First-in-human study of ZGGS18, a dual specific antibody targeting VEGF and TGF-β, as monotherapy in patients with advanced solid tumors.

2523 Background: ZGGS18 is a bifunctional antibody fusion protein, which consists of a monoclonal antibody (optimized Bevacizumab) against vascular endothelial growth factor A (VEGF-A) and an engineered human transforming growth factor-β receptor II extracellular domain (TGF-β RII ECD). It can specifically bind VEGF-A and "capture" TGF- β isomers. It plays a synergistic role in inhibiting tumor growth, such as inhibiting tumor angiogenesis and reducing tumor metastasis. In addition, ZGGS18 can also improve and regulate the tumor microenvironment, so it can enhance the tumor-killing effect in combination with anti-PD-(L) 1 antibody and other tumor immunotherapeutic drugs. We conducted a Phase 1 clinical study to assess the tolerability and safety of this drug. Methods: It was a dose-escalation study. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 20 (0.3, 1, 3, 6, 10, 15, 20) mg/kg, intravenous infusion, once every 2 weeks. An accelerated titration design (ATD) was utilized in the first three dose groups and a standard "3+3" design was used in the rest doses. The first 28-day period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZGGS18 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1. Results: At the data cut-off (4 Jan 2024), 21 patients (14 males and 7 females) were enrolled, with a median age of 60 years. 13 (61.9%) of them received at least 2 lines of antineoplastic therapies. 76.2% (16/21) of patients experienced treatment-related adverse events (TRAEs) and 19.0% (4/21) of patients had grade 3 TRAEs (1 Lower gastrointestinal hemorrhage in the 10 mg/kg, 1 pneumonia in the 15 mg/kg, 1 anemia in the 20 mg/kg, and 1 blood fibrinogen decreased in the 20 mg/kg dose group). Wherein, the grade 3 blood fibrinogen decreased was a DLT event. The most frequent TEAEs (with incidence >10%) were anemia, lymphocyte count decreased, gingival bleeding, epistaxis, hypoalbuminemia, proteinuria, hypocalcemia, hypokalemia, fever, aspartate aminotransferase increased, bile acids increased, and disease progression. There is one subject with endometrial carcinoma who has received 19 infusions of ZGGS18 and is remaining in this study, and another subject with rectal carcinoma had 29.65% tumor shrinkage at week 12. The C max and AUC increased from 0.3-20 mg/kg approximately in dose proportion. Conclusions: ZGGS18 demonstrated its safety and tolerability in this dose-escalation study, along with a good PK profile, providing a good basis for monotherapy and/or combination therapy for future use. Clinical trial information: NCT05584800 .