A phase 1 dose escalation and expansion study of ZG006, a trispecific T cell engager targeting CD3/DLL3/DLL3, as monotherapy in patients with refractory small cell lung cancer or neuroendocrine carcinoma.

8089 Background: ZG006 is a unique designed T cell engager, targeting CD3 and Delta-like ligand 3 (DLL3) with two distinct DLL3 epitopes, and bridges tumor cells and T cells by strongly binding to DLL3 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 (SCLC) or neuroendocrine carcinoma (NEC). Here, we report the complete results for the phase 1 study of ZG006 for the treatment of patients (pts) with refractory SCLC or NEC. Methods: This is a multi-center, open-label, phase 1 clinical study of ZG006 as monotherapy in pts with SCLC or NEC who failed or were intolerant to the standard therapies. A standard "3+3" design, with an accelerated approach for the first two lower dose levels was used during the dose escalation stage. Patients were treated with doses from 0.1 to 100 mg, intravenous infusion, once every 2 weeks. Tumor response was assessed by RECIST1.1. DLL3 expression was retrospectively evaluated by IHC. Results: As of data cut-off in Dec 2024, a total of 45 pts (41 SCLC pts and 4 NEC pts) were enrolled and received≥1 dose of ZG006, 4 at the dose group of 0.1 mg, 3 at 0.3 mg, 3 at 1 mg, 3 at 3 mg, 5 at 10 mg, 12 at 30 mg, 11 at 60 mg and 3 at 100 mg. Patients included 35 males and 10 females, with median age 59 years (range: 43-72). The majority (86.6%) had received ≥2 lines of prior treatments and 44.4% received ≥3 lines. Twenty-six pts (57.8%) had prior anti-PD-(L)1 treatment. Only one patient in 100 mg group experienced DLT events (grade 3 cytokine release syndrome and grade 4 pneumonia). Treatment-related adverse events (TRAEs) occurred in all 45 pts; most commonly: cytokine release syndrome (CRS), pyrexia, anemia, white blood cell count decreased, pruritus, decreased appetite, hyponatraemia, asthenia, neutrophil count decreased, nausea, hypoalbuminaemia, alanine aminotransferase increased and constipation. CRS occurred mostly after the first two doses and usually recovered within 2 days. Eleven pts (24.4%) experienced serious TRAEs. There was no TRAE leading to treatment discontinuation or death and no ICANS was reported. Twenty-three SCLC patients receiving ZG006 10-60 mg were efficacy-evaluable with at least one post-baseline tumor assessment, and the ORR was 60.9% (14/23, 10 confirmed) and the DCR was 78.3% (18/23). Among the 18 pts who had low/medium DLL3 expressions, 12 pts achieved PRs with an ORR of 66.7%, which demonstrated that ZG006 had a great anti-tumor activity in SCLC pts. ZG006 demonstrated a nearly dose-proportional increase in concentration with a half life of approximately 4 days after multiple doses. Conclusions: ZG006 exhibited a promising antitumor activity with acceptable safety profiles. Phase 2 dose expansion studies have been initiated to further investigate the efficacy and safety of ZG006 in pts with SCLC or NEC. Clinical trial information: NCT05978284 .