NANETS2025 18th Annual Multidisciplinary NET Medical Symposium NANETS 2025 Clinical – Chemo/SSA/Biologics (11 abstracts)
An ongoing phase 1 trial of obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression
Jaume Capdevila 1 , Valentina Gambardella 2 , Yasutoshi Kuboki 3 , Olatunji B. Alese 4 , Daniel Morgensztern 5 , Cyrus Sayehli 6 , Miguel F. Sanmamed 7 , Edurne Arriola 8 , Matus Studeny 9 , Mohamed Bouzaggou 10 , Zhiheng Chen 9 , Valeria Lifke 9 , Jürgen Wolf 11 & Martin Wermke 12
1Department of Medical Oncology, Vall d’Hebron University Hospital & Vall d’Hebron Institute of Oncology, Barcelona, Spain; 2Department of Medical Oncology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; 3Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan; 4Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA; 5Washington University School of Medicine, St. Louis, MO, USA;6Interdisciplinary Study Center with ECTU, Medical Clinic and Polyclinic II of the University Hospital Würzburg, Würzburg, Germany; 7Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain; 8Department of Medical Oncology, Hospital del Mar-CIBERONC (Centro de Investigación Biomédica en Red de Oncología); Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain; 9Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 10Boehringer Ingelheim France S.A.S., Reims, France; 11Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany; 12TU Dresden University of Technology, NCT/UCC Early Clinical Trial Unit, Dresden, Germany
Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC). Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive tumors. NCT04429087 is an ongoing, phase 1, dose-escalation trial of obrixtamig in patients with DLL3-positive pulmonary and extrapulmonary NEC (epNEC) who failed to respond to standard treatment.
Methods: Obrixtamig was given intravenously in 4 dose-escalation regimens (R): RA (fixed dose every 3 weeks [q3w]); RB1 (fixed dose weekly [qw]); RB2 (step-up dose, then qw); and RB3 (step-up dose, then qw for 3 weeks, then q3w). Efficacy was assessed through objective response rate (ORR) and disease control rate (DCR) using RECIST v1.1. Results are reported for patients who received obrixtamig RB2 or RB3, categorized as having high versus 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 patients with epNEC were included (gastroenteropancreatic: 45.0%, genitourinary: 30.0%, other/unknown primary site: 25.0%); 30 each DLL3-high and DLL3-low. Mean age: 63.9 years (DLL3-high), 59.1 (DLL3-low). Baseline characteristics were well-balanced across DLL3 groups. All patients had received prior systemic therapy; 30.0% of DLL3-high and 50.0% of DLL3-low patients had received >2 lines of prior treatment. Efficacy data are shown in the Table. After obrixtamig treatment, patients with high DLL3 expression had greater ORR, DCR, and duration of response (DoR) than DLL3-low patients. Responses were seen most frequently among patients with DLL3-high gastroenteropancreatic (50.0%) or genitourinary (60.0%) epNECs. Seven DLL3-high patients are still receiving treatment. Most treatment-related adverse events (TRAEs) were mild to moderate for both groups (Table).
| DLL3-ce (n = 30) | DLL3-low (n = 30) | |
| ORR, % (95% CI) | 40.0 (24.6–57.7) | 3.3 (0.6–16.7) |
| DCR, % (95% CI) | 66.7 (48.8–80.8) | 26.7 (14.2–44.4) |
| Median DoR (95% CI), months | 7.9 (6.2–NC) | 2.8 (NC–NC) |
| TRAEs, all grade/grade ≥3, (%) | 100.0/23.3 | 90.0/20.0 |
| Cytokine release syndrome, all grade/grade ≥3, (%) | 70.0/3.3 | 60.0/3.3 |
| Neurotoxicity, including immune effector cell–associated neurotoxicity syndrome*, all grade/grade ≥3, (%) | 16.7/6.7 | 10.0/3.3 |
| *Evaluated with a customized MedDRA query CI, confidence interval; NC, not calculable | ||
Conclusions: Analyses showed greater obrixtamig efficacy in patients with DLL3-high versus DLL3-low epNEC. The safety profile was manageable and comparable across both groups. The ORR of 40.0% and median DoR of 7.9 months in heavily pretreated epNEC tumors with high DLL3 expression are encouraging and support further development of obrixtamig for this subgroup.
Abstract ID #33400
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Endocrine Abstracts
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