Abstract LB-A003: Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: results from an ongoing Phase I trial

Abstract Background Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NECs). Obrixtamig (BI 764532) is a DLL3/CD3 immunoglobulin G-like T-cell engager that targets DLL3-positive (DLL3+) tumors. NCT04429087 is an ongoing, Phase I, dose-escalation trial of obrixtamig in patients (pts) with DLL3+ pulmonary and extrapulmonary NEC (epNEC) that failed to respond to standard treatment (Tx). The efficacy and safety of obrixtamig in pts with epNEC with high versus low DLL3 expression were examined. Methods Obrixtamig was given intravenously in 4 dose-escalation regimens (R’s)—RA (fixed dose every 3 weeks q3w), RB1 (fixed dose once weekly qw), RB2 (step-up dose, then qw), and RB3 (step-up dose, then qw for 3 weeks, then q3w)—until disease progression or unacceptable toxicity. Efficacy was assessed through objective response rate (ORR) and disease control rate (DCR) using RECIST version 1.1. Results are reported in pts who received obrixtamig RB2 or RB3, categorized as having high vs low DLL3, using a threshold of ≥50% of tumor cells stained with an investigational antibody for DLL3 (SP347; Roche Diagnostics). Results As of June 21, 2024, 60 pts with epNEC were included (gastroenteropancreatic GEP, 45%; genitourinary GU, 30%; other/unknown primary site, 25%), 30 each of DLL3-high and DLL3-low. Mean age was 63.9 years in DLL3-high pts, 59.1 years in DLL3-low pts. Baseline characteristics were well balanced across DLL3 groups. All pts had received prior systemic therapy; 30% of DLL3-high and 50% of DLL3-low pts had received 2 lines of prior Tx. After obrixtamig Tx, DLL3-high pts had better outcomes than DLL3-low pts (ORR, 40% vs 3.3%; DCR, 66.7% vs 26.7%; median duration of response DOR, 7.9 vs 2.8 months). Responses were seen most frequently in pts with DLL3-high GEP (50%) or GU (60%) epNECs. Seven DLL3-high pts are still receiving Tx. Most treatment-related AEs were mild to moderate in both groups. Rate of grade ≥3 cytokine release syndrome was 3.3% in each group. Grade ≥3 neurotoxicity, including immune effector cell-associated neurotoxicity syndrome, was 6.7% in the DLL3-high and 3.3% in the DLL3-low groups. Conclusions Analyses from this ongoing Phase I study showed greater obrixtamig efficacy in pts with epNEC with high vs low DLL3 expression, with a manageable safety profile that was comparable across both groups. The ORR of 40% and median DOR of 7.9 months in pts with heavily pretreated epNEC tumors with DLL3 high expression are encouraging and support further development of obrixtamig for this subgroup. Citation Format: Jaume Capdevila, Valentina Gambardella, Yasutoshi Kuboki, Olatunji B. Alese, Daniel Morgensztern, Cyrus Sayehli, Miguel F. Sanmamed, Edurne Arriola, Matus Studeny, Mohamed Bouzaggou, Zhiheng Chen, Valeria Lifke, Juergen Wolf, Tim Remus, Martin Wermke. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: results from an ongoing Phase I trial abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-A003.