DLL3 Expression in Neuroendocrine Neoplasms – an overview

Updated 20th August 2025

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Background

– Conventional therapeutic targets for neuroendocrine tumours (NETs) include somatostatin receptors (SSTRs), mammalian Target of Rapamycin (mTOR), Vascular Endothelial Growth Factor (VEGF), and tyrosine kinases. These pathways are crucial for tumour growth, survival, and angiogenesis. The most well known is SSTRs given that most NETs express these and allows targeted therapies such as somatostatin analogues (SSA) and peptide receptor radionuclide therapy (PRRT) to be used. Other targeted therapies like everolimus and sunitinib, which inhibit mTOR and tyrosine kinases respectively. Sunitinib also targets VEGF as does cabozantinib.

For neuroendocrine carcinomas (Grade 3 poorly differentiated), targeting has been difficult and these neoplasms have relied on systemic chemotherapy. Targeting using immunotherapy is appearing mainly by targeting Programmed cell death protein 1 (PD-1).

Personalised medicine is starting to appear in cancer treatment with the introduction of novel molecular targeted drugs. Scientists have uncovered a variety of molecular alterations that can be exploited for personalised treatment. These include (but are not limited to) HER2, PIK3CA, ERBB2, EGFR, BRAF, and NTRK mutations or fusions. These discoveries have led to the development of targeted therapies that can specifically inhibit these molecular alterations, thereby halting the progression of cancer. A few examples of molecular markers and targeted therapies:

HER2:In breast cancer, a protein called HER2 can be overexpressed. Drugs like trastuzumab and lapatinib can target HER2 and improve outcomes.
EGFR:In non-small cell lung cancer, mutations in the EGFR gene can be targeted with drugs like gefitinib and erlotinib.
BRAF:In melanoma, mutations in the BRAF gene, particularly the V600E mutation, can be targeted with vemurafenib and other BRAF inhibitors.

But what about Neuroendocrine Neoplasms?

Delta-like ligand 3 (DLL3) appears to be at the head of that pack but currently this is mainly with Neuroendocrine Carcinomas in the lung (small cell lung cancer). I wanted to focus the remainder of this post on DLL3, starting with scope which is really important in this heterogeneous collection of cancers.

It’s worth pointing out that these DLL3 targeted drugs tend to be used alongside and mediated via several different mechanisms (e.g., antibody-drug conjugates, T-cell engager molecules, CAR-Ts). Just to clarify why this is important – from Reference 3, antibody–drug conjugates (ADCs) are novel pharmacological agents, consisting of a monoclonal antibody targeting a specific tumour biomarker, linked to a cytotoxic drug. Once the antibody and its target bind, the drug is released in the tumoral environment, with reduced peripheral action. DLL3 has been investigated as a target for ADCs, given the discussed evidence and its association with NENs. Most studies have focused on SCLC due to their reported DLL3 overexpression and the limited availability of targeted therapies for this malignancy. One way of understanding that better is to think about how PRRT works; i.e. it comprises a somatostatin analogue which targets somatostatin receptors and delivers radiation to that area. The concept of DLL3 targeted therapy and the mediating mechanisms is similar in some ways to the mechanism of PRRT i.e. a targeted drug takes the ‘payload’ to the tumour.

Scope of DLL3 expression in Neuroendocrine Neoplasms

Why is this important?

One of the reasons for writing this blog is to ensure my readers are up to date with these developments. But also to ensure they understand that this treatment may not be suitable for them, and it it is, that it may not be available for them currently (even in clinical trials). Expectations need to be managed otherwise many people get false hope. This blog followed a post in my group where a lot of people who probably have zero or very low expression of DLL3, got very excited because the poster did not make this important point.

Which NEN types are more likely to have DLL3 expression?

DLL3 is overexpressed in many NENs, implicated in tumour progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN, particularly other Neuroendocrine Carcinomas.

Tarlatamab is a BiTE against delta-like ligand 3 (DLL3). Approved for extensive stage (ES). Technically SCLC is a pulmonary NEC, although that’s a moot point in thoracic circles (SCLC tends to be led by Lung MDTs). Reference 9.

