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[31]
Figure 1. Overview of FGFR pathway inhibitors (adapted from and Sandhu et al. [28] ). FGFR: fibroblast growth factor receptor; VEGFR:
vascular endothelial growth factor receptor
Most of the FGF/FGFR pathway inhibitors currently in development belong to the last category. These TKIs
can be further divided into multi-kinase inhibitors and the selective FGFR TKIs.

Most of the multi-kinase inhibitors have inhibitory effects on both VEGFR and FGFR because of the struc-
tural similarities in the kinase domains of both receptors, though they may vary in their relative potency for
inhibition for the two groups of receptors, with the majority having a higher potency for VEGFR than FGFR.
Whilst multi-kinase inhibitors may potentially increase therapeutic efficacy by simultaneously disrupting
resistance pathways, toxicity and off-target effects inevitably increase, which may limit the ability to achieve
doses required for effective FGFR inhibition [19,42] .

Selective FGFR inhibitors on the other hand, may have unique on-target dose-limiting toxicities. Preclinical
models with selective FGFR TKIS caused hyperphosphataemia-mediated tissue calcification through the in-
hibition of FGF23 signaling in the kidney and bone, where it plays a critical role in vitamin D and phosphate
homeostasis [43,44] . This was replicated in the clinical setting with 83% of patients treated at the maximum
[45]
tolerated dose in the BGJ398 phase I trial developing hyperphosphataemia . This resulted in repeated dose
interruptions and reductions, and ultimately prompted trial sponsors to explore an alternative intermittent
[45]
dosing schedule . An increase in serum FGF23, phosphate and vitamin D levels is being studied as poten-
[46]
tial on-target biomarkers for effective FGFR inhibition . Other mechanism-based toxicities observed in
preclinical models and clinical studies include cutaneous toxicities such as nail toxicities, xerostomia, stoma-
titis, as well as dose-dependent keratopathy and retinal pigment epithelial detachment. Although multiki-
nase VEGFR/FGFR inhibitors may cause hypertension and proteinuria, these problems seem to occur with a
lesser frequency with selective FGFR inhibitors.

COMPLETED CLINICAL STUDIES OF FGF/FGFR PATHWAY INHIBITORS IN HCC
An overview of the completed clinical studies of FGF/FGFR pathway inhibitors in HCC is given below
[Table 1].

Brivanib
Brivanib is a selective inhibitor of VEGFR2 and FGFR1. In preclinical studies, it attenuated hepatic fibrosis in
[48]
[47]
vivo and hence was postulated to be useful in slowing the progression of cirrhosis to HCC . In a single-