Dr Starr on the Rationale for Targeting DLL3 in Extrapulmonary Neuroendocrine Carcinomas

“The expression rate of DLL3 in [patients with epNECs] is up to 80%, which is quite high. We used the data that were evolving in SCLC to identify that this protein does exist and is overexpressed epNECs.”

Jason S. Starr, DO, an oncologist in the Department of Internal Medicine at Mayo Clinic, discussed the potential utility of delta-like ligand 3 (DLL3) as a treatment target in patients with extrapulmonary neuroendocrine carcinomas (epNECs).

DLL3, which is involved in a cell-to-cell signaling pathway, was first discovered in small cell lung cancer (SCLC), Starr began. SCLC is classified as a neuroendocrine carcinoma and DLL3 expression is observed on the cell surface of approximately 80% to 90% of SCLC cases, he continued. Due to the similarities between SCLC and epNECs, investigators evaluated the rate of DLL3 expression in patients with epNECs and found the rate to be approximately 80%, Starr explained.

During the 2025 ASCO Annual Meeting, investigators presented data from a phase 1 trial (NCT04429087) which evaluated the novel DLL3/CD3 IgG-like T-cell engager obrixtamig (BI 764532) in patients with epNECs with high (≥ 50% of tumor cells) or low (< 50% of tumor cells) expression of DLL3. The coprimary end points were determining the maximum tolerated dose (MTD) and dose-limiting toxicities during the MTD evaluation period. Secondary end points included objective response rate (ORR) per RECIST 1.1 criteria and pharmacokinetic parameters.

The ORR in the overall population was 22% (95% CI, 13%-34%) and the disease control rate (DCR) was 47% (95% CI, 35%-59%). The ORR and DCR among patients with high DLL3 expression (n = 30) was 40% (95% CI, 25%-58%) and 67% (95% CI, 49%-81%), respectively. In patients with low DLL3 expression (n = 30), the ORR and DCR were 3% (95% CI, 1%-17%) and 27% (95% CI, 14%-44%), respectively. The median duration of response in the DLL3-high and -low groups was 7.9 months (95% CI, 6.2-not evaluable [NE]) and 2.8 months (95% CI, NE-NE), respectively.

In terms of safety, any-grade treatment-related adverse effects (TRAEs) were reported in 95% of patients in the overall population. The most common any-grade TRAEs included cytokine release syndrome (65%), pyrexia (32%), and dysgeusia (25%).

In October 2023, the FDA granted fast track designation to obrixtamig for the treatment of patients with extensive-stage SCLC who experienced disease progression following at least 2 prior lines of treatment including platinum-based chemotherapy, and for patients with advanced or metastatic epNECs following disease progression with at least 1 prior line of treatment including platinum-based chemotherapy. The agent is being further evaluated in patients with relapsed/refractory DLL3-high epNECs in ongoing the phase 2 DAREON-5 trial (NCT05882058).