Obrixtamig (BI 764532) in patients (pts) with relapsed/refractory delta-like ligand 3 (DLL3)-high expressing extrapulmonary neuroendocrine carcinoma (epNEC): Dose expansion part of the phase II DAREON-5 trial.

TPS2 Background: Pts with relapsed/refractory epNEC have poor outcomes with currently available therapies. 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 (NCT04429087), obrixtamig monotherapy had promising efficacy in pts with DLL3+ 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 (NCT05882058) is a dose selection and expansion trial of obrixtamig monotherapy in pts with histologically confirmed relapsed/refractory SCLC, epNEC or LCNEC-L after prior standard of care. The completed dose selection part evaluated the safety and efficacy of two 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 pts with centrally assessed DLL3-high expressing epNEC; defined as ≥50% of evaluable tumor cells with moderate to strong membrane and/or cytoplasmic DLL3 staining using the VENTANA DLL3 (SP347) assay. Eligible pts have relapsed/refractory, advanced/metastatic, histologically confirmed epNEC after prior platinum-based chemotherapy (≥1 lines of therapy). Pts will receive IV obrixtamig infusions as step-up doses followed by the target dose. Primary endpoint is objective response per RECIST v1.1, assessed by blinded independent central review. Secondary endpoints include duration of objective response, PFS, disease control, overall survival, treatment-emergent AEs, and patient-reported outcomes. The planned enrollment for the expansion cohort is ~50 pts recruited from the following countries: Belgium, China, Germany, Japan, Portugal, South Korea, Spain, UK and USA. Previously presented at ESMO, FPN (Final publication Number): 1731TiP, Pavel et al. Reused with permission. Clinical trial information: NCT05882058 .