Rizzoli, Bologna, Italy.

Lauren A Byers, Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.

Hironobu Sasano, Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

John Umejiego, Amgen Inc., Thousand Oaks, CA, USA.

Marianne Pavel, Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Funding

This study was sponsored and funded by Amgen Inc.

Conflict of Interest

James Yao: Hutchmed, Ipsen, Amgen, Chiasm (C/A); Emily Bergsland: Amgen, RayzeBio, Hutchmed, Advanced Accelerator Applications (C/A [unpaid]), Merck (RF [institutional]); Rahul Aggarwal: Clovis Oncology (H), Dendreon, Advanced Accelerator Applications, Clovis Oncology, Axiom Biotechnologies, AstraZeneca, Pfizer, Merck, Amgen, Jubliant Pharmaceuticals, Alessa Therapeutics (C/A), Zenith Epigenetics, Novartis, Xynomic Pharma, Cancer Targeted Technology, Janssen, Merck, AbbVie, Amgen, AstraZeneca, BioXCel Therapeutics (RF [institutional]); Ana Aparicio: Astellas, Janssen (C/A), American Cancer Society (education services); Himisha Beltran: Janssen, Astellas, AstraZeneca, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Oncorus, Amgen (C/A), Janssen, AbbVie/Stemcentrx, Eli Lilly, Millennium Pharmaceuticals, Bristol Myers Squibb (RF), Amgen, Oncternal (SAB); Judy S. Crabtree: Amgen (SAB); Christine L. Hann: Janssen, AstraZeneca (C/A), Amgen, AbbVie, BMS, Genentech (RF [institutional]), Amgen (SAB); Toni Ibrahim: Amgen, Pharmamar (H, SAB); Lauren A. Byers: AstraZeneca, GenMab, Sierra Oncology, PharmaMar, AbbVie, Bristol Myers Squibb, Alethia, Merck, Pfizer, Jazz Pharmaceuticals, Genentech, Debiopharm Group (C/A), AstraZeneca, GenMab, Sierra Oncology, ToleroPharmaceuticals (RF); Hironobu Sasano: Novartis Oncology Japan, Teijin Pharm Co. Ltd., Nobel Pharma Co. Ltd. (RF, H); John Umejiego: Amgen (E, OI); Marianne Pavel: AAA, Ipsen, Novartis, Amgen, Lilly, Riemser (C/A), MSD, Boehringer Ingelheim, AAA, Ipsen, Novartis, Lilly (H), AAA, Crinetics (SAB).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board.

Author Contributions

Data analysis and interpretation, manuscript writing, and final approval of manuscript: All authors.

Data Availability

No data were generated for this article; published references are cited at the end of the article.

