Carneiro Benedito A, Gbolahan Olumide B, Abdul Razak Albiruni Abdul, Hilton John F, Lambert Arthur W, Hood John, Pluta Michael, Bragulat Veronique, Sanai Elhan, Kumar Rakesh, Jodrell Duncan I, LoRusso Patricia M
Division of Hematology/Oncology, Legorreta Cancer Center, Brown University, Providence, Rhode Island.
Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.
Cancer Res Commun. 2025 Jun 1;5(6):896-905. doi: 10.1158/2767-9764.CRC-24-0565.
Growth and differentiation factor 15 (GDF15) is overexpressed in multiple solid tumors and is thought to exert immunosuppressive effects in the tumor microenvironment. AZD8853 is an anti-GDF15 mAb.
This first-in-human, phase I/IIa, open-label study (NCT05397171) assessed AZD8853 monotherapy in previously treated patients with advanced/metastatic microsatellite-stable colorectal cancer and urothelial carcinoma. The primary objective was safety including dose-limiting toxicities. Secondary objectives included efficacy, pharmacokinetics, and pharmacodynamics (PD), including free serum GDF15. Exploratory objectives included biomarkers of clinical activity and effects on cancer cachexia.
During dose escalation, 16 patients received AZD8853 300 mg (n = 3), 1,000 mg (n = 6), or 3,000 mg (n = 7) intravenously every 3 weeks; 15 patients had microsatellite-stable colorectal cancer; and one patient had urothelial carcinoma. By June 6, 2023, all patients had discontinued treatment. Thirteen (81.3%) patients had treatment-emergent adverse events (TEAE); most commonly diarrhea (31.3%), abdominal pain (31.3%), and decreased appetite (25%). Eight (50.0%) patients had grade ≥3 TEAEs, and six (37.5%) had serious TEAEs, none treatment related. There were no dose-limiting toxicities. The best response per RECIST v1.1 was stable disease in five (31.3%) patients and disease progression in 11 (68.8%) patients. AZD8853 showed linear pharmacokinetics with a half-life of 5 to 10 days, supporting every 3 weeks dosing. AZD8853 suppression of GDF15 was transient. There was no evidence of ctDNA clearance or dose-dependent changes in peripheral T cells. Changes in body weight showed no apparent trends.
AZD8853 was well tolerated; however, no objective responses or PD effects were seen, and GDF15 suppression was not sustained. The study was terminated after dose escalation.
GDF15 is upregulated in the tumor microenvironment and suppresses antitumor immune responses. In this first-in-human trial, the anti-GDF15 antibody AZD8853 was well tolerated in previously treated patients with advanced/metastatic solid tumors, but no objective responses or PD effects were seen and GDF15 suppression was not sustained.
生长分化因子15（GDF15）在多种实体瘤中过表达，被认为在肿瘤微环境中发挥免疫抑制作用。AZD8853是一种抗GDF15单克隆抗体。
这项首次人体、I/IIa期、开放标签研究（NCT05397171）评估了AZD8853单药治疗先前接受过治疗的晚期/转移性微卫星稳定型结直肠癌和尿路上皮癌患者的疗效。主要目标是安全性，包括剂量限制性毒性。次要目标包括疗效、药代动力学和药效学（PD），包括游离血清GDF15。探索性目标包括临床活性生物标志物以及对癌症恶病质的影响。
在剂量爬坡阶段，16例患者每3周静脉注射一次AZD8853，剂量分别为300mg（n = 3）、1000mg（n = 6）或3000mg（n = 7）；15例患者患有微卫星稳定型结直肠癌；1例患者患有尿路上皮癌。截至2023年6月6日，所有患者均已停止治疗。13例（81.3%）患者出现治疗期间出现的不良事件（TEAE）；最常见的是腹泻（31.3%）、腹痛（31.3%）和食欲下降（25%）。8例（50.0%）患者发生≥3级TEAE，6例（37.5%）患者发生严重TEAE，均与治疗无关。没有剂量限制性毒性。根据RECIST v1.1标准，最佳疗效为5例（31.3%）患者病情稳定，11例（68.8%）患者病情进展。AZD8853呈现线性药代动力学，半衰期为5至10天，支持每3周给药一次。AZD8853对GDF15的抑制是短暂的。没有证据表明循环肿瘤DNA清除或外周T细胞有剂量依赖性变化。体重变化未显示明显趋势。
AZD8853耐受性良好；然而，未观察到客观缓解或PD效应，且对GDF15的抑制未持续。剂量爬坡后该研究终止。
GDF15在肿瘤微环境中上调并抑制抗肿瘤免疫反应。在这项首次人体试验中，抗GDF15抗体AZD8853在先前接受过治疗的晚期/转移性实体瘤患者中耐受性良好，但未观察到客观缓解或PD效应，且对GDF15的抑制未持续。
