特瑞普利单抗联合 HBM4003，一种抗 CTLA-4 重链仅抗体，治疗晚期黑色素瘤和其他实体瘤：一项开放标签的 I 期临床试验。
Toripalimab in combination with HBM4003, an anti-CTLA-4 heavy chain-only antibody, in advanced melanoma and other solid tumors: an open-label phase I trial.
机构信息
Peking University Cancer Hospital & Institute, Beijing, China.
Department of Medical Oncology, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China.
出版信息
J Immunother Cancer. 2024 Oct 4;12(10):e009662. doi: 10.1136/jitc-2024-009662.
BACKGROUND
HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.
METHODS
The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.
RESULTS
A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.
CONCLUSIONS
HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.
TRIAL REGISTRATION NUMBER
NCT04727164.
背景
HBM4003 是一种新型抗 CTLA-4 重链单域抗体，旨在增强 Treg 耗竭和抗体依赖性细胞介导的细胞毒性，同时确保可管理的安全性。这项 I 期临床试验研究了 HBM4003 联合抗 PD-1 抗体 toripalimab 在晚期实体瘤患者中的安全性、药代动力学、免疫原性和初步疗效，特别是在黑色素瘤患者中。
方法
这项多中心、开放标签的 I 期临床试验分为两部分：剂量递增阶段（第 1 部分）和剂量扩展阶段（第 2 部分）。在第 1 部分中，HBM4003 以 0.03、0.1、0.3mg/kg 的剂量联合 toripalimab 治疗，toripalimab 剂量固定为每 3 周 240mg。第 2 部分采用推荐的 II 期剂量（RP2D）。主要终点为第 1 部分的安全性和 RP2D 以及第 2 部分的客观缓解率（ORR）。探索了基于细胞因子和多重免疫荧光染色的生物标志物。
结果
共有 40 名患者接受了研究治疗，其中 36 名患者接受了 HBM4003 0.3mg/kg 联合 toripalimab 240mg 每 3 周的 RP2D 治疗。36 名参与者（90.0%）经历了至少一次治疗相关不良事件（TRAE），其中 10 名（25.0%）患者经历了≥3 级 TRAE，5 名（12.5%）经历了最大严重程度为 3 级的免疫介导的不良事件（irAE）。没有发生 4 级或 5 级 irAE。疗效分析集包括 32 名接受 RP2D 治疗且具有基线后可评估影像学数据的黑色素瘤患者。抗 PD-1/PD-L1 治疗初治亚组和抗 PD-1/PD-L1 治疗失败亚组的 ORR 分别为 33.3%和 5.9%。在黏膜黑色素瘤中，两个亚组的 ORR 分别为 40.0%和 10.0%。肿瘤中基线高 Treg/CD4+比率是免疫治疗疗效的独立预测因素。
结论
HBM4003 0.3mg/kg 联合 toripalimab 240mg 每 3 周治疗在实体瘤中具有可管理的安全性，没有新的安全性信号。有限的数据显示出有前景的抗肿瘤活性，特别是在 PD-1 治疗初治的黏膜黑色素瘤患者中。
临床试验注册号
NCT04727164。
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