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. 2021. NCCN.org. Accessed June 24, 2021.
2. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31:1770-1786. 10.1038/s41379-018-0110-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335-1342. https://jamanetwork.com/journals/jamaoncology/fullarticle/2621997 . [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Yao JC, Hassan M, Phan A, 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;26:3063-3072. [DOI] [PubMed] [Google Scholar]
5. Klöppel G. Neuroendocrine neoplasms: dichotomy, origin and classifications. Visc Med. 2017;33:324-330. 10.1159/000481390. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76:182-188. 10.1111/his.13975. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. La Rosa S, Uccella S.. Classification of neuroendocrine neoplasms: lights and shadows. Rev Endocr Metab Disord. 2021;22:527-538. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Frizziero M, Chakrabarty B, Nagy B, et al. Mixed neuroendocrine non-neuroendocrine neoplasms: a systematic review of a controversial and underestimated diagnosis. J Clin Med. 2020;9. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712. 10.1097/MPA.0b013e3181ec124e. [DOI] [PubMed] [Google Scholar]
10. Oronsky B, Ma PC, Morgensztern D, et al. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia. 2017;19:991-1002. 10.1016/j.neo.2017.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. von Arx C, Capozzi M, López-Jiménez E, et al. Updates on the role of molecular alterations and NOTCH signalling in the development of neuroendocrine neoplasms. J Clin Med. 2019;8. [DOI] [PMC free article] [PubMed] [Google Scholar]
12. van Riet J, van de Werken HJG, Cuppen E, et al. The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets. Nat Commun. 2021;12:4612. 10.1038/s41467-021-24812-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 2010;17:771-783. https://erc.bioscientifica.com/view/journals/erc/17/3/771.xml. [DOI] [PubMed] [Google Scholar]
14. Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543:65-71. 10.1038/nature21063. [DOI] [PubMed] [Google Scholar]
15. Olevian DC, Nikiforova MN, Chiosea S, et al. Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival. Hum Pathol. 2016;49:124-134. 10.1016/j.humpath.2015.11.004. [DOI] [PubMed] [Google Scholar]
16. Aggarwal R, Huang J, Alumkal JJ, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol. 2018;36:2492-2503. https://ascopubs.org/doi/10.1200/JCO.2017.77.6880 . [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Clermont P-L, Ci X, Pandha H, et al. Treatment-emergent neuroendocrine prostate cancer: molecularly driven clinical guidelines. Int J Endocr Oncol. 2019;6:IJE20. [Google Scholar]
18. Aggarwal RR, Feng FY, Small EJ.. Emerging categories of disease in advanced prostate cancer and their therapeutic implications. Oncology (Williston Park). 2017;31:467-474. [PubMed] [Google Scholar]
19. Cejas P, Xie Y, Font-Tello A, et al. Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer. Nat Commun. 2021;12:5775. 10.1038/s41467-021-26042-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Epstein JI, Amin MB, Beltran H, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38:756-767. https://journals.lww.com/ajsp/Abstract/2014/06000/Proposed_Morphologic_Classification_of_Prostate.3.aspx. [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Zhang Q, Han Y, Zhang Y, et al. Treatment-emergent neuroendocrine prostate cancer: a clinicopathological and immunohistochemical analysis of 94 cases. Front Oncol. 2020;10:571308. 10.3389/fonc.2020.571308. [DOI] [PMC free article] [PubMed] [Google Scholar]
22. Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer. 2008;113:2655-2664. 10.1002/cncr.23883. [DOI] [PubMed] [Google Scholar]
23. Das S, Dasari A.. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: are there global differences? Curr Oncol Rep. 2021;23:43-43. 10.1007/s11912-021-01029-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Leoncini E, Boffetta P, Shafir M, et al. Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine. 2017;58:368-379. 10.1007/s12020-017-1273-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Jensen RT, Bodei L, Capdevila J, et al. Unmet needs in functional and nonfunctional pancreatic neuroendocrine neoplasms. Neuroendocrinology. 2019;108:26-36. 10.1159/000494258. [DOI] [PubMed] [Google Scholar]
26. Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. 1998;129:484-494. https://www.acpjournals.org/doi/10.7326/0003-4819-129-6-199809150-00011. [DOI] [PubMed] [Google Scholar]
27. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199-1203. 10.1126/science.1200609. [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Venizelos A, Elvebakken H, Perren A, et al. The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2021;29:1-14. 10.1530/ERC-21-0152. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518. 10.1038/ncomms4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Yao J, Garg A, Chen D, et al. Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials. Endocr Relat Cancer. 2019;26:391-403. 10.1530/ERC-18-0332. [DOI] [PubMed] [Google Scholar]
31. Kawasaki K, Toshimitsu K, Matano M, et al. An organoid biobank of neuroendocrine neoplasms enables genotype-phenotype mapping. Cell. 2020;183:1420-1435.e21. 10.1016/j.cell.2020.10.023. [DOI] [PubMed] [Google Scholar]
32. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289-297. 10.1038/s41568-019-0133-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346-360.e7. 10.1016/j.ccell.2020.12.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Choi W, Hoffman-Censits JH, Fong M, et al. Molecular characterization of neuroendocrine bladder cancer. J Clin Oncol. 2020;38. [Google Scholar]
35. Conteduca V, Oromendia C, Eng KW, et al. Clinical features of neuroendocrine prostate cancer. Eur J Cancer. 2019;121:7-18. 10.1016/j.ejca.2019.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J Thorac Oncol. 2019;14:1784-1793. 10.1016/j.jtho.2019.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298-305. 10.1038/nm.4045. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Aggarwal RR, Quigley DA, Huang J, et al. Whole-genome and transcriptional analysis of treatment-emergent small-cell neuroendocrine prostate cancer demonstrates intraclass heterogeneity. Mol Cancer Res. 2019;17:1235-1240. 10.1158/1541-7786.MCR-18-1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Raoul JL, Heymann MF, Dumont F, et al. Case report: Grade 2 metastatic pancreatic neuroendocrine tumor with progression of one metastasis after pregnancy to grade 3 large-cell neuroendocrine carcinoma: one case cured by resection with genomic characterization of the two components. Front Oncol. 2021;11:646992. 10.3389/fonc.2021.646992. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Apostolidis L, Dal Buono A, Merola E, et al. Multicenter analysis of treatment outcomes for systemic therapy in well differentiated grade 3 neuroendocrine tumors (NET G3). Cancers (Basel). 2021;13:1936. [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Laffi A, Spada F, Bagnardi V, et al. Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis. J Endocrinol Invest. 2022;45:317-325. 10.1007/s40618-021-01642-0. [DOI] [PubMed] [Google Scholar]
42. Sackstein PE, O’Neil DS, Neugut AI, et al. Epidemiologic trends in neuroendocrine tumors: an examination of incidence rates and survival of specific patient subgroups over the past 20 years. Semin Oncol. 2018;45:249-258. 10.1053/j.seminoncol.2018.07.001. [DOI] [PubMed] [Google Scholar]
43. Trikalinos NA, Tan BR, Amin M, et al. Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014. BMC Endocr Disord. 2020;20:44. 10.1186/s12902-020-0525-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Borbath I, Bikmukhametov D, Maasberg S, et al. Assessing prognosis of neuroendocrine neoplasms: results of a collaborative multinational effort including over 10.000 European patients—The ENETS Registry. J Clin Oncol. 2018;36:4095-4095. [Google Scholar]
45. Kawasaki K, Fujii M, Sato T.. Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models. Dis Model Mech. 2018;11:dmm029595. [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Kaltsas G, Caplin M, Davies P, et al. ENETS Consensus Guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology. 2017;105:245-254. 10.1159/000461583. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17:600-606. 10.1200/JCO.1999.17.2.600. [DOI] [PubMed] [Google Scholar]
