At the NANETs 2025 Multidisciplinary NET Medical Symposium, investigators presented updated phase 1 results for obrixtamig, a DLL3/CD3 bispecific T-cell engager, showing encouraging efficacy in patients with DLL3-high extrapulmonary neuroendocrine carcinoma.

DLL3 is an inhibitory ligand selectively expressed in high-grade neuroendocrine carcinomas, making it an attractive therapeutic target. Obrixtamig, designed to redirect T cells toward DLL3-expressing tumor cells, is being evaluated in an ongoing phase 1 trial in patients with DLL3-positive pulmonary and extrapulmonary neuroendocrine carcinoma who have progressed on standard therapies.

The study included 60 patients with DLL3-positive extrapulmonary neuroendocrine carcinoma, evenly divided between DLL3-high and DLL3-low expression groups. Participants received obrixtamig via step-up or weekly dosing regimens. Baseline characteristics were well balanced between groups, with a median age of 63.9 years in DLL3-high and 59.1 years in DLL3-low cohorts. Nearly all patients were heavily pretreated, and up to half had received more than 2 prior lines of systemic therapy.

Efficacy outcomes favored the DLL3-high cohort. The objective response rate (ORR) was 40% (95% confidence interval [CI], 24.6 to 57.7) in DLL3-high tumors compared to 3.3% (95% CI, 0.6 to 16.7) in DLL3-low tumors. The disease control rate (DCR) was 66.7% vs 26.7%, respectively. Median duration of response reached 7.9 months (95% CI, 6.2 to not calculable) for DLL3-high tumors, compared with 2.8 months for DLL3-low. Responses occurred most often in DLL3-high gastroenteropancreatic (50%) and genitourinary (60%) primaries, and seven DLL3-high patients remain on treatment.

Treatment-related adverse events (TRAEs) were reported in all DLL3-high and 90% of DLL3-low patients. Grade ≥3 TRAEs occurred in 23.3% and 20%, respectively. Cytokine release syndrome (CRS) was observed in 70% of DLL3-high and 60% of DLL3-low patients, though grade ≥3 CRS was infrequent (3.3% each). Neurotoxicity, including immune effector cell–associated neurotoxicity syndrome, occurred in 16.7% and 10% of patients, respectively. Most events were mild to moderate and manageable with supportive care.

These findings suggest that obrixtamig delivers meaningful and durable responses in DLL3-high extrapulmonary neuroendocrine carcinoma, a population with limited therapeutic options. The manageable safety profile and 40% response rate support continued investigation of obrixtamig as a potential targeted immunotherapy for DLL3-expressing neuroendocrine carcinomas.

Source:

Capdevila J, Gambardella V, Kuboki Y, et al. An ongoing phase 1 trial of obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression. Presented at the NANETs 2025 Multidisciplinary NET Medical Symposium; October 23-25, 2025. Austin, Texas. Abstract ID 33400