Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
Advanced Medical Development Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
J Immunother Cancer. 2024 Jul 24;12(7):e009262. doi: 10.1136/jitc-2024-009262.
Immunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression and fibrosis in the TME. AMY109, a humanized anti-IL-8 monoclonal antibody, reduced fibrosis and decreased immunosuppressive cells in tumor tissue in animals. Combining AMY109 with atezolizumab (anti-PD-L1 antibody) may enhance its antitumor effects by making the TME more favorable to PD-L1 inhibition.
This multicenter, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and clinical activity of AMY109 plus atezolizumab in patients with previously treated advanced solid tumors and Eastern Cooperative Oncology Group performance status 0 or 1. Patients received AMY109 (2-45 mg/kg) plus atezolizumab (1200 mg) intravenously every 3 weeks in part 1, and AMY109 (15-45 mg/kg) plus atezolizumab (1200 mg) in part 2. Primary endpoints were the dose-limiting toxicity (DLT), safety, and pharmacokinetics of AMY109 and atezolizumab in Part 1, and safety and antitumor activity per investigator-assessed Response Evaluation Criteria in Solid Tumors 1.1 in part 2. Exploratory analyses of peripheral and tumor biomarker were conducted.
Overall, 38 patients (18 in part 1 and 20 in part 2) were enrolled. Part 1 showed no DLTs and a dose-proportional increase in AMY109 exposure over 2-45 mg/kg, with no apparent change in mean atezolizumab serum concentrations across AMY109 dosing. Plasma IL-8 concentration accumulation was seen in all dose cohorts after AMY109 initiation. Grade 1-3 treatment-related adverse events (AEs) occurred in 21 of 38 patients (55%). Treatment-related serious AEs occurred in two patients (5%). No AEs led to treatment withdrawal. Partial responses (PRs) occurred in 2 of 38 patients; the confirmed objective response rate was 5%. These patients had uterocervical and pancreatic cancer, respectively, and had been treated for >500 days at the cut-off date: one had received 45 mg/kg of AMY109 throughout, and the other received 30 mg/kg of AMY109 until cycle 5, then 45 mg/kg thereafter.
With no DLTs, AMY109 plus atezolizumab was well tolerated in patients with advanced solid tumors, with no new safety signals. AMY109 showed a dose-proportional increase in exposure. The PRs in two patients were durable.
肿瘤微环境（TME）中的免疫抑制条件可使肿瘤逃避免疫系统，包括阻碍程序性死亡配体 1（PD-L1）抑制剂的活性。白细胞介素（IL）-8 有助于 TME 中的纤维化和免疫抑制。AMY109 是一种人源化抗 IL-8 单克隆抗体，可减少动物肿瘤组织中的纤维化和免疫抑制细胞。AMY109 与阿替利珠单抗（抗 PD-L1 抗体）联合使用可能通过使 TME 更有利于 PD-L1 抑制来增强其抗肿瘤作用。
这项多中心、开放标签、剂量递增研究评估了先前接受过治疗的晚期实体瘤和东部肿瘤协作组体能状态 0 或 1 的患者中 AMY109 加阿替利珠单抗的安全性、药代动力学和临床活性。患者在第 1 部分接受 AMY109（2-45mg/kg）加阿替利珠单抗（1200mg）静脉输注，每 3 周一次，在第 2 部分接受 AMY109（15-45mg/kg）加阿替利珠单抗（1200mg）。主要终点是第 1 部分中 AMY109 和阿替利珠单抗的剂量限制毒性（DLT）、安全性和药代动力学，以及第 2 部分中研究者评估的实体瘤反应评估标准 1.1 的安全性和抗肿瘤活性。进行了外周和肿瘤生物标志物的探索性分析。
共有 38 名患者（第 1 部分 18 名，第 2 部分 20 名）入组。第 1 部分未观察到 DLT，AMY109 暴露量呈剂量比例增加，2-45mg/kg，AMY109 给药时阿替利珠单抗的平均血清浓度无明显变化。在 AMY109 起始后，所有剂量组的血浆 IL-8 浓度均有蓄积。38 名患者中有 21 名（55%）发生 1-3 级与治疗相关的不良事件（AE）。两名患者（5%）发生与治疗相关的严重 AE。没有 AE 导致治疗中断。38 名患者中有 2 名（5%）出现部分缓解（PR）；确认的客观缓解率为 5%。这两名患者分别患有子宫颈癌和胰腺癌，在截止日期时已接受治疗>500 天：一名患者全程接受 45mg/kg AMY109，另一名患者在第 5 周期前接受 30mg/kg AMY109，之后接受 45mg/kg AMY109。
在晚期实体瘤患者中，AMY109 加阿替利珠单抗耐受性良好，无新的安全性信号，未观察到剂量限制毒性。AMY109 显示出剂量比例增加的暴露。两名患者的 PR 持续时间较长。