48. Fisher GA Jr., Wolin EM, Liyanage N, et al. Patient-reported symptom control of diarrhea and flushing in patients with neuroendocrine tumors treated with lanreotide depot/autogel: results from a randomized, placebo-controlled, double-blind and 32-week open-label study. Oncologist. 2018;23:16-24. 10.1634/theoncologist.2017-0284. [DOI] [PMC free article] [PubMed] [Google Scholar]
49. Rinke A, Muller HH, Schade-Brittinger C, 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;27:4656-4663. 10.1200/JCO.2009.22.8510. [DOI] [PubMed] [Google Scholar]
50. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224-233. [DOI] [PubMed] [Google Scholar]
51. Rinke A, Gress TM.. Neuroendocrine cancer, therapeutic strategies in G3 cancers. Digestion. 2017;95:109-114. 10.1159/000454761. [DOI] [PubMed] [Google Scholar]
52. Horsch D, Baudin E, Singh S, et al. Lanreotide autogel/depot (LAN) in patients with advanced bronchopulmonary (BP) neuroendocrine tumors (NETs): results from the phase III SPINET study. Ann Oncol. 2021;32:S906-S920. [Google Scholar]
53. LUTATHERA® (lutetium Lu 177 dotatate). Full Prescribing Information, Advanced Accelerator Applications USA, Inc., NJ; 2021. [Google Scholar]
54. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125-135. 10.1056/NEJMoa1607427. [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Strosberg JR, Caplin ME, Kunz PL, et al. (177)Lu-dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22:1752-1763. 10.1016/S1470-2045(21)00572-6. [DOI] [PubMed] [Google Scholar]
56. Ramage J, Naraev BG, Halfdanarson TR.. Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors. Semin Oncol. 2018;45:236-248. 10.1053/j.seminoncol.2018.08.004. [DOI] [PubMed] [Google Scholar]
57. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-513. 10.1056/nejmoa1003825. [DOI] [PubMed] [Google Scholar]
58. Xu J. Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs). Ther Adv Med Oncol. 2021;13:17588359211042689. 10.1177/17588359211042689. [DOI] [PMC free article] [PubMed] [Google Scholar]
59. Xu J, Shen L, Zhou Z, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:1500-1512. 10.1016/S1470-2045(20)30496-4. [DOI] [PubMed] [Google Scholar]
60. Faivre S, Niccoli P, Castellano D, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017;28:339-343. 10.1093/annonc/mdw561. [DOI] [PubMed] [Google Scholar]
61. Dasari A, Li D, Sung MW, et al. Efficacy and safety of surufatinib in United States (US) patients (pts) with neuroendocrine tumors (NETs). J Clin Oncol. 2020;38:4610-4610. [Google Scholar]
62. Xu J, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:1489-1499. 10.1016/S1470-2045(20)30493-9. [DOI] [PubMed] [Google Scholar]
63. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33:1551-1556. 10.1200/JCO.2014.56.2082. [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523. 10.1056/NEJMoa1009290. [DOI] [PMC free article] [PubMed] [Google Scholar]
65. Yao JC, Fazio N, Singh S, 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. 2016;387:968-977. 10.1016/S0140-6736(15)00817-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
66. AFINITOR®/AFINITOR DISPERZ® (everolimus/everolimus tablets for oral suspension). Full Prescribing Information, Novartis Pharmaceuticals Corporation, NJ; 2021. [Google Scholar]
67. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005-2012. 10.1016/S0140-6736(11)61742-X. [DOI] [PubMed] [Google Scholar]
68. Pavel ME, Baudin E, Öberg KE, et al. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017;28:1569-1575. 10.1093/annonc/mdx193. [DOI] [PMC free article] [PubMed] [Google Scholar]
69. Dilz LM, Denecke T, Steffen IG, et al. Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. Eur J Cancer. 2015;51:1253-1262. 10.1016/j.ejca.2015.04.005. [DOI] [PubMed] [Google Scholar]
70. Kunz PL, Catalano PJ, Nimeiri H, 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;36:4004-4004. [DOI] [PMC free article] [PubMed] [Google Scholar]
71. Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657-664. 10.1530/ERC-15-0119. [DOI] [PubMed] [Google Scholar]
72. Hentic O, Hammel P, Couvelard A, et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr Relat Cancer. 2012;19:751-757. 10.1530/ERC-12-0002. [DOI] [PubMed] [Google Scholar]
73. Hadoux J, Malka D, Planchard D, et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr Relat Cancer. 2015;22:289-298. 10.1530/ERC-15-0075. [DOI] [PubMed] [Google Scholar]
74. de Mestier L, Lamarca A, Hernando J, et al. Treatment outcomes of advanced digestive well-differentiated grade 3 NETs. Endocr Relat Cancer. 2021;28:549-561. 10.1530/ERC-21-0109. [DOI] [PubMed] [Google Scholar]
75. Hijioka S, Hosoda W, Matsuo K, et al. Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: a Japanese multicenter pancreatic NEN-G3 study. Clin Cancer Res. 2017;23:4625-4632. 10.1158/1078-0432.CCR-16-3135. [DOI] [PubMed] [Google Scholar]
76. Klein O, Kee D, Markman B, 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;26:4454-4459. 10.1158/1078-0432.CCR-20-0621. [DOI] [PubMed] [Google Scholar]
77. Patel SP, Othus M, Chae YK, 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;26:2290-2296. 10.1158/1078-0432.CCR-19-3356. [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: high-grade neuroendocrine neoplasm cohort. Cancer. 2021;127:3194-3201. 10.1002/cncr.33591. [DOI] [PMC free article] [PubMed] [Google Scholar]
79. Girard N, Mazieres J, Otto J, et al. LBA41 – Nivolumab (nivo) ± ipilimumab (ipi) in pre-treated patients with advanced, refractory pulmonary or gastroenteropancreatic poorly differentiated neuroendocrine tumors (NECs) (GCO-001 NIPINEC). Ann Oncol. 2021;32:S1283-S1346. [Google Scholar]
80. Leonetti A, Facchinetti F, Minari R, et al. Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges. Cell Oncol (Dordr). 2019;42:261-273. 10.1007/s13402-019-00441-3 [DOI] [PubMed] [Google Scholar]
81. Crabtree JS, Miele L.. Neuroendocrine tumors: current therapies, notch signaling, and cancer stem cells. J Cancer Metastasis Treat. 2016;2:279-293. [Google Scholar]
82. Crabtree JS, Singleton CS, Miele L.. Notch signaling in neuroendocrine tumors. Front Oncol. 2016;6:94. 10.3389/fonc.2016.00094. [DOI] [PMC free article] [PubMed] [Google Scholar]
83. Xiu MX, Liu YM, Kuang BH.. The role of DLLs in cancer: a novel therapeutic target. Onco Targets Ther. 2020;13:3881-3901. 10.2147/OTT.S244860. [DOI] [PMC free article] [PubMed] [Google Scholar]
84. Ladi E, Nichols JT, Ge W, et al. The divergent DSL ligand DLL3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol. 2005;170:983-992. 10.1083/jcb.200503113. [DOI] [PMC free article] [PubMed] [Google Scholar]
85. Chapman G, Sparrow DB, Kremmer E, et al. Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20:905-916. 10.1093/hmg/ddq529. [DOI] [PubMed] [Google Scholar]
86. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7:302ra-136. [DOI] [PMC free article] [PubMed] [Google Scholar]
87. Sharma SK, Pourat J, Abdel-Atti D, et al. Noninvasive interrogation of DLL3 expression in metastatic small cell lung cancer. Cancer Res. 2017;77:3931-3941. 10.1158/0008-5472.CAN-17-0299. [DOI] [PMC free article] [PubMed] [Google Scholar]
88. Giffin MJ, Cooke K, Lobenhofer EK, et al. AMG 757, a half-life extended, DLL3-targeted bispecific T-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021;27:1526-1537. 10.1158/1078-0432.CCR-20-2845. [DOI] [PubMed] [Google Scholar]
89. Dylla SJ. Toppling high-grade pulmonary neuroendocrine tumors with a DLL3-targeted trojan horse. Mol Cell Oncol. 2016;3:e1101515. 10.1080/23723556.2015.1101515. [DOI] [PMC free article] [PubMed] [Google Scholar]
90. Tendler S, Kanter L, Lewensohn R, et al. The prognostic implications of Notch1, Hes1, Ascl1, and DLL3 protein expression in SCLC patients receiving platinum-based chemotherapy. PLoS One. 2020;15:e0240973. 10.1371/journal.pone.0240973. [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Furuta M, Sakakibara JK, Shoji T, et al. DLL3 regulates migration and invasion of small cell lung cancer. Cancer Res. 2018;78. [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Roper N, Velez MJ, Chiappori A, et al. Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer. Nat Commun. 2021;12:3880. 10.1038/s41467-021-24164-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
93. Puca L, Gavyert K, Sailer V, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11. [DOI] [PMC free article] [PubMed] [Google Scholar]
94. La Salvia A, Rapa I, Metovic J, et al. Extra-pulmonary neuroendocrine carcinomas display distinct transcriptional profiles according to the site of origin. Neuroendocrinology. 2019;108:29. [Google Scholar]
