Papadopoulos K P, El-Rayes B F, Tolcher A W, Patnaik A, Rasco D W, Harvey R D, LoRusso P M, Sachdev J C, Abbadessa G, Savage R E, Hall T, Schwartz B, Wang Y, Kazakin J, Shaib W L
South Texas Accelerated Research Therapeutics, 4383 Medical Drive, San Antonio, TX 78229, USA.
Winship Cancer Institute of Emory University, 1365-C Clifton Road NE, Atlanta, GA 30322, USA.
Br J Cancer. 2017 Nov 21;117(11):1592-1599. doi: 10.1038/bjc.2017.330. Epub 2017 Oct 3.
ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D).
Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement.
80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value<0.05) suggest phosphate and FGF19 levels as markers of target engagement. In 18 evaluable patients with FGFR genetic alterations, 3 confirmed partial responses (two intrahepatic cholangiocarcinomas (iCCA) with FGFR2 fusions and one urothelial cancer with FGFR2 and FGF19 amplification) and two durable stable disease at ⩾16 weeks with tumour reduction (FGFR2 fusion-positive iCCA and adrenocortical carcinoma with FGFR1 amplification) were observed.
ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.
ARQ 087是一种口服的具有多激酶活性的泛FGFR抑制剂。这项1期研究评估了ARQ 087的安全性、药代动力学和药效学，并确定了推荐的2期剂量（RP2D）。
晚期实体瘤患者接受ARQ 087治疗，初始剂量为每隔一天25mg，剂量递增至每日25至425mg（QD）持续给药。评估FGF19、21、23和血清磷酸盐作为靶点参与的潜在生物标志物。
共入组80例患者，61例在剂量递增/食物效应队列，19例在扩展队列中有预先定义的肿瘤类型。最常见的与ARQ 087相关的不良事件为疲劳（49%）、恶心（46%）、天冬氨酸转氨酶（AST）升高（30%）和腹泻（23%）。4例患者（5%）发生1级治疗相关高磷血症。剂量限制性毒性为可逆性3级AST升高。RP2D为300mg QD。药代动力学在25至325mg QD范围内呈线性且与剂量成比例，不受食物影响。具有统计学意义的变化（P值<0.05）表明磷酸盐和FGF19水平可作为靶点参与的标志物。在18例可评估的FGFR基因改变患者中，观察到3例确认的部分缓解（2例FGFR2融合的肝内胆管癌（iCCA）和1例FGFR2及FGF19扩增的尿路上皮癌），以及2例在≥16周时疾病持续稳定且肿瘤缩小（FGFR2融合阳性iCCA和FGFR1扩增的肾上腺皮质癌）。
ARQ 087在300mg QD的RP2D下具有可控的毒性，显示出药效学效应，并实现了客观缓解，尤其是在FGFR2基因改变的患者中。
