A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours

Abstract

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 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.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 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.Conclusions: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.

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

“…BGJ398, another selective FGFR1‐3 inhibitor, showed antitumor activity in several tumor types and had a tolerable safety profile in a phase I study in patients with advanced solid tumors, whereas JNJ‐42756493, a pan‐FGFR inhibitor recently approved by the FDA for urothelial carcinoma, showed a clinical response with acceptable safety in a similar patient population . Similar findings have been reported for the pan‐FGFR inhibitors LY2874455 and ARQ 087 . Clinical trials are ongoing for other highly selective FGFR inhibitors in development, such as TAS‐120 and INCB054828, in which patients are screened for FGFR abnormalities using next‐generation sequencing or FISH techniques.…”

“…Reasons for TEAE‐related dose interruptions included nausea (n = 3), vomiting (n = 2), anorexia (n = 2), nasopharyngitis (n = 1), and decreased neutrophil count (n = 1). Selective FGFR inhibition has been associated with an increased risk of hyperphosphatemia and eye toxicity, including retinal detachment . In the present study, there were nine AE of hyperphosphatemia and three AE of retinal detachment, but all were <grade 3 in severity and did not lead to dose reduction or discontinuation.…”

“…FGFR signaling is involved in the regulation of FGF23 expression, and increased FGF23 production has been implicated in the development of several hypophosphatemic diseases . Selective FGFR inhibitors are typically associated with on‐target toxicities such as hyperphosphatemia, which appears to play a role in FGF23 signaling and eye toxicity such as macular edema and retinal detachment, as reported previously . No clear relationship between these toxicities and the inhibition of FGFR has been found.…”

Current biologics for treatment of biliary tract cancers

“…Preclinical and phase I studies have suggested that these compounds have potent and selective anti-tumor activity against FGFRmutated cancers (80)(81)(82)(83). A recently developed monoclonal antibody against FGFR2 (BAY1179470) showed tumor suppressive potential in tumors with high FGFR2 expression (84).…”

Alteration in serum concentrations of FGF19, FGF21, and FGF23 in patients with urothelial carcinoma

“…A recent study showed FGF19 and 21 could act as biomarkers during treatment follow‐up using pan‐FGFR inhibitors in patients with advanced solid tumor. FGF19 and 21 were found to be increased during each treatment with a dose‐dependent trend, which implies that it reflects the patients' therapeutic response .…”