95. Feng J, Wang J, Liu Q, et al. DAPT, a γ-secretase inhibitor, suppresses tumorigenesis, and progression of growth hormone-producing adenomas by targeting notch signaling. Front Oncol. 2019;9:809. 10.3389/fonc.2019.00809. [DOI] [PMC free article] [PubMed] [Google Scholar]
96. Huang RSP, Holmes BF, Powell C, et al. Delta-like protein 3 prevalence in small cell lung cancer and DLL3 (SP347) assay characteristics. Arch Pathol Lab Med. 2019;143:1373-1377. 10.5858/arpa.2018-0497-OA. [DOI] [PubMed] [Google Scholar]
97. Alì G, Di Stefano I, Poma AM, et al. Prevalence of delta-like protein 3 in a consecutive series of surgically resected lung neuroendocrine neoplasms. Front Oncol. 2021;11:729765. 10.3389/fonc.2021.729765. [DOI] [PMC free article] [PubMed] [Google Scholar]
98. Hermans BCM, Derks JL, Thunnissen E, et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer. 2019;138:102-108. 10.1016/j.lungcan.2019.10.010. [DOI] [PubMed] [Google Scholar]
99. Lima CF, Rocha P, Fujimoto Jet al. Delta-Like Ligand 3 Immunohistochemical Expression Landscape in High-Grade Lung Neuroendocrine Tumors. Presented at: AACR; April 8-13, 2022; New Orleans. [Google Scholar]
100. Rand J, Balzer BL, Frishberg DP, et al. Prevalence of delta-like protein 3 expression in Merkel cell carcinoma. J Am Acad Dermatol. 2021;85:749-750. 10.1016/j.jaad.2019.09.069. [DOI] [PubMed] [Google Scholar]
101. Xie H, Kaye FJ, Isse K, et al. Delta-like protein 3 expression and targeting in Merkel cell carcinoma. Oncologist. 2020;25:810-817. 10.1634/theoncologist.2019-0877. [DOI] [PMC free article] [PubMed] [Google Scholar]
102. Liverani C, Bongiovanni A, Mercatali L, et al. Diagnostic and predictive role of DLL3 expression in gastroenteropancreatic neuroendocrine neoplasms. Endocr Pathol. 2021;32:309-317. 10.1007/s12022-020-09657-8. [DOI] [PubMed] [Google Scholar]
103. Koshkin VS, Garcia JA, Reynolds J, et al. Transcriptomic and protein analysis of small-cell bladder cancer (SCBC) identifies prognostic biomarkers and DLL3 as a relevant therapeutic target. Clin Cancer Res. 2019;25:210-221. 10.1158/1078-0432.CCR-18-1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
104. Aggarwal RR, Aparicio A, Heidenreich A, et al. Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2021;39:TPS5100-TPS5100. [Google Scholar]
105. Cimic A, Vranic S, Arguello D, et al. Molecular profiling reveals limited targetable biomarkers in neuroendocrine carcinoma of the cervix. Appl Immunohistochem Mol Morphol. 2021;29:299-304. 10.1097/PAI.0000000000000884. [DOI] [PMC free article] [PubMed] [Google Scholar]
106. Vranic S, Arguello D, Contreras E, et al. Molecular profiling reveals novel targetable biomarkers in neuroendocrine carcinoma of the uterine cervix. Ann Oncol. 2019;30:v430-v431. [DOI] [PMC free article] [PubMed] [Google Scholar]
107. Song HY, Wang Y, Lan H, et al. Expression of notch receptors and their ligands in pancreatic ductal adenocarcinoma. Exp Ther Med. 2018;16:53-60. 10.3892/etm.2018.6172. [DOI] [PMC free article] [PubMed] [Google Scholar]
108. Ingenwerth M, Brandenburg T, Fuhrer-Sakel D, et al. DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas. Endocr Connect. 2021;10:283-289. 10.1530/EC-20-0611. [DOI] [PMC free article] [PubMed] [Google Scholar]
109. Ogawa H, Sakai Y, Nishio W, et al. DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC. Thorac Cancer. 2020;11:2561-2569. 10.1111/1759-7714.13574. [DOI] [PMC free article] [PubMed] [Google Scholar]
110. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18:42-51. 10.1016/S1470-2045(16)30565-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
111. Tanaka K, Isse K, Fujihira T, et al. Prevalence of Delta-like protein 3 expression in patients with small cell lung cancer. Lung Cancer. 2018;115:116-120. 10.1016/j.lungcan.2017.11.018. [DOI] [PubMed] [Google Scholar]
112. Xie H, Boland JM, Maleszewski JJ, et al. Expression of delta-like protein 3 is reproducibly present in a subset of small cell lung carcinomas and pulmonary carcinoid tumors. Lung Cancer. 2019;135:73-79. 10.1016/j.lungcan.2019.07.016. [DOI] [PubMed] [Google Scholar]
113. Rath B, Plangger A, Krenbek D, et al. Rovalpituzumab tesirine resistance: analysis of a corresponding small cell lung cancer and circulating tumor cell line pair. Anticancer Drugs. 2022;33:300-307. 10.1097/CAD.0000000000001267. [DOI] [PubMed] [Google Scholar]
114. Messaritakis I, Nikolaou M, Koinis F, et al. Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment. J Clin Oncol. 2019;37. [DOI] [PubMed] [Google Scholar]
115. Muscarella LA, Mazza T, Fabrizio FP, et al. Neuroendocrine-related circulating transcripts in small-cell lung cancers: detection methods and future perspectives. Cancers (Basel). 2021;13. [DOI] [PMC free article] [PubMed] [Google Scholar]
116. Lim S, Hong M, Kim SP, et al. P2.12-18 Prevalence of DLL3 expression and its prognostic role in extensive stage small cell lung cancer. J Thorac Oncol. 2019;14(10 Suppl):S820. [Google Scholar]
117. Fu X, Liu Z, Xiang L, et al. PD-L1 predicts poor prognosis in surgically resected limited stage small-cell lung cancer. Cancer Manag Res. 2020;12:10939-10948. 10.2147/CMAR.S260599. [DOI] [PMC free article] [PubMed] [Google Scholar]
118. Akamatsu H, Udagawa H, Tanaka K, et al. Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC). J Clin Oncol. 2019;37:8557. [DOI] [PubMed] [Google Scholar]
119. Morgensztern D, Besse B, Greillier L, 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;25:6958-6966. 10.1158/1078-0432.CCR-19-1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
120. Alcala N, Leblay N, Gabriel AAG, et al. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun. 2019;10:3407. 10.1038/s41467-019-11276-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
121. Prieto T, Baldavira CM, Ab´saber A, et al. P47.11 DLL-3 and ASCL-1 expression emerge as promising therapeutic targets in high-grade neuroendocrine lung tumors: a preliminary study. J Thorac Oncol. 2021;16:S496-S497. [Google Scholar]
122. Chauhan A, Kim JT, Weiss H, et al. Potentiating mTOR’s antineoplastic effects with rovalpituzumab tesirate in neuroendocrine tumors. Pancreas. 2018;47:335. [Google Scholar]
123. Mansfield AS, Hong DS, Hann CL, et al. A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors. NPJ Precis Oncol. 2021;5:74. 10.1038/s41698-021-00214-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
124. Blackhall F, Jao K, Greillier L, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: results from the phase 3 TAHOE study. J Thorac Oncol. 2021;16:1547-1558. 10.1016/j.jtho.2021.02.009. [DOI] [PubMed] [Google Scholar]
125. Johnson ML, Zvirbule Z, Laktionov K, et al. Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: results from the phase 3 MERU study. J Thorac Oncol. 2021;16:1570-1581. 10.1016/j.jtho.2021.03.012. [DOI] [PubMed] [Google Scholar]
126. Morgensztern D, Johnson M, Rudin CM, et al. SC-002 in patients with relapsed or refractory small cell lung cancer and large cell neuroendocrine carcinoma: phase 1 study. Lung Cancer. 2020;145:126-131. 10.1016/j.lungcan.2020.04.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
127. Cooke K, Estrada J, Zhan J, et al. 627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer. J ImmunoTher Cancer. 2020;8:A663-A663. [Google Scholar]
128. Owonikoko T, Boyer M, Johnson M, et al. OA11.03 A phase 1 study of AMG 757, half-life extended bispecific T-cell engager (BiTE®) immune therapy against DLL3, in SCLC. J Thorac Oncol. 2021;16:S126. [Google Scholar]
129. Hipp S, Voynov V, Drobits-Handl B, et al. A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020;26:5258-5268. 10.1158/1078-0432.CCR-20-0926. [DOI] [PubMed] [Google Scholar]
130. Wermke M, Felip E, Gambardella V, et al. A phase I, open-label, dose-escalation trial of BI 764532, a DLL3/CD3 bispecific antibody, in patients (pts) with small cell lung carcinoma (SCLC) or other neuroendocrine neoplasms expressing DLL3. J Clin Oncol. 2021;39:TPS8588-TPS8588. [Google Scholar]
131. Aaron WH, Austin R, Barath M, et al. Abstract C033: HPN328: An anti-DLL3 T cell engager for treatment of small cell lung cancer. Mol Cancer Ther. 2019;18:C033-C033. [Google Scholar]
132. ClinicalTrials.gov. Study in Patients with Advanced Cancers Associated with Expression of DLL3 Who Have Failed Standard Available Therapy. https://clinicaltrials.gov/ct2/show/NCT04471727. Accessed September 26, 2021.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No data were generated for this article; published references are cited at the end of the article.

