LHC165 是一种 Toll 样受体 (TLR)-7 激动剂，可产生有效的肿瘤抗原特异性 T 细胞适应性免疫反应以及持久的抗肿瘤反应。我们的目的是评估 LHC165 单药 (SA) ± 斯帕他珠单抗 [PDR001；PDR001；抗程序性细胞死亡蛋白 1 (PD-1)] 在晚期实体瘤成年患者中的应用。在这项 I/Ib 期、开放标签、剂量递增/扩展研究中，患者通过瘤内注射每两周接受一次 LHC165 SA 100-600 μg (IT) 注射和 LHC165 600 μg 每两周一次静脉 (IV) 输注 400 mg Q4W。 纳入了 45 名患者：21 名患者接受 LHC165 SA，24 名患者接受 LHC165 spartalizumab。中位暴露时间为 8 周（范围 2-129 周）。未达到最大耐受剂量。推荐的剂量扩展确定为 LHC165 600 μg，每两周一次作为 SA，并与 spartalizumab 400 mg Q4W 联用。最常见的药物相关不良事件 (AE) 是发热 (22.2%)、瘙痒 (13.3%)、寒战 (11.1%) 和乏力 (4.4%)。唯一怀疑与研究药物相关的严重 AE (SAE) 是 3 级胰腺炎 (n = 1)。在所有肿瘤类型中，总体缓解率和疾病控制率分别为 6.7% 和 17.8%。总体中位无进展生存期 (PFS) 和免疫相关 PFS 为 1.7 个月。 LHC165 血清 PK 显示出最初的快速释放，随后由于 LHC165 从注射部位持续释放而缓慢释放。LHC165 作为 SA 以及与斯帕他珠单抗联合使用时均显示出可接受的安全性和耐受性，并且在成年患者中发现了有限的抗肿瘤活性的证据患有复发/难治性或转移性实体瘤。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors.In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 μg biweekly through intratumoral (IT) injection and LHC165 600 μg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion.Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site.LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.