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First-in-human, phase I study of AK109, an anti-VEGFR2 antibody in patients with advanced or metastatic solid tumors
1Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou.
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.
Insights
The first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, demonstrated a manageable safety profile and promising antitumor activity in patients with solid tumors. Recommended phase II doses were established for further clinical development.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Vascular endothelial growth factor receptor 2 (VEGFR2) is a key target in antiangiogenesis cancer therapy.
- AK109 is a novel monoclonal antibody targeting VEGFR2.
Purpose of the Study:
- To evaluate the safety and tolerability of AK109 in a first-in-human study.
- To characterize the pharmacokinetics/pharmacodynamics (PK/PD) of AK109.
- To explore the preliminary antitumor efficacy of AK109 in patients with solid tumors.
Main Methods:
- A multicenter, open-label, phase I study with dose escalation and expansion (NCT04547205).
- Utilized a 3+3 design to determine the maximum tolerated dose (MTD).
- Monitored safety, PK/PD, and antitumor responses in patients with advanced cancers.
Main Results:
- No dose-limiting toxicities were observed in 40 enrolled patients.
- Most common treatment-related adverse events (TRAEs) included proteinuria and hypertension.
- AK109 showed linear PK exposure, rapid target engagement, and preliminary antitumor activity (10% ORR, 62.5% DCR).
Conclusions:
- AK109 exhibits a manageable safety profile and promising antitumor activity.
- The recommended phase II doses (RP2D) of 12 mg/kg Q2W and 15 mg/kg Q3W were identified.
- AK109 supports further clinical development in a larger patient population.