[CIT0001] 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. 2021. NCCN.org. Accessed June 24, 2021.

[CIT0002] 2. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31:1770-1786. 10.1038/s41379-018-0110-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0003] 3. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335-1342. https://jamanetwork.com/journals/jamaoncology/fullarticle/2621997 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0004] 4. Yao JC, Hassan M, Phan A, 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;26:3063-3072. [DOI] [PubMed] [Google Scholar]

[CIT0005] 5. Klöppel G. Neuroendocrine neoplasms: dichotomy, origin and classifications. Visc Med. 2017;33:324-330. 10.1159/000481390. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0006] 6. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76:182-188. 10.1111/his.13975. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0007] 7. La Rosa S, Uccella S.. Classification of neuroendocrine neoplasms: lights and shadows. Rev Endocr Metab Disord. 2021;22:527-538. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0008] 8. Frizziero M, Chakrabarty B, Nagy B, et al. Mixed neuroendocrine non-neuroendocrine neoplasms: a systematic review of a controversial and underestimated diagnosis. J Clin Med. 2020;9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0009] 9. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712. 10.1097/MPA.0b013e3181ec124e. [DOI] [PubMed] [Google Scholar]

[CIT0010] 10. Oronsky B, Ma PC, Morgensztern D, et al. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia. 2017;19:991-1002. 10.1016/j.neo.2017.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0011] 11. von Arx C, Capozzi M, López-Jiménez E, et al. Updates on the role of molecular alterations and NOTCH signalling in the development of neuroendocrine neoplasms. J Clin Med. 2019;8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0012] 12. van Riet J, van de Werken HJG, Cuppen E, et al. The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets. Nat Commun. 2021;12:4612. 10.1038/s41467-021-24812-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0013] 13. Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 2010;17:771-783. https://erc.bioscientifica.com/view/journals/erc/17/3/771.xml. [DOI] [PubMed] [Google Scholar]

[CIT0014] 14. Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543:65-71. 10.1038/nature21063. [DOI] [PubMed] [Google Scholar]

[CIT0015] 15. Olevian DC, Nikiforova MN, Chiosea S, et al. Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival. Hum Pathol. 2016;49:124-134. 10.1016/j.humpath.2015.11.004. [DOI] [PubMed] [Google Scholar]

[CIT0016] 16. Aggarwal R, Huang J, Alumkal JJ, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol. 2018;36:2492-2503. https://ascopubs.org/doi/10.1200/JCO.2017.77.6880 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0017] 17. Clermont P-L, Ci X, Pandha H, et al. Treatment-emergent neuroendocrine prostate cancer: molecularly driven clinical guidelines. Int J Endocr Oncol. 2019;6:IJE20. [Google Scholar]

[CIT0018] 18. Aggarwal RR, Feng FY, Small EJ.. Emerging categories of disease in advanced prostate cancer and their therapeutic implications. Oncology (Williston Park). 2017;31:467-474. [PubMed] [Google Scholar]

[CIT0019] 19. Cejas P, Xie Y, Font-Tello A, et al. Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer. Nat Commun. 2021;12:5775. 10.1038/s41467-021-26042-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0020] 20. Epstein JI, Amin MB, Beltran H, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38:756-767. https://journals.lww.com/ajsp/Abstract/2014/06000/Proposed_Morphologic_Classification_of_Prostate.3.aspx. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0021] 21. Zhang Q, Han Y, Zhang Y, et al. Treatment-emergent neuroendocrine prostate cancer: a clinicopathological and immunohistochemical analysis of 94 cases. Front Oncol. 2020;10:571308. 10.3389/fonc.2020.571308. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0022] 22. Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer. 2008;113:2655-2664. 10.1002/cncr.23883. [DOI] [PubMed] [Google Scholar]

[CIT0023] 23. Das S, Dasari A.. Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: are there global differences? Curr Oncol Rep. 2021;23:43-43. 10.1007/s11912-021-01029-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0024] 24. Leoncini E, Boffetta P, Shafir M, et al. Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine. 2017;58:368-379. 10.1007/s12020-017-1273-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0025] 25. Jensen RT, Bodei L, Capdevila J, et al. Unmet needs in functional and nonfunctional pancreatic neuroendocrine neoplasms. Neuroendocrinology. 2019;108:26-36. 10.1159/000494258. [DOI] [PubMed] [Google Scholar]

[CIT0026] 26. Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. 1998;129:484-494. https://www.acpjournals.org/doi/10.7326/0003-4819-129-6-199809150-00011. [DOI] [PubMed] [Google Scholar]

[CIT0027] 27. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199-1203. 10.1126/science.1200609. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0028] 28. Venizelos A, Elvebakken H, Perren A, et al. The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2021;29:1-14. 10.1530/ERC-21-0152. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0029] 29. Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518. 10.1038/ncomms4518. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0030] 30. Yao J, Garg A, Chen D, et al. Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials. Endocr Relat Cancer. 2019;26:391-403. 10.1530/ERC-18-0332. [DOI] [PubMed] [Google Scholar]

[CIT0031] 31. Kawasaki K, Toshimitsu K, Matano M, et al. An organoid biobank of neuroendocrine neoplasms enables genotype-phenotype mapping. Cell. 2020;183:1420-1435.e21. 10.1016/j.cell.2020.10.023. [DOI] [PubMed] [Google Scholar]

[CIT0032] 32. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289-297. 10.1038/s41568-019-0133-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0033] 33. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346-360.e7. 10.1016/j.ccell.2020.12.014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0034] 34. Choi W, Hoffman-Censits JH, Fong M, et al. Molecular characterization of neuroendocrine bladder cancer. J Clin Oncol. 2020;38. [Google Scholar]

[CIT0035] 35. Conteduca V, Oromendia C, Eng KW, et al. Clinical features of neuroendocrine prostate cancer. Eur J Cancer. 2019;121:7-18. 10.1016/j.ejca.2019.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0036] 36. Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J Thorac Oncol. 2019;14:1784-1793. 10.1016/j.jtho.2019.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0037] 37. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298-305. 10.1038/nm.4045. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0038] 38. Aggarwal RR, Quigley DA, Huang J, et al. Whole-genome and transcriptional analysis of treatment-emergent small-cell neuroendocrine prostate cancer demonstrates intraclass heterogeneity. Mol Cancer Res. 2019;17:1235-1240. 10.1158/1541-7786.MCR-18-1101. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0039] 39. Raoul JL, Heymann MF, Dumont F, et al. Case report: Grade 2 metastatic pancreatic neuroendocrine tumor with progression of one metastasis after pregnancy to grade 3 large-cell neuroendocrine carcinoma: one case cured by resection with genomic characterization of the two components. Front Oncol. 2021;11:646992. 10.3389/fonc.2021.646992. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0040] 40. Apostolidis L, Dal Buono A, Merola E, et al. Multicenter analysis of treatment outcomes for systemic therapy in well differentiated grade 3 neuroendocrine tumors (NET G3). Cancers (Basel). 2021;13:1936. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0041] 41. Laffi A, Spada F, Bagnardi V, et al. Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis. J Endocrinol Invest. 2022;45:317-325. 10.1007/s40618-021-01642-0. [DOI] [PubMed] [Google Scholar]

