A phase 2 dose expansion study of ZG006, a trispecific T cell engager targeting CD3/DLL3/DLL3, as monotherapy in patients with advanced neuroendocrine carcinoma.

e16341 Background: ZG006 is a trispecific T cell engager (Tri-TE) targeting Delta-like ligand 3 (DLL3) and CD3, designed to bridge tumor cells and T cells by binding to two distinct DLL3 epitopes on tumor cells and CD3 on T cells, thereby mediating T cell-specific killing of DLL3-expressing tumor cells such as small cell lung cancer and neuroendocrine carcinoma (NEC). Here, we report the preliminary results from the ongoing phase 2 study of ZG006 in patients (pts) with advanced NEC. Methods: This is a randomization, multi-center, open-label phase 2 study of ZG006 as monotherapy in NEC pts failed to at least 1 prior lines of standard systemic treatment. Based on ZG006 phase 1 study results, both 10 mg and 30 mg Q2W doses with a priming dose of 1 mg are being evaluated in this phase 2 dose optimization study. Planned to have 60 pts be randomized at 1:1 ratio to receive one of the two ZG006 doses. The primary endpoint is objective response rate (ORR) according to RECIST1.1. The DLL3 expression is not required for the study entry but will be retrospectively evaluated by a central lab. Results: As of Dec. 31, 2024, a total of 17 NEC pts were randomized (8 on 10 mg, 9 on 30 mg) and received≥1 dose of ZG006; Pts included 7 males and 10 females, with median age 54.0 years (range: 30-71). All pts had received ≥1 line of prior treatment, and the majority (76.5%) received ≥2 lines. 58.8% (10/17) had received a prior anti-PD-(L)1 treatment. The primary tumor sites included colorectum (4/17), cervix (4/17), esophagus (3/17), stomach (2/17), gallbladder (2/17), liver (1/17) and appendix (1/17). Treatment-related adverse events (TRAEs) occurred in 15 pts (88.2%); most commonly (≥20%): pyrexia (70.6%), cytokine release syndrome (58.3%), aspartate aminotransferase increased (35.3%), anemia (29.4%), asthenia (29.4%) and alanine aminotransferase increased (23.5%). Four pts (23.5%) experienced six grade 3/4 TRAEs (1 each of neutrophil count decreased, platelet count decreased, asthenia, hypertension, hypokalemia and metabolic acidosis), and no pts experienced TRAEs leading to treatment discontinuation or death. Two pts (11.8%) experienced treatment-related serious adverse events. No significant difference was observed in the safety profile between the two dose groups. Three pts (1 on 10 mg, 2 on 30 mg) were efficacy-evaluable with at least one post-baseline tumor assessment. Of them, one patient with cervical neuroendocrine carcinoma on 30 mg achieved confirmed partial response and one patient with colorectal neuroendocrine carcinoma on 10 mg was stable disease. Overall, the ORR was 33.3% and the DCR was 66.7%. DoR and PFS have not matured. Conclusions: With a limited data, ZG006 exhibited an anti-tumor activity trend in NEC pts who failed to prior standard treatments. The safety profiles were generally similar to those observed in the ZG006 Phase 1 dose escalation study. Clinical trial information: NCT06440057 .