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

3004 Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC). Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive (DLL3+) tumors. NCT04429087 is an ongoing, Phase (Ph) I dose-escalation trial of obrixtamig in patients (pts) with DLL3+ pulmonary and extrapulmonary NEC (epNEC), who had failed to respond to standard treatment (Tx). This analysis examined the efficacy and safety of obrixtamig in pts with epNEC with high vs low DLL3 expression. 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 objective response rate (ORR) and disease control rate (DCR) using RECIST v1.1. Results are reported for pts who received obrixtamig RB2 or RB3, categorized as having high vs low DLL3, using a threshold of ≥50% of tumor cells stained with an investigational antibody for DLL3 (SP347, Roche Diagnostics). Results: As of June 21, 2024, 60 pts with epNEC were included (gastroenteropancreatic [GEP]: 45.0%, genitourinary [GU]: 30.0%, other/unknown primary site: 25.0%); 30 each DLL3-high and DLL3-low. Mean age: 63.9 years in DLL3-high; 59.1 in DLL3-low pts. Baseline characteristics were well-balanced across DLL3 groups. All pts had received prior systemic therapy; 30.0% of DLL3-high and 50.0% of DLL3-low pts had received > 2 lines of prior Tx. Efficacy data are shown in the Table. After obrixtamig Tx, pts with high DLL3 expression had greater ORR, DCR, and duration of response (DoR) than DLL3-low pts. Responses were seen most frequently amongst pts with DLL3-high GEP (50.0%) or GU (60.0%) epNECs. Seven DLL3-high pts are still receiving Tx. Most treatment-related AEs (TRAEs) were mild to moderate for both groups (Table). Conclusions: Analyses from this ongoing Ph I study show greater obrixtamig efficacy in patients with epNEC with high DLL3 expression compared with low DLL3 expression, with a manageable safety profile that is comparable across both groups. The ORR of 40.0% and median DoR of 7.9 months in heavily pretreated epNEC tumors with DLL3 high expression are encouraging, and support further development of obrixtamig for this subgroup. Clinical trial information: NCT04429087 . Efficacy/safety parameter DLL3-high (n=30) DLL3-low (n=30) ORR, % (95% CI) 40.0 (24.6–57.7) 3.3 (0.6–16.7) DCR, % (95% CI) 66.7 (48.8–80.8) 26.7 (14.2–44.4) Median DoR (95% CI), months 7.9 (6.2–NC) 2.8 (NC–NC) TRAEs, all G/G ≥3, (%) 100.0/23.3 90.0/20.0 Cytokine release syndrome, all G/G ≥3, (%) 70.0/3.3 60.0/3.3 Neurotoxicity, including immune effector cell-associated neurotoxicity syndrome*, all G/G ≥3, (%) 16.7/6.7 10.0/3.3 *Evaluated with a customised MedDRA query. CI, confidence interval; NC, not calculable.