Luke Jason J, Pinato David J, Juric Dejan, LoRusso Patricia, Hosein Peter J, Desai Anupam M, Haddad Robert, de Miguel María, Cervantes Andrés, Kim Won Seog, Marabelle Aurélien, Zhang Yan, Rong Yuanxin, Yuan Xiaobin, Champiat Stéphane
UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2025 Feb 20;13(2):e010511. doi: 10.1136/jitc-2024-010511.
E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg. The most frequent treatment-related treatment-emergent adverse events were chills (50.0%; 85.7%), fever (40.0%; 85.7%), and fatigue (30.0%; 35.7%) in patients who received non-visceral and visceral injections, respectively. Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-α, IFN-β, IFN-γ, TNF-α, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.
E7766是一种新型的干扰素基因（STING）激动剂，能够有效激活免疫细胞，并在临床前小鼠肿瘤模型中产生强烈的抗肿瘤反应。在此，我们展示了肿瘤内注射E7766用于晚期实体瘤患者的首次人体I/Ib期研究的安全性、疗效和生物标志物结果。符合条件的复发/难治性癌症患者（n = 24）被纳入剂量递增队列，接受肿瘤内注射75至1000μg的E7766。接受非内脏和内脏注射的患者中，最常见的与治疗相关的治疗中出现的不良事件分别是寒战（50.0%；85.7%）、发热（40.0%；85.7%）和疲劳（30.0%；35.7%）。根据实体瘤改良版疗效评价标准1.1，8名患者（33.3%）达到疾病稳定作为最佳反应，注射和未注射的病灶之间存在差异。在所有可评估的患者中，注射后10小时内，血浆中IFN-α、IFN-β、IFN-γ、TNF-α、IL-6、IP-10、MCP1和MIP-1b水平短暂升高，然后降至基线水平。在大多数检测的干扰素相关和STING基因中，血液和肿瘤基因表达水平升高。在不同剂量水平的一些患者中，还观察到程序性死亡配体1和分化簇8在RNA和蛋白质水平上的进一步增加。总体而言，E7766在实体瘤患者中产生了靶向药效学效应。有必要在同质患者群体中进一步探索以评估疗效。
