Janku F, Tan D S P, Martin-Liberal J, Takahashi S, Geva R, Gucalp A, Razak A, Kan R, Reiners R, Mataraza J, Szpakowski S, Subramanian K, Chen X, Lai C, Bedard P L
The University of Texas MD Anderson Cancer Center, Houston, USA.
National University Cancer Institute Singapore, National University Hospital, Singapore, Singapore; Cancer Science Institute, National University of Singapore, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
ESMO Open. 2025 May 16;10(6):105051. doi: 10.1016/j.esmoop.2025.105051.
FAZ053 triggers an antitumor response by targeting programmed death-ligand 1 (PD-L1), thereby activating effector T cells and negatively regulating T cells. This study assessed the safety, tolerability, and preliminary efficacy of FAZ053 monotherapy and in combination with spartalizumab in patients with advanced solid tumors.
This phase I, multicenter, open-label study (NCT02936102) included dose escalation and dose expansion. The primary objectives were safety and tolerability; secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
Of the 154 patients treated, 49 (52.7%) patients receiving FAZ053 monotherapy experienced at least one treatment-related adverse event (TRAE), of whom 6 (6.5%) experienced grade ≥3 TRAEs; 35 patients (57.4%) receiving combination therapy experienced TRAEs, of whom 3 (4.9%) experienced grade ≥3 TRAEs. One patient who received FAZ053 1600 mg every 6 weeks (Q6W) and one who received FAZ053 20 mg every 3 weeks (Q3W) with spartalizumab 300 mg Q3W experienced dose-limiting toxicities of grade 4 creatinine increase and grade 3 liver function test increased, respectively. The median duration of exposure was 105 days for monotherapy and 85 days for combination therapy. During dose escalation, response was observed in 3 (5.1%) and 3 (4.9%) patients receiving FAZ053 monotherapy and combination therapy, respectively. In dose expansion, response was observed in 2 (50%) patients with advanced alveolar soft part sarcoma (ASPS) and 3 (30%) patients with advanced chordoma receiving FAZ053 monotherapy. FAZ053 demonstrated a dose-proportional pharmacokinetic profile with a terminal half-life of 20.6 days at 1200 mg Q3W. Biomarker analysis showed increased immune gene expression following FAZ053 treatment. The recommended dose for expansion was 1200 mg Q3W.
FAZ053 monotherapy was well tolerated and effective in maintaining disease control in various tumors including ASPS and chordoma. The anticipated synergistic effect of combined programmed cell death protein 1 (PD-1) and PD-L1 inhibition was not observed. These findings contribute to the growing evidence that rare, phenotypically 'immune cold' sarcomas, such as ASPS and chordoma, can become responsive to immune checkpoint inhibitors.
FAZ053通过靶向程序性死亡配体1（PD-L1）触发抗肿瘤反应，从而激活效应T细胞并对T细胞进行负调控。本研究评估了FAZ053单药治疗以及与斯巴特珠单抗联合治疗晚期实体瘤患者的安全性、耐受性和初步疗效。
这项I期多中心开放标签研究（NCT02936102）包括剂量递增和剂量扩展阶段。主要目标是安全性和耐受性；次要目标是药代动力学、药效学和初步抗肿瘤活性。
在接受治疗的154例患者中，49例（52.7%）接受FAZ053单药治疗的患者发生了至少1次治疗相关不良事件（TRAE），其中6例（6.5%）发生了≥3级TRAE；35例（57.4%）接受联合治疗的患者发生了TRAE，其中3例（4.9%）发生了≥3级TRAE。1例每6周接受1600mg FAZ053（Q6W）治疗的患者和1例每3周接受20mg FAZ053（Q3W）联合每3周300mg斯巴特珠单抗治疗的患者分别发生了4级肌酐升高和3级肝功能检查指标升高的剂量限制性毒性。单药治疗的中位暴露持续时间为105天，联合治疗为85天。在剂量递增阶段，接受FAZ053单药治疗和联合治疗的患者中分别有3例（5.1%）和3例（4.9%）观察到缓解。在剂量扩展阶段，2例（50%）晚期肺泡软组织肉瘤（ASPS）患者和3例（30%）晚期脊索瘤患者接受FAZ053单药治疗后观察到缓解。FAZ053在每3周1200mg剂量下显示出剂量成正比的药代动力学特征，终末半衰期为20.6天。生物标志物分析显示FAZ053治疗后免疫基因表达增加。扩展阶段的推荐剂量为每3周1200mg。
FAZ053单药治疗耐受性良好，在包括ASPS和脊索瘤在内的各种肿瘤中有效维持疾病控制。未观察到程序性细胞死亡蛋白1（PD-1）和PD-L1联合抑制的预期协同效应。这些发现进一步证明了罕见的、表型为“免疫冷”的肉瘤，如ASPS和脊索瘤，可对免疫检查点抑制剂产生反应。
