Phase I Trial of DLL3/CD3 IgG-Like T-Cell Engager obrixtamig (BI 764532) in Patients with DLL3-Positive Tumors: Patients with LCNEC

Introduction: Delta-like ligand 3 (DLL3) is expressed on many cancers, including large cell neuroendocrine carcinoma of the lung (LCNEC). Prognosis in patients (pts) with locally advanced (adv.)/metastatic (met.) LCNEC is poor (5-y survival: ~5%). Obrixtamig (O) is a DLL3/CD3 IgG-like TcE that binds to DLL3 on tumor cells and CD3 on T-cells, resulting in T-cell-mediated immune response directed at DLL3-expressing tumor cells. NCT04429087 is an ongoing Phase I trial of O in pts with locally adv./met. DLL3-positive SCLC, extrapulmonary neuroendocrine carcinoma (epNEC), or LCNEC. Key aim: To determine the MTD and/or the recommended dose for expansion of O. Other objectives: safety, tolerability, PK, PD, and preliminary efficacy. Here, we focus on pts with LCNEC.

Methods: O was given intravenously in 4 regimens (R): R A (fixed dose Q3W; R B1 (fixed dose Q1W); R B2 and R B3 (step-in dose, followed by target dose). Treatment continued until progression, unacceptable toxicity, other reasons for withdrawal, or max. treatment duration of 36 months (mos).

Results: As of Feb 21, 2024, 168 pts had≥1 dose of O (R A: n=24; R B1: n=10; R B2: n=79; R B3: n=55); 32 pts (19%) were ongoing. 6 dose-limiting toxicities (DLTs) were reported during the MTD evaluation period: 1 pt on R A (grade 3 confusion) and 5 pts on R B2 (grade 4 cytokine release syndrome [CRS]; grade 3 CRS; grade 5 immune effector cell-associated neurotoxicity syndrome; grade 3 nervous system disorder; and grade 2 infusion-related reaction). No DLTs occurred in LCNEC pts; the AE profile was consistent with the overall population. The MTD was not reached. 14 pts with LCNEC were treated. In 13 evaluable pts with LCNEC (ORR/DCR across all dose levels was 54%/77% (70%/90% in 10 pts who received≥90 µg/kg). mDoR has not been reached. The estimated 6-mos rates of DoR/PFS were 63%/28%, and mPFS was 3.6 mos (2.4-not calculated). At data cut-off, 5 of 7 responding pts (71%) were still on treatment.

Conclusions: O showed promising efficacy and safety in pts with LCNEC, with an ORR of 70% at active dose levels.

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Artikel online veröffentlicht:
18. März 2025