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

8007 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 (SCLC). Here, we report the results from the phase 2 dose expansion study of ZG006 for the treatment of patients (pts) with advanced SCLC. Methods: This is a randomization, multi-center, open-label phase 2 study of ZG006 as monotherapy in SCLC pts failed to at least 2 prior lines of standard systemic treatments. Based on ZG006 phase 1 study results, both 10 mg and 30 mg Q2W dose levels with a priming dose of 1 mg are being evaluated in this phase 2 dose optimization study, 60 pts are to be randomized at a ratio of 1:1 to receive ZG006. The primary endpoint was objective response rate (ORR) according to RECIST1.1. DLL3 expression was not required but retrospectively evaluated by IHC. Results: As of Dec. 31, 2024, a total of 40 SCLC pts were randomized (19 on 10 mg, 21 on 30 mg) and received≥1 dose of ZG006. Median age was 57.5 (range: 48-73) years. Of the 40 pts, 31 (77.5%) were males and 27 (67.5%) had smoking history; all had received ≥2 prior line treatments and 45.0% ≥3 lines; majority (72.5%) had prior anti-PD-(L)1 treatments. Baseline metastatic sites of liver and brain accounted 52.5% (21/40) and 20.0% (8/40), respectively. Among 27 (13 at 10 mg, 14 at 30 mg) efficacy-evaluable SCLC pts who had at least one post-baseline tumor scan, 18 (5 confirmed, others pending confirmed) achieved partial response (7 at 10 mg, 11 at 30 mg). Overall, the ORR was 66.7% and the DCR was 92.6%. For the 10 mg group, ORR was 53.8% and DCR was 84.6%; for the 30 mg group, ORR was 78.6% and DCR was 100.0%. DoR and PFS, not yet matured and will be updated with additional follow-up time. Among the all combined 27 pts, 21 (77.8%) pts had low (N = 17) or medium (N = 4) DLL3 expression at baseline, and they demonstrated reasonably great anti-tumor efficacy with 15 PRs and 71.4% ORR. Treatment-related adverse events (TRAEs) occurred in 35 pts (87.5%); most commonly (≥20%): pyrexia (57.5%), cytokine release syndrome (CRS, 47.5%), vomiting (27.5%), rash (25.0%), decreased appetite (25.0%), aspartate aminotransferase increased (22.5%), white blood cell count decreased (22.5%) and platelet count decreased (22.5%). Only five pts (12.5%) experienced grade 3/4 TRAEs including one grade 3 CRS, and no pts experienced TRAEs leading to treatment discontinuation or death. Five pts (12.5%) experienced serious TRAEs. No significant difference was observed in the safety profile between these two dose groups. Conclusions: ZG006 exhibited promising efficacy and acceptable safety in SCLC pts receiving ≥2 lines of prior treatment, even in pts with low DLL3 expression. The enrollment of ZG006-002 study is ongoing. Clinical trial information: NCT06283719 .