Abstract Background Patients with relapsed/refractory extrapulmonary neuroendocrine carcinoma (epNEC) have poor outcomes with currently available therapies. Delta-like ligand 3 (DLL3) is expressed on the surface of many epNEC cells, offering a promising therapeutic target. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in immune-mediated tumor cell lysis. In an ongoing first-in-human Phase I trial, obrixtamig monotherapy had promising efficacy in patients with DLL3+ small cell lung cancer (SCLC), epNEC, or large-cell NEC of the lung (LCNEC-L) and a manageable toxicity profile, justifying further clinical investigation. The Phase II DAREON-5 trial is a dose-selection and -expansion trial of obrixtamig monotherapy in patients with histologically confirmed relapsed/refractory SCLC, epNEC, or LCNEC-L after prior standard of care therapy. The completed dose-selection part evaluated the safety and efficacy of 2 obrixtamig doses. We describe the design of the expansion part of the study that is currently enrolling. Methods The expansion part of DAREON-5 is assessing obrixtamig antitumor activity at the selected dose for expansion in patients with centrally assessed DLL3 high-expressing epNEC (NCT05882058); defined as ≥50% of evaluable tumor cells with moderate to strong membrane and/or cytoplasmic DLL3 staining using the VENTANA DLL3 (SP347) assay. Eligible patients have relapsed/refractory, advanced/metastatic, histologically confirmed epNEC after prior platinum-based chemotherapy (≥1 line of therapy). Patients will receive IV obrixtamig infusions as step-up doses followed by the target dose. Primary endpoint is objective response per RECIST v 1.1, assessed by blinded independent central review. Secondary endpoints include duration of objective response, progression-free survival, disease control, overall survival, treatment-emergent adverse events, and patient-reported outcomes. The planned enrollment for the expansion cohort is ∼50 patients recruited from the following countries: Belgium, China, Germany, Japan, Portugal, South Korea, Spain, UK, and USA. Citation Format: Marianne Pavel, Chris Verslype, Pedro Rocha, Alastair Greystoke, Aman Chauhan, Julia Koevi, Martha Mueller, Eric Song, Valeria Lifke, Emily Bergsland. Obrixtamig (BI 764532) in patients with relapsed/refractory delta-like ligand 3 (DLL3) high-expressing extrapulmonary neuroendocrine carcinoma (epNEC): trial in progress of the dose expansion part of the Phase II DAREON-5 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-A001.
Pavel et al. (Thu,) studied this question.