Abstract LB-A004: DAREON-7: Phase I open-label dose-escalation/-expansion study of first-line obrixtamig (BI 764532) plus chemotherapy in patients with DLL3-positive neuroendocrine carcinomas

Abstract Background Delta-like ligand 3 (DLL3) is widely expressed in neuroendocrine carcinomas (NECs). Obrixtamig is a DLL3/CD3 IgG-like T-cell engager that binds simultaneously to DLL3 on tumor cells and to CD3 on T cells. We report initial safety and efficacy data from the dose-escalation part of the Phase I DAREON-7 (NCT06132113) trial assessing obrixtamig plus platinum-doublet chemotherapy (carboplatin/cisplatin plus etoposide) in patients with DLL3-positive NECs. Methods Patients with locally advanced or metastatic DLL3-positive extrapulmonary NEC (epNEC), large cell NEC of the lung (LCNEC-L), or NEC of unknown primary site received obrixtamig (3 dose levels: 10, 30, 60 mg) as step-up dosing followed by the target dose, guided by Bayesian logistic regression model with overdose control. Carboplatin plus etoposide was given per label. Antitumor activity was assessed using RECIST v1.1 (investigator-assessed). The ongoing dose-expansion part will assess obrixtamig plus chemotherapy at the dose selected during dose escalation. Results As of August 28, 2025, 25 patients were enrolled (epNEC: 88%, LCNEC-L: 4%, unknown primary site, 8%; median age, 67 years [range: 42–79]; ECOG PS 0/1, 76%/24%). Overall, 25 patients received ≥1 dose of obrixtamig plus carboplatin and etoposide; in these patients, the median number of obrixtamig cycles was 8 (range: 2–17) and median treatment exposure was 6.9 months (range: 1.4–12). There were no dose-limiting toxicities during maximum tolerated dose (MTD) evaluation period, and the MTD was not reached. Most frequent treatment-related adverse events were any (n=23; 92%), cytokine release syndrome (CRS; n=18; 72%), asthenia (n=8; 32%), neutropenia (n=3; 12%), increased alanine aminotransferase (n=2; 8%), increased aspartate aminotransferase (n=1; 4%), and thrombocytopenia (n=1; 4%). Of patients experiencing CRS, most cases were grade (G) 1 (n=14; 56%), with no G≥3 cases. One patient (4%) experienced a potential obrixtamig-related neurotoxicity (G1 immune effector cell-associated neurotoxicity syndrome). One patient (4%) experienced G3 febrile neutropenia. Confirmed objective response rate in evaluable patients (n=25) was 72% (95% CI: 52%–86%; partial response 18%). Stable disease, 16%; progressive disease, 12%. The disease control rate was 88% (95% CI: 70%–96%). Median duration of response was 8.8 months (95% CI: 5.4–not calculable). Median progression-free survival was 7.6 (95% CI: 5.8–9.5) months. Conclusion Obrixtamig plus chemotherapy was tolerable with no unexpected toxicities. The reported frequency and severity of adverse events was consistent with the expected safety profile of the individual treatments, with no additional toxicities. Preliminary efficacy results were encouraging, warranting further development of the combination in this setting. Citation Format: Aman Chauhan, Saori Mishima, Ana Custodio, Timon Vandamme, Patricia Niccoli, Ken Kato, Rocio Garcia-Carbonero, Kazuyoshi Ohkawa, Martin E. Gutierrez, Michael Duruisseaux, Janie Zhang, Julia Koevi, Ping Sun, Michael Woodward, Zilu Liu, Jaume Capdevila. DAREON-7: Phase I open-label dose-escalation/-expansion study of first-line obrixtamig (BI 764532) plus chemotherapy in patients with DLL3-positive neuroendocrine carcinomas [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-A004.