Journal
BRITISH JOURNAL OF CANCER
Volume 117, Issue 11, Pages 1592-1599Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2017.330
Keywords
FGFR inhibitor; solid tumours; FGFR2 fusion; phase 1
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Funding
- ArQule, Inc.
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Background: 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). Methods: Patients with advanced solid tumours received ARQ 087 administered initially at 25mg every other day and dose-escalated from 25 to 425mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. Results: 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 300mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325mg QD, and were unaffected by food. Statistically significant changes (P-valueo0.05) 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. Conclusions: ARQ 087 had manageable toxicity at the RP2D of 300mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.
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