[CIT0042] 42. Sackstein PE, O’Neil DS, Neugut AI, et al. Epidemiologic trends in neuroendocrine tumors: an examination of incidence rates and survival of specific patient subgroups over the past 20 years. Semin Oncol. 2018;45:249-258. 10.1053/j.seminoncol.2018.07.001. [DOI] [PubMed] [Google Scholar]

[CIT0043] 43. Trikalinos NA, Tan BR, Amin M, et al. Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014. BMC Endocr Disord. 2020;20:44. 10.1186/s12902-020-0525-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0044] 44. Borbath I, Bikmukhametov D, Maasberg S, et al. Assessing prognosis of neuroendocrine neoplasms: results of a collaborative multinational effort including over 10.000 European patients—The ENETS Registry. J Clin Oncol. 2018;36:4095-4095. [Google Scholar]

[CIT0045] 45. Kawasaki K, Fujii M, Sato T.. Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models. Dis Model Mech. 2018;11:dmm029595. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0046] 46. Kaltsas G, Caplin M, Davies P, et al. ENETS Consensus Guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology. 2017;105:245-254. 10.1159/000461583. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0047] 47. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17:600-606. 10.1200/JCO.1999.17.2.600. [DOI] [PubMed] [Google Scholar]

[CIT0048] 48. Fisher GA Jr., Wolin EM, Liyanage N, et al. Patient-reported symptom control of diarrhea and flushing in patients with neuroendocrine tumors treated with lanreotide depot/autogel: results from a randomized, placebo-controlled, double-blind and 32-week open-label study. Oncologist. 2018;23:16-24. 10.1634/theoncologist.2017-0284. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0049] 49. Rinke A, Muller HH, Schade-Brittinger C, 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;27:4656-4663. 10.1200/JCO.2009.22.8510. [DOI] [PubMed] [Google Scholar]

[CIT0050] 50. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224-233. [DOI] [PubMed] [Google Scholar]

[CIT0051] 51. Rinke A, Gress TM.. Neuroendocrine cancer, therapeutic strategies in G3 cancers. Digestion. 2017;95:109-114. 10.1159/000454761. [DOI] [PubMed] [Google Scholar]

[CIT0052] 52. Horsch D, Baudin E, Singh S, et al. Lanreotide autogel/depot (LAN) in patients with advanced bronchopulmonary (BP) neuroendocrine tumors (NETs): results from the phase III SPINET study. Ann Oncol. 2021;32:S906-S920. [Google Scholar]

[CIT0053] 53. LUTATHERA® (lutetium Lu 177 dotatate). Full Prescribing Information, Advanced Accelerator Applications USA, Inc., NJ; 2021. [Google Scholar]

[CIT0054] 54. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125-135. 10.1056/NEJMoa1607427. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0055] 55. Strosberg JR, Caplin ME, Kunz PL, et al. (177)Lu-dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22:1752-1763. 10.1016/S1470-2045(21)00572-6. [DOI] [PubMed] [Google Scholar]

[CIT0056] 56. Ramage J, Naraev BG, Halfdanarson TR.. Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors. Semin Oncol. 2018;45:236-248. 10.1053/j.seminoncol.2018.08.004. [DOI] [PubMed] [Google Scholar]

[CIT0057] 57. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-513. 10.1056/nejmoa1003825. [DOI] [PubMed] [Google Scholar]

[CIT0058] 58. Xu J. Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs). Ther Adv Med Oncol. 2021;13:17588359211042689. 10.1177/17588359211042689. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0059] 59. Xu J, Shen L, Zhou Z, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:1500-1512. 10.1016/S1470-2045(20)30496-4. [DOI] [PubMed] [Google Scholar]

[CIT0060] 60. Faivre S, Niccoli P, Castellano D, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017;28:339-343. 10.1093/annonc/mdw561. [DOI] [PubMed] [Google Scholar]

[CIT0061] 61. Dasari A, Li D, Sung MW, et al. Efficacy and safety of surufatinib in United States (US) patients (pts) with neuroendocrine tumors (NETs). J Clin Oncol. 2020;38:4610-4610. [Google Scholar]

[CIT0062] 62. Xu J, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:1489-1499. 10.1016/S1470-2045(20)30493-9. [DOI] [PubMed] [Google Scholar]

[CIT0063] 63. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33:1551-1556. 10.1200/JCO.2014.56.2082. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0064] 64. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523. 10.1056/NEJMoa1009290. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0065] 65. Yao JC, Fazio N, Singh S, 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. 2016;387:968-977. 10.1016/S0140-6736(15)00817-X. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0066] 66. AFINITOR®/AFINITOR DISPERZ® (everolimus/everolimus tablets for oral suspension). Full Prescribing Information, Novartis Pharmaceuticals Corporation, NJ; 2021. [Google Scholar]

[CIT0067] 67. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005-2012. 10.1016/S0140-6736(11)61742-X. [DOI] [PubMed] [Google Scholar]

[CIT0068] 68. Pavel ME, Baudin E, Öberg KE, et al. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017;28:1569-1575. 10.1093/annonc/mdx193. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0069] 69. Dilz LM, Denecke T, Steffen IG, et al. Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. Eur J Cancer. 2015;51:1253-1262. 10.1016/j.ejca.2015.04.005. [DOI] [PubMed] [Google Scholar]

[CIT0070] 70. Kunz PL, Catalano PJ, Nimeiri H, 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;36:4004-4004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0071] 71. Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657-664. 10.1530/ERC-15-0119. [DOI] [PubMed] [Google Scholar]

[CIT0072] 72. Hentic O, Hammel P, Couvelard A, et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr Relat Cancer. 2012;19:751-757. 10.1530/ERC-12-0002. [DOI] [PubMed] [Google Scholar]

[CIT0073] 73. Hadoux J, Malka D, Planchard D, et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr Relat Cancer. 2015;22:289-298. 10.1530/ERC-15-0075. [DOI] [PubMed] [Google Scholar]

[CIT0074] 74. de Mestier L, Lamarca A, Hernando J, et al. Treatment outcomes of advanced digestive well-differentiated grade 3 NETs. Endocr Relat Cancer. 2021;28:549-561. 10.1530/ERC-21-0109. [DOI] [PubMed] [Google Scholar]

[CIT0075] 75. Hijioka S, Hosoda W, Matsuo K, et al. Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: a Japanese multicenter pancreatic NEN-G3 study. Clin Cancer Res. 2017;23:4625-4632. 10.1158/1078-0432.CCR-16-3135. [DOI] [PubMed] [Google Scholar]

[CIT0076] 76. Klein O, Kee D, Markman B, 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;26:4454-4459. 10.1158/1078-0432.CCR-20-0621. [DOI] [PubMed] [Google Scholar]

