BI 764532 T-Cell Engager Shows Promise in DLL3-Positive Neuroendocrine Carcinomas with 29% Response Rate
核心洞察
BI 764532, a DLL3 (搜索)/CD3 (搜索) T-cell engager, demonstrated a 29% objective response rate in patients with extrapulmonary neuroendocrine carcinomas (搜索) in an ongoing phase 1 trial.
The treatment showed clinically manageable tolerability with cytokine release syndrome (搜索) as the most common treatment-related adverse event occurring in 72% of patients.
Maximum tolerated dose has not been reached across multiple dosing regimens, with 58% of responding patients with epNEC still continuing treatment.
BI 764532, a novel DLL3 (搜索)/CD3 (搜索) T-cell engager, has demonstrated promising antitumor activity in patients with extrapulmonary neuroendocrine carcinomas (搜索) (epNECs), achieving a 29% objective response rate in a phase 1 dose-escalation trial. The ongoing study (NCT04429087) represents the first clinical evaluation of this bispecific antibody targeting delta-like ligand 3 (搜索) (DLL3), a protein highly expressed on several cancer types including neuroendocrine tumors.
Trial Design and Patient Population
The multicenter, open-label phase 1 trial enrolled patients with locally advanced or metastatic DLL3 (搜索)-positive small cell lung cancer (搜索), epNEC, or large cell neuroendocrine lung carcinoma (搜索). As of August 14, 2023, 132 patients had received at least one dose of BI 764532 across four different dosing regimens: fixed dose every three weeks (Regimen A), fixed dose weekly (Regimen B1), and two step-in dose approaches followed by target doses (Regimens B2 and B3).
The patient population was heavily pretreated, with 70% having received two or more prior lines of therapy and 48% having previous PD-1/PD-L1 treatment. The median age was 60 years, with 60% of patients being male and 71% having an ECOG performance status of 1.
Safety Profile and Tolerability
BI 764532 demonstrated clinically manageable tolerability across all dosing regimens. The maximum tolerated dose has not been reached despite dose escalation through multiple levels. Dose-limiting toxicities were observed in six patients total: one patient on Regimen A experienced Grade 3 confusion, while five patients on Regimen B2 experienced various toxicities including Grade 4 cytokine release syndrome (搜索) (CRS), Grade 3 CRS, Grade 3 immune effector cell-associated neurotoxicity syndrome (搜索) (ICANS), Grade 3 nervous system disorder, and Grade 2 infusion-related reaction.
Among the 54 patients with epNEC specifically, treatment-related adverse events occurred in 94% of patients, with 19% experiencing Grade 3 or higher events. The most common treatment-related adverse events were CRS (72% of patients, with 4% experiencing Grade 3 or higher), pyrexia (30%), and dysgeusia (19%). There was one Grade 5 treatment-related adverse event due to ICANS.
Efficacy Results in Neuroendocrine Carcinomas
The efficacy data focused on patients who received clinically active doses of BI 764532. In the overall population of 98 evaluable patients, the objective response rate was 28% with a disease control rate of 54%. Among the 41 patients with epNEC who received clinically active doses, the objective response rate was 29% with a disease control rate of 49%.
Breaking down the epNEC responses by primary site, gastrointestinal neuroendocrine carcinomas (n=21) showed a 29% response rate with 43% disease control, while genitourinary neuroendocrine carcinomas (n=14) demonstrated a 36% response rate with 57% disease control. Patients with neuroendocrine carcinomas of unknown origin (n=6) had a 17% response rate with 50% disease control.
Notably, seven of the 12 responding patients with epNEC (58%) were still continuing treatment at the time of data cutoff, suggesting durable responses in a subset of patients.
Mechanism and Clinical Significance
BI 764532 functions as a DLL3 (搜索)/CD3 (搜索) immunoglobulin G-like T-cell engager, designed to redirect T cells to attack DLL3-expressing cancer cells. DLL3 serves as an inhibitory Notch ligand that is highly expressed on the cell surface of neuroendocrine tumors, making it an attractive therapeutic target for these difficult-to-treat malignancies.
The clinical activity observed in this heavily pretreated patient population is particularly noteworthy given the limited treatment options available for patients with advanced neuroendocrine carcinomas. The manageable safety profile, combined with the lack of a reached maximum tolerated dose, suggests potential for further dose optimization.
Ongoing Development
The phase 1 trial continues with dose escalation ongoing across multiple regimens. The study aims to determine the optimal dosing strategy for future development while continuing to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy. Treatment can continue for up to 36 months or until disease progression, unacceptable toxicity, or other withdrawal criteria are met.