Analysis of delta-like ligand 3 (DLL3) expression levels and characteristics of patients (pts) with advanced extrapulmonary neuroendocrine carcinomas (epNECs) from an ongoing phase I trial.

Abstract

2642 Background: Specific DLL3 expression on the surface of epNEC tumor cells makes it a promising therapeutic target, but there is a lack of prospective data on DLL3 expression patterns in pts with epNEC. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager. The first-in-human phase I trial (NCT04429087) showed obrixtamig activity in pts with DLL3-positive epNEC, especially pts with DLL3-high tumors (Capdevila et al, ASCO 2025, #3004). We report updated DLL3 expression data and pt/tumor characteristics in pts with epNEC from NCT04429087. Methods: DLL3 IHC was performed with an investigational DLL3 antibody (SP347) at the Roche CDx CAP/CLIA Laboratory. DLL3 expression was categorized as: negative (absent or weak tumor cell [TC] membrane/cytoplasm staining), positive (moderate-to-strong staining in any TCs), high (≥50% moderate-to-strong TC staining), or low (<50% moderate-to-strong TC staining). Results: As of Sept 4, 2025, 282 of 365 screened pts with epNEC were DLL3-evaluable, of whom 235 (83.3%) had DLL3-positive tumors (DLL3-high: n=120 [42.6%], DLL3-low: n=115 [40.8%]); 47 (16.7%) were DLL3-negative. In the DLL3-positive treated set (n=93), 51 pts (54.8%) had DLL3-high and 42 (45.2%) had DLL3-low tumors. The prevalence of DLL3-high tumors in male/female pts was 47.5%/68.8%, and prevalence in pts with liver/brain metastases was 57.1%/70.0%. DLL3-high prevalence by primary tumor site, GI/GU/cancer of unknown primary site (CUP), was 44.9%/67.7%/60.0%. Pt characteristics in obrixtamig-treated DLL3-high and -low epNEC subgroups are in Table 1. Conclusions: In the largest prospectively screened cohort of pts with epNEC, high (83.3%) prevalence of DLL3 expression was seen, underscoring DLL3 as a promising target for clinical development of DLL3-targeted therapies such as obrixtamig. Obrixtamig safety and efficacy in pts with DLL3-positive epNEC are being assessed in several ongoing trials, including DAREON-5 (NCT05882058), with the data expected to inform and support Phase III development. Clinical trial information: NCT04429087 . DLL3-high (n=51) DLL3-low (n=42) Male / female, n (%) 29 (56.9) / 22 (43.1) 32 (76.2) / 10 (23.8) Primary tumor site: GI / GU / CUP, n (%) 22 (43.1) / 21 (41.2) / 6 (11.8) 27 (64.3) / 10 (23.8) / 4 (9.5) Lactate dehydrogenase ≤ULN / >ULN, n (%) 22 (43.1) / 29 (56.9) 16 (38.1) / 26 (61.9) Prior lines of therapy: 1 / 2 / 3 / >3 12 (23.5) / 17 (33.3) / 9 (17.6) / 13 (25.5) 11 (26.2) / 12 (28.6) / 10 (23.8) / 9 (21.4) Median duration of prior anticancer treatment, weeks (range) 22 (5–349) 22 (8–148) Prior radiotherapy / surgery / anti PD-(L)1, n (%) 22 (43.1) / 28 (54.9) / 14 (27.5) 11 (26.2) / 24 (57.1) / 9 (21.4) Liver / brain metastases, n (%) 40 (78.4) / 7 (13.7) 30 (71.4) / 3 (7.1) Median sum of diameters of target lesions, mm (IQR) 87.5 (64.0–123.0) 117.3 (66.2–176.0)