在晚期实体瘤患者中进行的 Futibatinib（一种高度选择性、不可逆的 FGFR1-4 抑制剂）的 I 期首次人体研究。
Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors.
机构信息
Early Drug Development Department (DITEP), Gustave Roussy Cancer Center, Villejuif, France.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA.
出版信息
Ann Oncol. 2020 Oct;31(10):1405-1412. doi: 10.1016/j.annonc.2020.06.018. Epub 2020 Jul 2.
BACKGROUND
Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors.
PATIENTS AND METHODS
Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.).
RESULTS
A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%).
CONCLUSIONS
Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D.
CLINICAL TRIAL REGISTRATION
FOENIX-101 (ClinicalTrials.gov, NCT02052778).
背景
富替替尼是一种口服、不可逆、高度选择性成纤维细胞生长因子受体（FGFR）1-4 抑制剂，在具有 FGFR 异常的肿瘤的临床前研究中具有强大的活性。这是一项首次人体、I 期剂量递增试验（NCT02052778），评估了 Futibatinib 在晚期实体瘤中的安全性、药代动力学/药效学。
患者和方法
在标准的 3+3 剂量递增设计下，标准治疗耐药的晚期实体瘤患者接受 Futibatinib 8-200mg，每周 3 次（t.i.w.）或 4-24mg，每日 1 次（q.d.）。
结果
共纳入 9 个 t.i.w. 组（n=42）和 5 个 q.d. 组（n=44）的 86 例患者；71 例（83%）患者存在 FGF/FGFR 异常的肿瘤。24mg q.d. 组的 3 例患者发生剂量限制毒性，包括 1 例丙氨酸转氨酶、天冬氨酸转氨酶和血胆红素升高（各 1 例）。确定 20mg q.d. 为最大耐受剂量（MTD）；t.i.w. 方案未定义 MTD。在所有 86 例患者中，最常见的治疗相关不良事件（TEAEs）为高磷血症（59%）、腹泻（37%）和便秘（34%）；48%的患者发生 3 级 TEAEs。55%、14%和 3%的患者因 TEAEs 分别导致剂量中断、剂量减少和治疗终止。所有 q.d. 剂量的药代动力学均呈剂量相关性，但并非所有 t.i.w. 剂量均如此，在 80-200mg t.i.w. 时观察到饱和。两种方案下，血清磷均随 Futibatinib 剂量依赖性增加，但 q.d. 给药时观察到更强的暴露-反应关系，支持 20mg q.d. 作为推荐的 II 期剂量（RP2D）。总体而言，5 例患者观察到部分缓解（FGFR2 融合阳性肝内胆管癌 n=3，FGFR1 突变原发性脑肿瘤 n=2），41 例（48%）患者疾病稳定。
结论
Futibatinib 治疗可使晚期实体瘤患者的安全性、药效学和初步疗效得到控制。这项 I 期剂量递增试验的结果支持 Futibatinib 20mg q.d.作为 RP2D。
临床试验注册
FOENIX-101（ClinicalTrials.gov，NCT02052778）。
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