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ic patients failed to show improved overall survival and anti-tumour activity with dovitinib. Of note though,
subgroup analysis showed that the subset of patients with higher baseline plasma soluble VEGFR1 (sVEGFR1)
[55]
levels had longer median overall survival , and although inconclusive, it suggests that the enrichment of a
patient population through biomarker selection may be a feasible approach for future studies. No phase III
trials were or are being conducted using dovitinib for the indication of HCC.

Orantinib (TSU-68)
Orantinib, a multi-kinase inhibitor of FGFR, VEGFR and PDGFR, showed promising efficacy in pretreated
patients with advanced HCC, with 51% of patients achieving disease control, and a good safety profile in
[56]
phase I/II HCC studies . Following a similarly designed phase II study suggesting prolonged progres-
[57]
sion free survival , a randomized phase III trial was conducted in Asia in patients with unresectable HCC
studying either orantinib or placebo after TACE. This study was however terminated early for futility after
[58]
interim analysis showed no improvement in overall survival with the use of orantinib .

Nintedanib (BIBF 1120)
Nintedanib, a multikinase VEGFR/PDGFR/FGFR inhibitor, showed inhibition of HCC cell line growth in
[59]
vitro and decreased tumour growth and angiogenesis in a xenograft mouse model of HCC . Two phase I/
randomized phase II trials comparing nintedanib and sorafenib in patients with unresectable HCC were
[61]
[60]
performed in the Western population and the Asian population with similar results. Both trials report-
ed similar overall survival and time to progression results with both drugs, with fewer serious drug-related
adverse events but higher drug discontinuation rates. We await further studies of this compound in patients
with advanced HCC.

Lenvantinb (E7080)
Lenvantinib is a multi-kinase inhibitor with inhibitory effects against VEGFR, FGFR1 - 4, KIT and RET.
Although higher doses have been tested in other solid tumour types, a lower dose of 12 mg was tested in a
[62]
phase I trial of lenvantinib in HCC patients , and used subsequently in a Phase II trial conducted in Japan
[63]
and South Korea . This led to the phase III study comparing lenvatinib and sorafenib in patients with un-
resectable HCC (REFLECT), showing non-inferiority of lenvatinib in terms of overall survival, and improve-
[64]
ments in secondary endpoints of progressive free survival and objective response rate with lenvatinib .
Following this study, further studies of lenvatinib in advanced HCC are being conducted or planned, such as
a trial studying the combination of lenvatinib and anti-programmed death 1 (anti-PD1) inhibitors in the first
line setting (NCT03418922, NCT03006926), as well as a trial studying the safety and efficacy of subsequently
second-line treatment after initial lenvatinib use (NCT03433703).

ONGOING CLINICAL STUDIES OF OTHER FGF/FGFR INHIBITORS IN HCC
Although most of the completed clinical studies in HCC used multi-kinase inhibitors, several ongoing clini-
cal studies are being conducted with promising selective FGFR inhibitors.

Erdafinitib (JNJ-4276493)
Erdafinitib is an oral selective pan-FGFR inhibitor which has shown a manageable safety profile in a phase
I study in advanced or refractory solid tumours. Common drug-related adverse events encountered in the
phase I study included hyperphosphataemia, nausea, stomatitis and dysguesia, with one dose-limiting toxici-
[65]
ty of bilateral retinal pigment epithelium detachment necessitating treatment discontinuation . An ongoing
phase I/IIa study is currently recruiting targeting Asian patients with advanced HCC with FGF19 amplifica-
tion (NCT02421185). Phase II and III trials are also being conducted with the drug in other tumour types,
and notably, the drug received FDA breakthrough therapy designation in the treatment of FGFR-alteration
[66]
positive urothelial cancer recently, following promising results in a phase II clinical trial .
BLU-554
BLU-554, a selective and potent inhibitor of FGFR4, was derived from an earlier compound BLU9931 which
[67]
suppressed proliferation in HCC tumour xenograft models with an activated FGFR4 signaling pathway . A