[CIT0077] 77. Patel SP, Othus M, Chae YK, 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;26:2290-2296. 10.1158/1078-0432.CCR-19-3356. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0078] 78. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: high-grade neuroendocrine neoplasm cohort. Cancer. 2021;127:3194-3201. 10.1002/cncr.33591. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0079] 79. Girard N, Mazieres J, Otto J, et al. LBA41 – Nivolumab (nivo) ± ipilimumab (ipi) in pre-treated patients with advanced, refractory pulmonary or gastroenteropancreatic poorly differentiated neuroendocrine tumors (NECs) (GCO-001 NIPINEC). Ann Oncol. 2021;32:S1283-S1346. [Google Scholar]

[CIT0080] 80. Leonetti A, Facchinetti F, Minari R, et al. Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges. Cell Oncol (Dordr). 2019;42:261-273. 10.1007/s13402-019-00441-3 [DOI] [PubMed] [Google Scholar]

[CIT0081] 81. Crabtree JS, Miele L.. Neuroendocrine tumors: current therapies, notch signaling, and cancer stem cells. J Cancer Metastasis Treat. 2016;2:279-293. [Google Scholar]

[CIT0082] 82. Crabtree JS, Singleton CS, Miele L.. Notch signaling in neuroendocrine tumors. Front Oncol. 2016;6:94. 10.3389/fonc.2016.00094. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0083] 83. Xiu MX, Liu YM, Kuang BH.. The role of DLLs in cancer: a novel therapeutic target. Onco Targets Ther. 2020;13:3881-3901. 10.2147/OTT.S244860. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0084] 84. Ladi E, Nichols JT, Ge W, et al. The divergent DSL ligand DLL3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol. 2005;170:983-992. 10.1083/jcb.200503113. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0085] 85. Chapman G, Sparrow DB, Kremmer E, et al. Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20:905-916. 10.1093/hmg/ddq529. [DOI] [PubMed] [Google Scholar]

[CIT0086] 86. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7:302ra-136. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0087] 87. Sharma SK, Pourat J, Abdel-Atti D, et al. Noninvasive interrogation of DLL3 expression in metastatic small cell lung cancer. Cancer Res. 2017;77:3931-3941. 10.1158/0008-5472.CAN-17-0299. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0088] 88. Giffin MJ, Cooke K, Lobenhofer EK, et al. AMG 757, a half-life extended, DLL3-targeted bispecific T-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021;27:1526-1537. 10.1158/1078-0432.CCR-20-2845. [DOI] [PubMed] [Google Scholar]

[CIT0089] 89. Dylla SJ. Toppling high-grade pulmonary neuroendocrine tumors with a DLL3-targeted trojan horse. Mol Cell Oncol. 2016;3:e1101515. 10.1080/23723556.2015.1101515. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0090] 90. Tendler S, Kanter L, Lewensohn R, et al. The prognostic implications of Notch1, Hes1, Ascl1, and DLL3 protein expression in SCLC patients receiving platinum-based chemotherapy. PLoS One. 2020;15:e0240973. 10.1371/journal.pone.0240973. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0091] 91. Furuta M, Sakakibara JK, Shoji T, et al. DLL3 regulates migration and invasion of small cell lung cancer. Cancer Res. 2018;78. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0092] 92. Roper N, Velez MJ, Chiappori A, et al. Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer. Nat Commun. 2021;12:3880. 10.1038/s41467-021-24164-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0093] 93. Puca L, Gavyert K, Sailer V, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0094] 94. La Salvia A, Rapa I, Metovic J, et al. Extra-pulmonary neuroendocrine carcinomas display distinct transcriptional profiles according to the site of origin. Neuroendocrinology. 2019;108:29. [Google Scholar]

[CIT0095] 95. Feng J, Wang J, Liu Q, et al. DAPT, a γ-secretase inhibitor, suppresses tumorigenesis, and progression of growth hormone-producing adenomas by targeting notch signaling. Front Oncol. 2019;9:809. 10.3389/fonc.2019.00809. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0096] 96. Huang RSP, Holmes BF, Powell C, et al. Delta-like protein 3 prevalence in small cell lung cancer and DLL3 (SP347) assay characteristics. Arch Pathol Lab Med. 2019;143:1373-1377. 10.5858/arpa.2018-0497-OA. [DOI] [PubMed] [Google Scholar]

[CIT0097] 97. Alì G, Di Stefano I, Poma AM, et al. Prevalence of delta-like protein 3 in a consecutive series of surgically resected lung neuroendocrine neoplasms. Front Oncol. 2021;11:729765. 10.3389/fonc.2021.729765. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0098] 98. Hermans BCM, Derks JL, Thunnissen E, et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer. 2019;138:102-108. 10.1016/j.lungcan.2019.10.010. [DOI] [PubMed] [Google Scholar]

[CIT0099] 99. Lima CF, Rocha P, Fujimoto Jet al. Delta-Like Ligand 3 Immunohistochemical Expression Landscape in High-Grade Lung Neuroendocrine Tumors. Presented at: AACR; April 8-13, 2022; New Orleans. [Google Scholar]

[CIT0100] 100. Rand J, Balzer BL, Frishberg DP, et al. Prevalence of delta-like protein 3 expression in Merkel cell carcinoma. J Am Acad Dermatol. 2021;85:749-750. 10.1016/j.jaad.2019.09.069. [DOI] [PubMed] [Google Scholar]

[CIT0101] 101. Xie H, Kaye FJ, Isse K, et al. Delta-like protein 3 expression and targeting in Merkel cell carcinoma. Oncologist. 2020;25:810-817. 10.1634/theoncologist.2019-0877. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0102] 102. Liverani C, Bongiovanni A, Mercatali L, et al. Diagnostic and predictive role of DLL3 expression in gastroenteropancreatic neuroendocrine neoplasms. Endocr Pathol. 2021;32:309-317. 10.1007/s12022-020-09657-8. [DOI] [PubMed] [Google Scholar]

[CIT0103] 103. Koshkin VS, Garcia JA, Reynolds J, et al. Transcriptomic and protein analysis of small-cell bladder cancer (SCBC) identifies prognostic biomarkers and DLL3 as a relevant therapeutic target. Clin Cancer Res. 2019;25:210-221. 10.1158/1078-0432.CCR-18-1278. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0104] 104. Aggarwal RR, Aparicio A, Heidenreich A, et al. Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2021;39:TPS5100-TPS5100. [Google Scholar]

