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

Y Zheng; H Zhong; F Zhao; H Zhou; C Mao; W Lv; M Yuan; J Qian; H Jiang; Z Wang; C Xiao; J Guo; T Liu; W Liu; Z M Wang; B Li; M Xia; N Xu

doi:10.1016/j.esmoop.2023.101156

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

ESMO Open. 2023 Apr;8(2):101156. doi: 10.1016/j.esmoop.2023.101156. Epub 2023 Mar 28.

Authors

Y Zheng¹, H Zhong², F Zhao³, H Zhou³, C Mao¹, W Lv², M Yuan², J Qian¹, H Jiang¹, Z Wang³, C Xiao¹, J Guo⁴, T Liu⁴, W Liu⁴, Z M Wang⁴, B Li⁴, M Xia⁴, N Xu⁵

Affiliations

¹ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou.
² The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou.
³ The First Affiliated Hospital, Bengbu Medical College, Bengbu.
⁴ Akeso Biopharma, Inc., Zhongshan, China.
⁵ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou. Electronic address: nongxu@zju.edu.cn.

Abstract

Background: Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in antiangiogenesis which has been an essential strategy for cancer treatment. We report the first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, to characterize the safety profile and pharmacokinetics/pharmacodynamics (PK/PD) properties, and explore the preliminary antitumor efficacy in patients with solid tumors.

Patients and methods: This was a multicenter, open-label, phase I study, including dose escalation and dose expansion (NCT04547205). Patients with advanced cancers were treated 2 and 3 weekly with escalating doses of AK109. A 3 + 3 design was used to determine the maximum tolerated dose. Blood was sampled for PK/PD analysis. The primary endpoint was safety and recommended phase II dose (RP2D).

Results: A total of 40 patients were enrolled. No dose-limiting toxicity was observed. However, 38 patients reported treatment-related adverse events (TRAEs); grade ≥3 TRAEs occurred in 10 patients. The most common TRAEs were proteinuria (n = 24, 60%), hypertension (n = 13, 32.5%), increased aspartate transaminase (n = 11, 27.5%), thrombopenia (n = 10, 25%), and anemia (n = 10, 25%). A total of 28 patients (70%) reported adverse events of special interest (AESIs). The most common AESIs were proteinuria (60%), hypertension (32.5%), and hemorrhage (32.5%), mainly including gum bleeding and urethrorrhagia. AK109 exhibited an approximately linear PK exposure with dose escalation at 2-12 mg/kg. PD analyses showed rapid target engagement. Among the 40 patients, 4 achieved partial response and 21 achieved stable disease with an objective response rate of 10% and a disease control rate of 62.5%. Based on the safety profile, the PK/PD profile, and preliminary antitumor activities, 12 mg/kg Q2W and 15 mg/kg Q3W were selected as RP2D.

Conclusions: AK109 showed manageable safety profile and promising antitumor activity, supporting further clinical development in a large population.

Keywords: AK109; anti-VEGFR2 antibody; phase I study; solid tumors.

Publication types

Clinical Trial, Phase I
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Neoplasms* / pathology
Vascular Endothelial Growth Factor A / therapeutic use
Vascular Endothelial Growth Factor Receptor-2* / therapeutic use

Substances

Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor A

Associated data

ClinicalTrials.gov/NCT04547205