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

IF 3.1 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2025-03-20 DOI:10.1002/cam4.70653

Fenghua Wang, Xiaoli Wei, Yulong Zheng, Jing Wang, Jieer Ying, Xiaozhong Chen, Suxia Luo, Huiyan Luo, Xufang Yu, Benchao Chen, Lei Ma, Ruihua Xu

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Abstract

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)

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针对 PD-1 和血管内皮生长因子的新型双特异性抗体 Ivonescimab 在中国晚期实体瘤患者中的安全性、药代动力学和药效学评估

背景：Ivonescimab （AK112）是一类双特异性抗体，可同时靶向程序性死亡-1 （PD-1）和血管内皮生长因子（VEGF）协同结合。我们报告了ivonescimab在晚期实体瘤患者中的安全性、药代动力学（PK）和药效学（PD）概况。方法：在中国五家医院进行了一项多中心、开放标签、剂量递增的I期研究。Ivonescimab作为单药治疗。ivonescimab静脉给药剂量为每2周3、5、10、20和30 mg/kg (Q2W)，每3周10和20 mg/kg （Q3W）。评估ivonescimab的安全性、PK和PD。结果：共治疗59例患者。在10 mg/kg Q2W组中，9例患者中只有1例发生了一种剂量限制性毒性（DLT），表明没有达到最大耐受剂量。在参与者中，53名患者（89.8%）经历了治疗相关不良事件（TRAEs），其中最常见的是蛋白尿（33.9%）、天冬氨酸转氨酶升高（27.1%）、白细胞计数下降（22.0%）、丙氨酸转氨酶升高（20.3%）和贫血（20.3%）。14例（23.7%）发生≥3级trae， 7例（11.9%）发生严重trae。值得注意的是，没有与TRAEs相关的死亡报告，也没有观察到不良事件的剂量依赖性增加。ivonescimab在所有剂量水平单次给药后的半衰期为5.0至7.3天。依替西单抗的血清浓度随着剂量的增加呈近似剂量比例增加。多次给药后，积累比在1.1 ~ 1.7之间，提示依维单抗有轻度积累。5次给药后达到稳定状态。Ivonescimab在整个治疗期间对PD-1的占用率维持在80%以上。每次给药后血清VEGF水平迅速下调。结论：在晚期实体瘤患者中，ivonescimab单药治疗耐受性良好，并表现出线性PK特征。PD资料显示ivonescimab在晚期实体瘤治疗方面具有良好的潜力。试验注册：ClinicalTrials.gov （NCT04597541）。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.