[CIT0105] 105. Cimic A, Vranic S, Arguello D, et al. Molecular profiling reveals limited targetable biomarkers in neuroendocrine carcinoma of the cervix. Appl Immunohistochem Mol Morphol. 2021;29:299-304. 10.1097/PAI.0000000000000884. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0106] 106. Vranic S, Arguello D, Contreras E, et al. Molecular profiling reveals novel targetable biomarkers in neuroendocrine carcinoma of the uterine cervix. Ann Oncol. 2019;30:v430-v431. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0107] 107. Song HY, Wang Y, Lan H, et al. Expression of notch receptors and their ligands in pancreatic ductal adenocarcinoma. Exp Ther Med. 2018;16:53-60. 10.3892/etm.2018.6172. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0108] 108. Ingenwerth M, Brandenburg T, Fuhrer-Sakel D, et al. DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas. Endocr Connect. 2021;10:283-289. 10.1530/EC-20-0611. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0109] 109. Ogawa H, Sakai Y, Nishio W, et al. DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC. Thorac Cancer. 2020;11:2561-2569. 10.1111/1759-7714.13574. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0110] 110. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18:42-51. 10.1016/S1470-2045(16)30565-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0111] 111. Tanaka K, Isse K, Fujihira T, et al. Prevalence of Delta-like protein 3 expression in patients with small cell lung cancer. Lung Cancer. 2018;115:116-120. 10.1016/j.lungcan.2017.11.018. [DOI] [PubMed] [Google Scholar]

[CIT0112] 112. Xie H, Boland JM, Maleszewski JJ, et al. Expression of delta-like protein 3 is reproducibly present in a subset of small cell lung carcinomas and pulmonary carcinoid tumors. Lung Cancer. 2019;135:73-79. 10.1016/j.lungcan.2019.07.016. [DOI] [PubMed] [Google Scholar]

[CIT0113] 113. Rath B, Plangger A, Krenbek D, et al. Rovalpituzumab tesirine resistance: analysis of a corresponding small cell lung cancer and circulating tumor cell line pair. Anticancer Drugs. 2022;33:300-307. 10.1097/CAD.0000000000001267. [DOI] [PubMed] [Google Scholar]

[CIT0114] 114. Messaritakis I, Nikolaou M, Koinis F, et al. Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment. J Clin Oncol. 2019;37. [DOI] [PubMed] [Google Scholar]

[CIT0115] 115. Muscarella LA, Mazza T, Fabrizio FP, et al. Neuroendocrine-related circulating transcripts in small-cell lung cancers: detection methods and future perspectives. Cancers (Basel). 2021;13. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0116] 116. Lim S, Hong M, Kim SP, et al. P2.12-18 Prevalence of DLL3 expression and its prognostic role in extensive stage small cell lung cancer. J Thorac Oncol. 2019;14(10 Suppl):S820. [Google Scholar]

[CIT0117] 117. Fu X, Liu Z, Xiang L, et al. PD-L1 predicts poor prognosis in surgically resected limited stage small-cell lung cancer. Cancer Manag Res. 2020;12:10939-10948. 10.2147/CMAR.S260599. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0118] 118. Akamatsu H, Udagawa H, Tanaka K, et al. Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC). J Clin Oncol. 2019;37:8557. [DOI] [PubMed] [Google Scholar]

[CIT0119] 119. Morgensztern D, Besse B, Greillier L, 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;25:6958-6966. 10.1158/1078-0432.CCR-19-1133. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0120] 120. Alcala N, Leblay N, Gabriel AAG, et al. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun. 2019;10:3407. 10.1038/s41467-019-11276-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0121] 121. Prieto T, Baldavira CM, Ab´saber A, et al. P47.11 DLL-3 and ASCL-1 expression emerge as promising therapeutic targets in high-grade neuroendocrine lung tumors: a preliminary study. J Thorac Oncol. 2021;16:S496-S497. [Google Scholar]

[CIT0122] 122. Chauhan A, Kim JT, Weiss H, et al. Potentiating mTOR’s antineoplastic effects with rovalpituzumab tesirate in neuroendocrine tumors. Pancreas. 2018;47:335. [Google Scholar]

[CIT0123] 123. Mansfield AS, Hong DS, Hann CL, et al. A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors. NPJ Precis Oncol. 2021;5:74. 10.1038/s41698-021-00214-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0124] 124. Blackhall F, Jao K, Greillier L, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: results from the phase 3 TAHOE study. J Thorac Oncol. 2021;16:1547-1558. 10.1016/j.jtho.2021.02.009. [DOI] [PubMed] [Google Scholar]

[CIT0125] 125. Johnson ML, Zvirbule Z, Laktionov K, et al. Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: results from the phase 3 MERU study. J Thorac Oncol. 2021;16:1570-1581. 10.1016/j.jtho.2021.03.012. [DOI] [PubMed] [Google Scholar]

[CIT0126] 126. Morgensztern D, Johnson M, Rudin CM, et al. SC-002 in patients with relapsed or refractory small cell lung cancer and large cell neuroendocrine carcinoma: phase 1 study. Lung Cancer. 2020;145:126-131. 10.1016/j.lungcan.2020.04.017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0127] 127. Cooke K, Estrada J, Zhan J, et al. 627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer. J ImmunoTher Cancer. 2020;8:A663-A663. [Google Scholar]

[CIT0128] 128. Owonikoko T, Boyer M, Johnson M, et al. OA11.03 A phase 1 study of AMG 757, half-life extended bispecific T-cell engager (BiTE®) immune therapy against DLL3, in SCLC. J Thorac Oncol. 2021;16:S126. [Google Scholar]

[CIT0129] 129. Hipp S, Voynov V, Drobits-Handl B, et al. A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020;26:5258-5268. 10.1158/1078-0432.CCR-20-0926. [DOI] [PubMed] [Google Scholar]

[CIT0130] 130. Wermke M, Felip E, Gambardella V, et al. A phase I, open-label, dose-escalation trial of BI 764532, a DLL3/CD3 bispecific antibody, in patients (pts) with small cell lung carcinoma (SCLC) or other neuroendocrine neoplasms expressing DLL3. J Clin Oncol. 2021;39:TPS8588-TPS8588. [Google Scholar]

[CIT0131] 131. Aaron WH, Austin R, Barath M, et al. Abstract C033: HPN328: An anti-DLL3 T cell engager for treatment of small cell lung cancer. Mol Cancer Ther. 2019;18:C033-C033. [Google Scholar]

[CIT0132] 132. ClinicalTrials.gov. Study in Patients with Advanced Cancers Associated with Expression of DLL3 Who Have Failed Standard Available Therapy. https://clinicaltrials.gov/ct2/show/NCT04471727. Accessed September 26, 2021.

PERMALINK

DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

James Yao

Emily Bergsland

Rahul Aggarwal

Ana Aparicio

Himisha Beltran

Judy S Crabtree

Christine L Hann

Toni Ibrahim

Lauren A Byers

Hironobu Sasano

John Umejiego

Marianne Pavel

Abstract

Introduction

Methods

Discussion

Conclusions

Implications for Practice.

Introduction

Methods

Overview of NEN

Classification

Table 1.

Incidence

Pathogenesis

Evolution and Prognosis

Current Management

DLL3 Signaling in NEN Tumorigenesis

Tumorigenesis of Notch1, DLL3 in NEN

DLL3 and Notch in Development of NEN

DLL3 and Inflammatory Biomarkers in NEN

DLL3 Expression in NEN

Figure 1.

Figure 2.

Prevalence in NET

Prevalence in NEC

Pulmonary NEC and SCLC

NEPC

Other NEC

Clinical Implications of DLL3 in NEN

DLL3-Targeting Therapies

Table 2.

Conclusions

Acknowledgments

Contributor Information

Funding

Conflict of Interest

Author Contributions

Data Availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases