Safety, Pharmacokinetics, and Pharmacodynamics Evaluation of Ivonescimab, a Novel Bispecific Antibody Targeting PD-1 and VEGF, in Chinese Patients With Advanced Solid Tumors

Background

Ivonescimab (AK112) is a first-in-class bispecific antibody that simultaneously targets programmed death-1 (PD-1) and vascular endothelial growth factor (VEGF) with cooperative binding. We report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of ivonescimab in patients suffered from advanced solid tumors.

Methods

A multicenter, open-label, dose-escalation, phase I study was conducted in five hospitals in China. Ivonescimab was used as a monotherapy. The dose of ivonescimab intravenously administered was 3, 5, 10, 20, and 30 mg/kg every 2 weeks (Q2W), and 10 and 20 mg/kg every 3 weeks (Q3W). Safety, PK, and PD of ivonescimab were evaluated.

Results

A total of 59 patients treated in the study. Only one dose-limiting toxicity (DLT) occurred in 1 out of 9 patients in the 10 mg/kg Q2W cohort, indicating that no maximum tolerated dose was reached. Among the participants, 53 patients (89.8%) experienced treatment-related adverse events (TRAEs), with the most common being proteinuria (33.9%), aspartate aminotransferase elevation (27.1%), white blood cell count decrease (22.0%), alanine aminotransferase elevation (20.3%), and anemia (20.3%). Fourteen patients (23.7%) had ≥ Grade 3 TRAEs, and 7 patients (11.9%) experienced serious TRAEs. Notably, there were no reported deaths associated with the TRAEs, and no dose-dependent increase in adverse events was observed. The half-life of ivonescimab ranged from 5.0 to 7.3 days following single-dose administration across all dose levels. The serum concentrations of ivonescimab increased with escalating doses in an approximately dose-proportional manner. Following multiple doses, the accumulation ratio ranged from 1.1 to 1.7, suggesting mild accumulation of ivonescimab. The steady state was achieved after 5 doses. Ivonescimab occupancy on PD-1 sustained over 80% across the treatment period. Serum VEGF level was rapidly down-regulated after each administration.

Conclusions

In patients with advanced solid tumors, ivonescimab monotherapy was well-tolerated and demonstrated a linear PK characteristics. PD profiles showed the promising potential of ivonescimab for the management of advanced solid tumors.

Trial Registration: ClinicalTrials.gov (NCT04597541)