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

Delta-like ligand 3 (DLL3) is an emerging target across neuroendocrine cancers, but remains underexplored in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) including poorly differentiated neuroendocrine carcinomas (GEP NECs) and well differentiated neuroendocrine tumors (NETs). We aimed to define the landscape of DLL3 expression and feasibility of DLL3-targeted imaging in this population.

We completed DLL3 immunohistochemistry (IHC) on 360 tumor samples from patients with GEP NENs, analyzing associations between DLL3 IHC positivity and clinicopathologic features and outcomes. [⁸⁹Zr]Zr-DFO-SC16.56 DLL3 immunoPET-CT imaging was performed in six patients with DLL3 IHC-positive advanced GEP NENs as part of a phase II clinical trial.

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.

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.