Livingston J Andrew, Blay Jean-Yves, Trent Jonathan, Valverde Claudia, Agulnik Mark, Gounder Mrinal, Le Cesne Axel, McKean Meredith, Wagner Michael J, Stacchiotti Silvia, Agresta Samuel, Quintás-Cardama Alfonso, Reilly Sarah A, Healy Kathleen, Hickman Denice, Zhao Tina, Ballesteros-Perez Alex, Khalil Alexis, Collins Michael P, Piel Jessica, Horrigan Kim, Lefkovith Ariel, Innis Scott, Lazar Alexander J, Cote Gregory M, Wagner Andrew J
The University of Texas MD Anderson Cancer Center, Houston, Texas.
Centre Léon Bérard, Lyon, France.
Clin Cancer Res. 2025 Feb 17;31(4):628-638. doi: 10.1158/1078-0432.CCR-24-2583.
FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.
In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15).
Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients.
FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.
评估强效、选择性、异双功能含溴结构域蛋白9（BRD9）降解剂FHD-609治疗晚期滑膜肉瘤或SMARCB1缺陷肿瘤患者的效果。
在这项多中心、开放标签的I期研究（NCT04965753）中，患者接受递增剂量的FHD-609静脉注射，每周两次（5-80毫克；n = 40）或每周一次（40-120毫克；n = 15）。
55名患者接受了FHD-609治疗，中位治疗时间为43天。最大耐受剂量为每周两次40毫克，等效每周剂量为每周一次80毫克。在每周两次40毫克和60毫克时观察到剂量限制性毒性，即QTc（心率校正QT间期）延长和晕厥。治疗相关不良事件的严重程度主要为1至2级，最常见的是味觉障碍（40%）、口干（29.1%）、疲劳（27.3%）和贫血（25.5%）。11名（20%）患者出现治疗中出现的QTc（弗里德里西亚公式）延长，之前有T波倒置；21名（38.2%）患者出现T波倒置，但无进一步心脏事件或心电图异常。FHD-609的药代动力学暴露呈剂量依赖性增加，无明显蓄积。肿瘤组织中BRD9的广泛降解与癌细胞增殖基因集的下调相对应。1名（2%）患者获得部分缓解；8名（15%）患者病情稳定，其中2名患者的病情稳定持续超过6个月。
FHD-609的全身暴露和药效学反应特征呈剂量依赖性增加。确定了最大耐受剂量（每周两次40毫克/每周一次80毫克）并观察到初步临床活性。鉴于本研究中观察到的QTc延长，未来BRD9降解剂的研究将需要严格的心脏监测。