If you study Reference 1, you will see the scope is wide although common in some areas but not in others. For example, DLL3 expression was significantly higher in NEC (average 64.0%) compared to GEP-NET and pulmonary carcinoids, although the latter has a respectable figure (see below). The expression is particularly strong in small cell NEC (SCNEC) (80.4%), followed by Large Cell NEC (LCNEC) (62.6%) and Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN) (28.6%).

Also from, Reference 1, DLL3 was common in typical/atypical Lung NET (aka pulmonary carcinoids) (41.5%), but rare in Gastroenteropancreatic NETs (GEPNET) (5.1%) and non-neuroendocrine carcinomas (1.3%). The latter is important to note when pathologists are looking to differentiate between Neuroendocrine Carcinomas and non-Neuroendocrine Carcinomas. Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%) – my interpretation of that is that the sample could be taken from either a primary or a secondary tumour and still be accurate.

Reference 2, is a highly technical paper but it does confirm the findings above that DLL3 was not found in high-grade, well-differentiated GEP-NETs, whereas it was expressed in 76.9 % of poorly differentiated NECs. (But see Reference 8 below regarding high grade pancreatic NETs). The assumption from this statement is that the same would apply to grades 1 and 2 GEP-NETs. That said, there are always outliers and Reference 1 stated that 5.1% of GEP-NETs had some form of DLL3 expression. This is potentially contradicted by Reference 3 which concluded that DLL3 is expressed on a majority of GEP-NECs and on a subset of high grade PanNETs marked by poor outcomes. Functional imaging suggests DLL3 as a promising therapeutic target in both GEP-NECs and high grade PanNETs (see also addition dated 3rd Aug 2025 below)

The other important point to note is that some NETs rarely ‘dedifferentiate’ over time and need different types of treatment. This might explain the evidence of DLL3 in a small fraction of GEPNETs but it also provides a glimmer of hope that something else is potentially available in such scenarios.

Interestingly, Reference 2 confirms some DLL3 expression in Medullary Thyroid Cancer, Cervical NEC, Bladder NEN, Neuroendocrine Prostate Cancer (NEPC) and Merkel Cell Carcinoma (a NEC of the skin).

Added 3rd August 2025.

Delta-like ligand 3 expression and functional imaging in gastroenteropancreatic neuroendocrine neoplasms

Rohit Thummalapalli, Salomon Tendler, Joanne F. Chou, Zeynep C. Tarcan, Courtney Porfido, Jonathan Willner, Irina Linkov, Umesh Bhanot, Alissa J. Cooper, Jierui Xu, James J. Harding, Natasha Rekhtman, Laura H. Tang, Charles M. Rudin, Yelena Y. Janjigian, Heiko Schöder, John T. Porier, Jinru Shia, Olca Basturk, Diane Reidy-Lagunes, Marinela Capanu, Jason S. Lewis, Lisa Bodei, Mark P. Dunphy, Nitya Raj

doi: https://doi.org/10.1101/2025.06.24.25330227

This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Results Among GEP NECs, DLL3 expression was identified in 53/75 (71%) samples, was enriched for small cell histology, and did not demonstrate prognostic significance. Among well differentiated pancreatic NETs (PanNETs), DLL3 expression was identified in 22/51 (43%) grade 3 (G3) tumors, with univariate analysis revealing increased mortality risk among patients with DLL3-positive advanced G3 PanNETs (hazard ratio 3.27, 95% confidence interval 1.09-9.78). Between May 28, 2024 and February 10, 2025, six patients with DLL3 IHC-positive GEP NENs were enrolled onto the imaging protocol. [⁸⁹Zr]Zr-DFO-SC16.56 immunoPET-CT imaging delineated DLL3-avid tumor lesions in five of six patients (two of two GEP NECs, three of four G3 PanNETs). Tumor-specific uptake of [⁸⁹Zr]Zr-DFO-SC16.56 varied between patients, with maximum standard uptake values ranging from 7.4-36.7, with four of six cases demonstrating DLL3 avidity in ≥ 50% of tumor lesions.

Conclusion DLL3 is expressed on a majority of GEP NECs and on a subset of high grade PanNETs marked by poor outcomes. Functional imaging suggests DLL3 as a promising therapeutic target in both GEP NECs and high grade PanNETs.

Author’s note. I believe this is an important point for well differentiated Grade 3 pancreatic NET. This imaging can provide a DLL-3 phenotype assessment in the same way as SSTR PETs/FDG PETs which can help to guide treatment.

