Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with genitourinary extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial.

Abstract

152 Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC), including extrapulmonary NECs (epNEC) of a genitourinary (GU) origin. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive tumors. A recent analysis from a Phase I dose-escalation trial of obrixtamig (NCT04429087) showed manageable safety and promising efficacy in patients (pts) with advanced previously treated epNEC (objective response rate [ORR] of 40% and median duration of response [DoR] of 7.9 months in pts with tumors expressing high levels of DLL3 [DLL3-high]). This sub-analysis examined the efficacy and safety of obrixtamig in epNEC GU. Methods: Obrixtamig was given IV in 4 dose-escalation regimens (R): RA (fixed dose q3w), RB1 (fixed dose qw), RB2 (step-up dose, then qw), and RB3 (step-up dose, then qw for 3 weeks, then q3w), until disease progression or unacceptable toxicity. Efficacy was assessed through confirmed ORR and disease control rate (DCR) using RECIST v1.1 (investigator review). Results are reported for pts who received obrixtamig RB2 or RB3, categorized as having high or low DLL3, using a threshold of ≥50% of tumor cells with moderate and/or strong (2+/3+) membrane and/or cytoplasmic staining with an investigational antibody for DLL3 (SP347, Roche Diagnostics). Results: As of June 21, 2024, 20 pts with epNEC GU were included (prostate: 45%, bladder: 40%, gynecological: 15%); 60% DLL3-high and 40% DLL3-low. Median age: 69 years. Female: 20%. ECOG PS (0/1/missing): 30%/65%/5%. Efficacy data are shown in the Table. In the DLL3-high group ORR/DCR was 50%/75% with responses observed across tumor types (prostate: 60%, bladder: 50%, gynecological: 33%). Median DoR was not reached. Five of 6 responding pts are ongoing. Most treatment-related AEs (TRAEs) were mild to moderate with no cases of grade ≥3 cytokine release syndrome (Table). Conclusions: Obrixtamig showed preliminary efficacy and durable responses in heavily pretreated patients with DLL3-high epNEC GU, with a manageable safety profile. These data support further development of obrixtamig in this setting. Clinical trial information: NCT04429087 . Efficacy/safety parameter Overall (N=20) DLL3-high (n=12) DLL3-low (n=8) ORR, % (95% CI) 30 (15–52) 50 (25–75) 0 (0–32) DCR, % (95% CI) 55 (34–74) 75 (47–91) 25 (7–59) 6-month DoR, %* 100 100 – TRAEs, all/G ≥3, (%) 95/25 100/33 88/13 CRS, all/G ≥3, (%) 65/0 75/0 50/0 Obrixtamig-related potential neurological toxicity † , including ICANS, all/G ≥3, (%) 10/5 17/8 0/0 *Kaplan−Meier estimate. † Evaluated with a customized MedDRA query. CI, confidence interval; ICANS, immune effector cell-associated neurotoxicity syndrome; CRS, cytokine release syndrome; MedDRA, Medical Dictionary for Regulatory Activities.