Sooi Kenneth, Tan Tuan Zea, Kim Jae-Weon, Lee Jung Yun, Kim Byoung-Gie, Micklem David, Jackson Akil, Pinato David J, Gourley Charlie, Kristeleit Rebecca, Blagden Sarah P, Bjorge Line, Tan David Shao Peng
National University Hospital, Singapore, Singapore.
National University Cancer Institute, Singapore, Singapore.
Br J Cancer. 2025 Jul 22. doi: 10.1038/s41416-025-03090-6.
Tilvestamab is a highly selective humanised immunoglobulin G1 anti-AXL monoclonal antibody. This phase 1 study evaluated its optimal dose, safety, tolerability, immunogenicity and pharmacokinetics (PK) in relapsed platinum-resistant HGSOC patients.
Patients received tilvestamab in three dose levels (1 mg/kg, 3 mg/kg and 5 mg/kg) via IV infusion every 2 weeks. Primary objectives included safety, tolerability and PK. Exploratory objectives included overall response, progression-free survival (PFS) and quality-of-life measures. Pharmacodynamic included AXL expression, gene and protein changes by transcriptomic and proteomic analysis.
Between 25 February 2021 and 4 February 2022, 16 patients were enroled across 8 sites in Singapore, Korea, United Kingdom, and Norway. Median treatment duration was 6.1 weeks. Grade 3 or higher treatment-emergent adverse events occurred in 62.5% patients, but none were tilvestamab-related. Common events included fatigue (38%), anorexia (38%) infections (31%), anaemia (25%) and dyspnoea (25%). No objective responses were observed, but 7 (44%) had stable disease at 6 weeks. PK showed dose-proportional exposure and steady-state by the second dose. Pharmacodynamic analyses revealed reduced fibrosis-related gene signatures and AXL protein expression. Epithelial-mesenchymal transition reversal was seen in 2 patients.
Tilvestamab was well-tolerated and further studies to examine the efficacy of AXL inhibition in other indications are required.
This trial is registered at https://clinicaltrials.gov .
NCT04893551. EudraCT Number: 2020-001382-36.
替维司他单抗是一种高度选择性的人源化免疫球蛋白G1抗AXL单克隆抗体。这项1期研究评估了其在复发的铂耐药高级别浆液性卵巢癌（HGSOC）患者中的最佳剂量、安全性、耐受性、免疫原性和药代动力学（PK）。
患者每2周通过静脉输注接受三个剂量水平（1mg/kg、3mg/kg和5mg/kg）的替维司他单抗。主要目标包括安全性、耐受性和PK。探索性目标包括总体缓解率、无进展生存期（PFS）和生活质量指标。药效学包括通过转录组学和蛋白质组学分析检测AXL表达、基因和蛋白质变化。
在2021年2月25日至2022年2月4日期间，新加坡、韩国、英国和挪威的8个地点招募了16名患者。中位治疗持续时间为6.1周。62.5%的患者发生了3级或更高等级的治疗中出现的不良事件，但均与替维司他单抗无关。常见事件包括疲劳（38%）、厌食（38%）、感染（31%）、贫血（25%）和呼吸困难（25%）。未观察到客观缓解，但7例（44%）在6周时病情稳定。PK显示剂量成正比的暴露和第二剂时达到稳态。药效学分析显示纤维化相关基因特征和AXL蛋白表达降低。2例患者出现上皮-间质转化逆转。
替维司他单抗耐受性良好，需要进一步研究以检验AXL抑制在其他适应症中的疗效。
本试验在https://clinicaltrials.gov注册。
NCT04893551。欧盟临床试验注册号：2020-001382-36。