What clinical trials are available for DLL3 targeted therapies in Neuroendocrine Neoplasms?

As above, most are focused on small cell lung cancer (a type of Lung NEC). One example is this one (Reference 4) – A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301). Click here. There are others for SCLC, see this table here. from Reference 5. Note, the source is from 2023, so it is possible some clinical trials are complete or no longer recruiting. *Note in 2024, the FDA approved tarlatamab for extensive stage (ES) SCLC (see Reference 9).

See also the Darian trial below which covers both pulmonary NEC and extrapulmonary NEC below. DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers. ASCO recently published some output from the Phase 1 trial where they concluded that the trial demonstrated tolerability and efficacy of obrixtamig regimens, administered as step-up followed by target doses of 90-1,080 μg/kg (once weekly or once every 3 weeks), in patients with heavily pretreated DLL3-positive tumors support further exploration in SCLC, epNEC, and LCNEC-L. See Reference 7 below.

What about outside the lung (extrapulmonary) ?

Clinical Trials database is now showing a bunch of new trials for extrapulmonary NEC – click here to read more. See also the international Darian trial below which covers both pulmonary NEC and extrapulmonary NEC using a drug called Obrixtamig (BI 764532). An update of the phase 1 trial is tagged at Reference 7.

Click here to read an article covering this trial.
Click here. to read the clinical trial document.

What about lower grade NETs?

This trial is based in California only and looks at regular NETs not already mentioned (the terms typical carcinod and atypical carcinod refer to Lung NET/Thymic NET).

Criteria

Histologically or cytologically confirmed malignancy other than de novo (i.e., non-transformed) SCLC or NEPC. Must be stage IV (metastatic); participants with stage III disease are eligible provided that they are not candidates for surgery and/or radiotherapy with curative intent. Acceptable tumor types include the following:

a. Low and intermediate grade neuroendocrine NET (including carcinoid and atypical carcinoid)
b. Gastroenteropancreatic NEN
c. Large cell neuroendocrine carcinoma
d. SCLC transformed from previously-treated NSCLC
e. Extrapulmonary small cell carcinoma, with the exception of NEPC
f. Any other tumor type that meets staging and DLL3 positivity criteria*
g. Positive DLL3 expression by immunohistochemistry on tumor biopsy.

2 Positive DLL3 expression, for purposes of this study, defined as at least 25% for participants enrolling into Stage 1 or 1% for participants enrolling into Stage 2.

3. Participants must have progressed on or following at least one line of therapy, if a standard of care therapy exists for the tumor type.

Click here to read the clinical trial document. NCT06788938

I will add others as I find them.

Summary

I decided to provide the conclusions to Reference 5 which should keep you grounded.

Conclusions
DLL3 is an inhibitory ligand of the Notch receptor, mostly studied in SCLC, although it has been found to be expressed in most NENs. Its role is related to tumorigenesis and poor prognosis. Since NENs are heterogeneous and have different features and behaviours according to their clinical history, a potentially ubiquitous target could be a useful tool for expanding diagnostic and therapeutic strategies. Current evidence regarding DLL3 has prompted multiple clinical trials investigating innovative therapies and molecular imaging methods. Nonetheless, certain issues must be resolved to comprehensively understand and examine the potential clinical application of this molecule, including the absence of universally recognized kits for evaluating DLL3 expression and the observed extreme toxicity of recently created drugs. In conclusion, DLL3 is a surface molecule expressed in various NE malignancies, which holds great potential as a target for diagnostic and therapeutic options while also providing significant prognostic value. Although the collected evidence is promising, further studies are required to determine the actionable implications of this target for clinical practice, evaluating novel imaging techniques and new drug options in larger populations.

Author’s note. I’m sure this will be of more interest to those in the Neuroendocrine Carcinoma community (including GEPNEC). However, those with typical/atypical Lung NETs probably want to keep an eye on developments given the relatively high rates of DLL3 expression (actually quite similar to their rate of SSTR expression). If you’re from the GEPNET community, some caution is advised in interpreting what others say inside patient support groups and what you read online about these novel treatment therapies for Neuroendocrine Neoplasms (NENs). See Scope of DLL3 expression above and remember that NENs are a highly heterogenous collection of cancers.

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