Abstract CT222: 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 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 intravenous obrixtamig infusions as step-up doses followed by the target dose. Primary endpoint is objective response per Response Evaluation Criteria in Solid Tumors version 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, Andrea Standring, 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 American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT222.