PO.CT01.01 · 临床试验
FX-909治疗膀胱癌的0期瘤内微装置研究显示出靶向抗肿瘤活性和免疫调节作用，且与抗PD-1联用时增强
Phase 0 intratumoral microdevice study of FX-909 in bladder cancer demonstrates on-target anti-tumor activity and immune modulation, enhanced in combination with anti-PD-1
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摘要 Abstract
中文摘要
引言
以高PPARG表达为特征的腔面型(luminal)晚期尿路上皮癌(UC)约占UC病例的65%，且与不良临床结局相关1,2。FX-909是一种同类首创(first-in-class)的口服PPARG抑制剂，在1a期中显示出早期临床活性和可接受的安全性，相关生物标志物分析提示免疫激活3,4。在此，我们报告0期结果(NCT06204614)，采用瘤内微装置(intratumoral microdevice, IMD)5的植入和取出，评估FX-909单药及与抗PD-1联用在原发性膀胱癌中的瘤内效应。
方法
受试者为局限性膀胱癌(T2-T3 N0)，肿瘤含有≥1 cm病灶，并计划行膀胱切除术。入组要求临床稳定且肿瘤体积充足。数据来自两例患者(Pt1、Pt2)，IMD原位留置48-72小时。测试了两种FX-909剂量(D1，200 mg；D2，350 mg)。通过MALDI-TOF评估瘤内药物渗透，通过免疫组化(IHC)评估PPARG6和剪切型caspase-3(CC3)，通过循环免疫荧光(cIF)评估CD3和CD8，并使用NanoString CosMx进行空间转录组学(ST)分析。
结果
FX-909组织渗透显示出剂量和距离依赖性的浓度梯度，在装置-组织界面附近最高。FX-909浓度在距装置100-400 μm处趋于平台，暴露区与未暴露对照区的组织形态相似。在两例患者中，FX-909均显示PPARG表达细胞比例的剂量依赖性下降(Pt1：D1时32.1%，D2时71.4%；Pt2：D1时69.9%，D2时86.0%)。凋亡评估显示FX-909单药中CC3+细胞的剂量依赖性增加(Pt1：D1时16%，D2时44%；Pt2：D1时12%，D2时18%)，而在FX-909与抗PD-1联用中观察到显著更高的水平(Pt1：D1时120%，D2时142%；Pt2：D1时136%，D2时289%)。ST分析显示FX-909抑制肿瘤细胞中的增殖和细胞周期通路，而在巨噬细胞中则调节与促炎状态相关的关键基因的表达变化。cIF显示FX-909使CD8⁺ T细胞浸润呈剂量依赖性增加，在FX-909与抗PD-1联用中观察到更高水平。
结论
在这项0期研究中，FX-909在原发性膀胱癌中显示出瘤内渗透和靶向活性，伴有剂量依赖性PPARG调节、肿瘤凋亡增加和CD8+ T细胞浸润。与抗PD-1联用时，FX-909增强了免疫激活和肿瘤增殖抑制，支持在UC中进一步临床评估该联合方案4。
参考文献
1. Robertson等，Cell 2017:171
2. Motley等，Eur J Cancer 2022:174S1
3. Gao等，AACR-NCI-EORTC 2025
4. Milowsky等，J Immunother Cancer 2025:13(Suppl 3)
5. Peruzzi等，Sci Transl Med 2023:15
6. Gjini等，J Clin Oncol 2025:43
查看英文原文 English abstract
INTRODUCTION
Luminal advanced urothelial carcinoma (UC), defined by high PPARG expression, represents ~65% of UC cases and is associated with poor clinical outcomes 1,2 . FX-909, a first-in-class oral PPARG inhibitor, demonstrated early clinical activity and acceptable safety in Phase 1a, with correlative biomarker analyses indicating immune activation 3,4 . Here, we report Phase 0 results (NCT06204614) assessing intratumoral effects of FX-909 alone and with anti-PD-1 using intratumoral microdevice (IMD) 5 implantation and retrieval in primary bladder cancer.
METHODS
Participants had localized bladder cancer (T2-T3 N0) with tumors containing a ≥1 cm lesion and were planned for cystectomy. Eligibility required clinical stability and sufficient tumor volume. Data are shown from two patients (Pt1, Pt2), with IMDs remaining in situ for 48-72 hours. Two FX-909 doses (D1, 200 mg; D2, 350 mg) were tested. Intratumoral drug penetration was assessed by MALDI-TOF, PPARG 6 and cleaved caspase-3 (CC3) by immunohistochemistry (IHC), CD3 and CD8 by cyclic immunofluorescence (cIF), and spatial transcriptomics (ST) using NanoString CosMx.
RESULTS
FX-909 tissue penetration showed a dose- and distance-dependent concentration gradient, highest near the device-tissue interface. FX-909 concentrations plateaued at 100-400 μm from the device, with similar histomorphology in exposed and unexposed control-regions. In both patients, FX-909 showed a dose-dependent decrease in the proportion of PPARG expressing cells (Pt1: 32.1% at D1, 71.4% at D2; Pt2: 69.9% at D1, 86.0% at D2). Apoptosis assessment demonstrated dose-dependent increases in CC3+ cells in FX-909 alone (Pt1: 16% at D1, 44% at D2; Pt2: 12% at D1, 18% at D2), with substantially higher levels observed in FX-909 and anti-PD-1 combination (Pt1: 120% at D1, 142% at D2; Pt2: 136% at D1, 289% at D2). ST analyses showed FX-909 suppressed proliferation and cell cycle pathways in tumor cells, while in macrophages it modulated expression changes in key genes associated with a pro-inflammatory state. cIF showed dose-dependent increases in CD8⁺ T-cell infiltration with FX-909, with higher levels observed in FX-909 and anti-PD-1 combination.
CONCLUSIONS
In this Phase 0 study, FX-909 showed intratumoral penetration and on-target activity in primary bladder cancer, with dose-dependent PPARG modulation, increased tumor apoptosis and CD8 + T-cell infiltration. Combined with anti-PD-1, FX-909 enhanced immune activation and tumor proliferation suppression, supporting further clinical evaluation of this combination in UC 4 .
REFERENCES
1. Robertson et al, Cell 2017:171
2. Motley et al, Eur J Cancer 2022:174S1
3. Gao et al, AACR-NCI-EORTC 2025
4. Milowsky et al, J Immunother Cancer 2025:13(Suppl 3)
5. Peruzzi et al, Sci Transl Med 2023:15
6. Gjini et al, J Clin Oncol 2025:43
利益披露 Disclosure
P. A. Nguyen,
Flare Therapeutics Employment.
P. M. Szabo,
Flare Therapeutics Independent Contractor.
J. Kotler, None..
S. Chow, None.
B. Kakrecha,
Flare Therapeutics Employment.
N. Onochie, None..
F. Santa, None.
M. Bowden,
Flare Therapeutics Employment.
O. Jonas,
Kibur Medical Employment.
M. Mossanen, None.
E. Gjini,
Flare Therapeutics Employment.