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DLL3 EP NECs
DLL3 Targeting in Extrapulmonary Neuroendocrine Carcinomas: A New Approach for an Unmet Clinical Need

Released: November 17, 2025

Daniel Morgensztern
Daniel Morgensztern, MD
Jonathan Strosberg
Jonathan Strosberg, MD
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Key Takeaways
  • EP-NECs are highly aggressive tumors with limited treatment options and poor prognosis using current standard-of-care approaches.
  • DLL3 is highly expressed in many EP-NECs and represents a promising, tumor-specific target for therapeutic intervention.
  • Obrixtamig, a DLL3/CD3 T-cell engager, has shown encouraging early efficacy in EP-NECs and is under investigation in both second and first lines of therapy.

Extrapulmonary (EP) neuroendocrine carcinomas (NECs) remain among the most aggressive and therapeutically underserved malignancies in oncology. Although treatment has long been limited to platinum-based chemotherapy regimens, recent advances in DLL3-targeted agents may finally offer a distinct and promising pathway forward. In this commentary, we provide our clinical perspectives on the biology and evolving treatment landscape of EP-NECs and the therapeutic potential of DLL3-targeted T-cell engagers (TCEs) for this disease type.

Defining EP-NECs: Histology and Prognosis 

Jonathan Strosberg, MD:
EP-NECs are a rare and challenging group of malignancies that lie on the most aggressive end of the neuroendocrine neoplasm spectrum. Although well-differentiated neuroendocrine tumors (NETs) are classified into 3 grades by Ki-67 proliferation index and mitotic count, poorly differentiated NECs are high grade by definition and distinguished by markedly elevated Ki-67—often 60% to 100%—and an aggressive clinical course.

Histologically, EP-NECs are subdivided into small-cell and large-cell types and often have pleomorphic features, high nuclear-to-cytoplasmic ratios, and widespread necrosis. Although this histologic division mirrors the classification used in pulmonary NECs, it is still uncertain whether small-cell vs large-cell histology has true prognostic or clinical implications in the EP setting.

Most NECs originate in the lung and are primarily SCLC whereas EP cases account for approximately 10% of all NECs. These EP cases are diverse in origin, with approximately one third arising from the gastrointestinal tract—commonly colon, pancreas, and esophagus—another one third from urogenital organs like the cervix or bladder, and many of the remainder presenting as cancers of unknown primary origin.

In practice, distinguishing between well-differentiated NETs and poorly differentiated NECs via pathology is usually straightforward, but ambiguities exist. In those cases, genomic profiling can offer insights. NECs commonly have mutations in TP53, RB1, and occasionally SMAD4, or mutations common to adenocarcinomas from the corresponding organ, like KRAS or BRAF in colon NECs. Somatostatin receptor imaging (typically negative in NEC) and FDG-PET imaging can offer supportive diagnostic evidence, although it is not definitive.

Similar to SCLC, EP-NECs are usually identified in the metastatic stage. The prognosis is poor with median overall survival of approximately 7-8 months compared with more than 21 months for grade 3 NETs. Patients with poor performance status have lower median overall survival and in many cases are unable to even initiate treatment.

The Gap in Treatment for EP-NECs 

Jonathan Strosberg, MD:
EP-NEC treatment has long mirrored SCLC approaches. First-line therapy is typically platinum/etoposide, although alternatives like FOLFIRINOX are sometimes considered for gastrointestinal disease. Response rates range from 30% to 50%, but durability is short lived. Beyond the first line, no standard therapies exist. If a patient has more than a 3- to 6-month interval of benefit after first-line platinum/etoposide, we tend to resume the same chemotherapy. Other options include FOLFOX, FOLFIRI, and sometimes capecitabine/temozolomide, but outcomes remain poor, with median overall survival of approximately 6 months.

Checkpoint inhibitors, although demonstrating benefit in SCLC, have not yet shown definitive benefit in EP-NEC populations. Single-agent checkpoint inhibitors are relatively ineffective and combination strategies have demonstrated only modest benefit in a subset of patients. There is an urgent, unmet need for targeted therapies that can effectively engage the unique biology of this disease.

