First-in-human, phase I study of AK109, an anti-VEGFR2 antibody, in patients (pts) with advanced or metastatic solid tumors.

3021 Background: AK109 is a fully-human monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2 (VEGFR2), thereby block vascular endothelial growth factor (VEGF)/VEGFR2 signaling pathway to inhibit angiogenesis, endothelial cell migration and proliferation of tumor cells. This phase I study is the first-in-human trial of AK109, which was designed to evaluate safety, tolerability of AK109, to determine the maximum tolerated dose (MTD), recommend phase II dose (RP2D) and to gain preliminary data on pharmacokinetics (PK), pharmacodynamics, immunogenicity and clinical activity for AK109 in pts with advanced or metastatic solid tumors resistant to standard therapies (NCT04547205). Methods: This open-label, multi-center, phase I study included a dose escalation phase (part 1) using a 3+3 design to determine MTD and potential RP2D (n = 36 max), with planned dosing of 2, 4, 8, 12 and 18 mg/kg q2w and 15mg q3w, followed by a dose expansion phase (part 2), at 2 potential RP2Ds in q2w or q3w respectively (n = 24-30). The PK characteristics, dose limiting toxicity (DLT), adverse events per CTCAE 5.0 and efficacy (ORR, DCR, DoR, PFS per RECIST v1.1, OS, etc.) of AK109 were evaluated. Results: As of December 30 th , 2021 (median follow-up: 6.0 months), 40 pts (median age: 59.5 years) were enrolled, 16 pts in part 1 and 24 pts in part 2. No DLT was observed AK109 in part 1. Tumor types included gastric cancer (n = 9), non-small cell lung cancer (n = 8), hepatocellular carcinoma (n = 8), colorectal cancer (n = 5), pancreatic carcinoma (n = 2) and oesophagus cancer (n = 2), etc. Preliminary PK analyses showed systemic exposure in C max and AUC last increased dose proportionally at doses of 8 mg/kg and above, with a mean half-life of 8.5 to 10 days. 12mg/kg q2w and 15mg/kg q3w were selected as RP2Ds. Average exposure of AK109 was 6.9 cycles. Eight pts received over 10 cycles of AK109. Treatment related adverse events(TRAE) occurred in 38 (95%) of all pts. Grade 3 and 4 TRAE occurred in 16 (40%) of all pts. The most common TRAEs were proteinuria (22/40, 55%), hypertension (13/40, 32.5%) and AST increased (11/40, 27.5%). Serious adverse event (SAE) occurred in 11 (27.5%) pts, 2 (5%) of which were AK109 related. ORR and DCR were 10.0% and 62.5%, respectively. The median PFS of non-small cell lung cancer (n = 8) and gastric cancer (n = 9) were 5.6 months (95% CI, 1.3, NE) and 5.5 months (95% CI, 1.4, NE), respectively. Conclusions: AK109 showed manageable safety and promising anti-tumor activity. Two phase II studies of AK109 combined with AK104 (anti PD-1/CTLA-4 bi-specific antibody) are ongoing to evaluate the efficacy of AK109 combined with AK104 in patients with multiple solid tumors (NCT05142423, NCT04982276). Clinical trial information: NCT04547205.