OX40是在抗原激活的T细胞上上调并在调节性T细胞(Tregs)上组成型表达的共刺激受体。INCAGN01949,一种全人免疫球蛋白G1κ抗OX40激动剂单克隆抗体,旨在通过效应T细胞激活和Fcγ受体介导的Treg消耗来促进肿瘤特异性免疫。这项首次在人类中的研究是为了确定安全性,耐受性,和INCAGN01949的初步功效。
第一阶段/第二阶段,开放标签,非随机化,在晚期或转移性实体瘤患者中进行的剂量递增和剂量扩大研究。患者在14天周期内接受INCAGN01949单药治疗(7-1400mg),同时获得益处。安全措施,临床活动,药代动力学,和药效学效果进行了评估和总结与描述性统计。
共纳入87例患者;最常见的肿瘤类型是结直肠(17.2%),卵巢(8.0%),非小细胞肺癌(6.9%)。患者接受了中位数为3(范围1-9)的先前治疗,包括24例患者(27.6%)的免疫治疗。未达到最大耐受剂量;一名接受350mg剂量的患者(1.1%)报告了3级结肠炎的剂量限制性毒性。45例患者(51.7%)报告了与治疗相关的不良事件,疲劳(16(18.4%)),皮疹(6例(6.9%)),腹泻(6例(6.9%))最常见。1例(1.1%)转移性胆囊癌患者获得部分缓解(持续时间6.3个月),23例患者(26.4%)病情稳定(1例患者持续6个月)。OX40受体占有率在所有接受≥200mg剂量的患者中维持在90%以上,而在所有剂量水平中均未检测到治疗时出现的抗药物抗体。药效学结果表明,用INCAGN01949治疗不能增强外周血T细胞的增殖或活化,也不能减少循环Tregs,和分析的肿瘤活检没有显示任何一致的增加效应T细胞浸润或功能,或减少渗透Tregs。
在转移性或晚期实体瘤患者中,INCAGN01949单药治疗未观察到安全性问题。然而,对外周血和治疗后肿瘤活检中T细胞的肿瘤反应和药效学效应有限.需要评估INCAGN01949与其他疗法组合的研究,以进一步评估OX40激动作为晚期实体瘤患者治疗方法的潜力。
NCT02923349。
OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human
study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.
Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion
study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.
Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs.
No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.
NCT02923349.