DLL3: From Developmental Biology to Therapeutic Opportunity 

Daniel Morgensztern, MD:
DLL3 is emerging as a pivotal biomarker and therapeutic target in high-grade NECs. A member of the Notch signaling family, DLL3 is a ligand that is normally confined to intracellular compartments but, in SCLC and EP-NECs, is often overexpressed and aberrantly expressed on the cell surface.

Conveniently, there is little expression in normal tissue. This selective expression profile has made DLL3 one of the most promising targets in NECs.

Early efforts to target DLL3 via antibody–drug conjugates, such as rovalpituzumab tesirine, were ultimately unsuccessful because of poor efficacy and marked toxicity. However, those trials established the clinical relevance of DLL3 as a therapeutic target and paved the way for the current generation of DLL3-directed therapies, particularly bispecific antibodies.

Obrixtamig and the Rise of DLL3-Directed Bispecific TCEs

Daniel Morgensztern, MD:

Among the most promising developments in DLL3-targeted therapy is obrixtamig, a bispecific antibody that simultaneously binds to DLL3 on tumor cells and CD3 on T-cells. Unlike tarlatamab, which has been evaluated primarily in SCLC, obrixtamig has shown activity in a broader range of neuroendocrine cancers, including EP-NECs.

In a recent phase I study enrolling patients with DLL3-positive advanced NECs, including SCLC, EP-NEC, and large-cell NEC, obrixtamig demonstrated an overall response rate of 23% across all tumor types. Critically, among patients with EP-NECs and high DLL3 expression (defined as ≥50% of tumor cells being positive for DLL3), the overall response rate was 40%, with a disease control rate of 67%. Duration of response was 7.9 months for these patients with DLL3high EP-NECs. The adverse effect profile was generally manageable and comparable to other DLL3-targeting TCEs with cytokine-release syndrome occurring in more than one half of patients, although most cases were low grade. Neurologic adverse events, including immune effector cell–associated neurotoxicity syndrome, were rare but still a consideration when selecting patients for this treatment in the future.

Ongoing trials are expanding the evidence for DLL3-targeting TCEs in EP-NECs. For example, the actively recruiting phase II DAREON-5 study (NCT05882058) is evaluating obrixtamig monotherapy in patients with EP-NECs after at least 1 line of prior therapy, among other NECs. The phase I DAREON-7 trial (NCT06132113) is combining obrixtamig with platinum-etoposide for non-SCLC NECs in the frontline setting and is still enrolling patients. Tarlatamab is also being investigated for various EP-NECs in the phase II TAURUS and RAGNAR trials, and there are 2 other DLL3-targeted bispecific antibodies in ongoing trials for the treatment of NECs.

The promising results of the phase I obrixtamig trial, these ongoing studies, and obrixtamig’s fast track designation by the FDA for EP-NECs in the second-line setting suggest that DLL3-targeted therapies may fill the need for effective treatment options in these diseases.

A Future for Targeted Therapies in EP-NECs 

Jonathan Strosberg, MD:
Naturally, these agents are first tested in the second line and beyond and after positive results could be tested and incorporated into the first line. There are many cases where patients are unfit for second-line chemotherapy, so if DLL3-targeted TCEs could be added to first-line chemotherapy or possibly instead of chemotherapy, this could be of great benefit to patient prognosis.

Daniel Morgensztern, MD:
I can also see the possibility of borrowing other targeted agents from SCLC, such as those targeting SEZ6, B7-H3, and TROP2, which could expand treatment options further. For instance, a DLL3-targeted TCE could be followed by an antibody–drug conjugate for TROP2 with a topo I payload, but these targets would need to be confirmed as overexpressed in EP-NECs. The next several years will be exciting for the EP-NEC treatment paradigm as we shift away from chemotherapy.

Your Thoughts
What challenges have you faced when treating patients with EP-NECs? What barriers do you foresee in integrating DLL3-targeted agents into clinical practice? Share your perspectives on how these therapies could reshape care for this rare and challenging disease type.

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How often do you discuss clinical trials of investigational agents, such as DLL3-targeted therapies, with your patients diagnosed with EP-NECs?

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