Imaging with [ ⁸⁹ Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with neuroendocrine tumors of the prostate: A phase 1/2, first-in-human trial.

e15057 Background: Delta-like ligand 3 (DLL3) is expressed on the tumor cell surface of some neuroendocrine prostate cancer (NEPC). We assessed the safety and feasibility of the DLL3-targeted imaging tracer [ 89 Zr]Zr-DFO-SC16.56, which is composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine (DFO) and zirconium-89 in patients with NEPC. Methods: We conducted an open-label, first-in-human study of immunoPET/CT imaging with [ 89 Zr]Zr-DFO-SC16.56. The initial phase I included patients with small-cell lung cancer (n=3) that showed high tumoral uptake of the diagnostic tracer without any major adverse events. The expansion cohort included NEPC patients that received a single infusion of [ 89 Zr]Zr-DFO-SC16.56 at the same activity (1-2 mCi) and mass dose (2-3 mg) as in the initial cohort followed by a single PET-CT scan 3–5 days later. Retrospectively collected tumor biopsy samples were assessed for DLL3 by immunohistochemistry (IHC). DLL3 positive expression was defined as ≥ 5% weak (1+) IHC staining intensity. The primary endpoint of the expansion cohort was to determine the correlation between tumor uptake of [ 89 Zr]Zr-DFO-SC16.56 with expression of DLL3 as determined by IHC. Results: Between April 2023, and October 2024, 11 men with NEPC were enrolled, with a median age of 60 years (range 51–80). A single immunoPET/CT scan on day 3–5 post-administration could delineate DLL3-avid tumors in 6 (55%) of 11 patients. A range in tumoral uptake was observed within individual patients as well as the entire cohort, with a wide range in maximum standardized uptake value (from 0·4 to 75·5). Tumoral uptake by [ 89 Zr]Zr-DFO-SC16.56 was associated with protein expressionin 8 (80%) of 10 patients who had DLL3 IHC performed.None of the patients had any adverse events noted, and no clinically meaningful changes were observed in vital signs or laboratory parameters post injection. Conclusions: DLL3 PETCT imaging of patients with NEPC is safe and feasible. These results show the potential utility of [ 89 Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of NEPC patients. Clinical trial information: 19-292 . Characteristics of patients included in the study. Age DLL3 avid SUV max of highest DLL3-avid lesion (anatomic location of most avid lesion) Blood uptake from day 3–5 images, SUV mean Biopsy location (immunohistochemistry H-score) Patient 1 71 No 2·2 (liver) 3·7 Liver (0) Patient 2 58 Yes 75·5 (liver) 2·4 Liver (220) Patient 3 57 No 0·4 (Sacrum) 0·7 Prostate (0) Patient 4 60 Yes 11·3 (Humerus) 1·3 Liver (190) Patient 5 80 Yes 39·9 (liver) 5·8 Pleurae (280) Patient 6 62 Yes 10·4 (Sacrum) 7·1 Liver (0) Patient 7 51 No 6·7 (lymph node) 6·5 Lymph node (170) Patient 8 60 Yes 36·4 (liver) 6·3 Liver (230) Patient 9 55 Yes 20·3 (liver) 7·0 R Liver (170) Patient 10 74 No 3·9 (vertebrae) 7·5 Liver (NA) Patient 11 65 No 1·7 (vertebrae)