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Lee et al. Hepatoma Res 2018;4:52 I http://dx.doi.org/10.20517/2394-5079.2018.42 Page 5 of 11

Table 1. Summary of completed clinical trials of FGFR multikinase inhibitors in hepatocellular carcinoma (adapted and
updated from [76] )
Trial Endpoints
Brivanib PII: 1L systemic therapy in advanced HCC [49] 6m PFS 18.2%
n = 55 mPFS 2.7m
NCT00355238 mOS 10 m
PII: 2L systemic therapy in advanced HCC mTTP 2 m
n = 41
NCT00355238
PIII: 1L systemic therapy in advanced HCC (non-inferiority trial) [50] mOS 9.5 m (brivanib) vs. 9.9 m (sorafenib)
n = 1155
NCT00858871
PIII: 2L systemic therapy in advanced HCC mOS 9.4 m (brivanib) vs. 8.2 m (placebo) (NS)
n = 295 mTTP 4.2 m (brivanib) vs. 2.8 m (placebo) (SS)
NCT00825955 ORR 10% (brivanib) vs. 2% (placebo) (SS)
PIII: in combination with TACE as adjuvant [52] mOS 26.4 m (TACE/brivanib) vs. 26.1 m (TACE/
NCT00908752 placebo)
Dovitinib RPII: 1L systemic therapy in advanced HCC in Asia-Pacific population mOS 8.0 m (dovitinib) vs. 8.4 m (sorafenib)
n = 165 mTTP 4.1 m (dovitinib) vs. 4.1 m (sorafenib)
NCT01232296
Orantinib PI/II: any line systemic therapy advanced HCC [56] ORR: 2.9% CR, 5.7% PR, 42.8% SD
(TSU-68) n = 12 (PI) n = 35 (PII) mTTP 2.1 m, mOS 13.1 m
NCT00784290
PIII: in combination with TACE as adjuvant [58] mOS 31.1 m (TACE/orantinib) vs. 32.3 m (TACE/
n = 889 placebo)
NCT01465464

Nintedanib PI/RPII: 1L systemic therapy in advanced HCC in Western population [60] mTTP 5.5 m (nintedanib) vs. 4.6 m (sorafenib)
(BIBF 1120) n = 93 (PII) mOS 11.9 m (nintedanib) vs. 11.4 m (sorafenib)
NCT01004003 mPFS 5.3m (nintedanib) vs. 3.9m (sorafenib)
G3 or higher AE 68% (nintedanib) vs. 90% (sorafenib)
PI/RPII: 1L systemic therapy in advanced HCC in Asian patients mTTP 2.8 m (nintedanib) vs. 3.0 m (sorafenib)
n = 95 (RPII) [61] mOS 10.2 m (nintedanib) vs. 10.7 m (sorafenib)
NCT00987935 G3 or higher AE 56% (nintedanib) vs. 84%
(sorafenib)
Lenvatinib PII: 1L systemic therapy in advanced HCC in Asian patients [63] mTTP 7.4 m
(E7080) n = 46 mOS 18.7 m
NCT00946153 ORR 37% DCR 78%
RPIII: 1L systemic therapy in advanced HCC (non-inferiority trial) [64] mOS 13.6 m (lenvatinib) vs. 12.3 m (sorafenib)
n = 954
NCT01761266
HCC: hepatocellular carcinoma.

arm phase II study in advanced HCC, brivanib was shown to have anti-tumour activity in both the frontline
and second-line setting, reporting a 6-month progression free survival rate of 18% when used as first line
[49]
treatment . The registration phase III trial (BRISK-FL) however was a negative trial, with brivanib failing
to demonstrate non-inferiority to sorafenib in the first-line setting, though it had similar anti-tumour activ-
[50]
ity albeit a less well-tolerated safety profile with higher rates of drug discontinuation . A second-line phase
III study of brivanib against placebo after sorafenib failure or intolerance (BRISK-PS) also failed to show an
[51]
overall survival advantage though it had a better improved time to progression and overall response rate .
Following the results of these two trials, the phase III trial of brivanib as adjuvant therapy to transarterial
chemoembolization (TACE) was prematurely terminated though analysis similarly suggested no improve-
[52]
ment in survival with brivanib use .
Dovitinib
Dovitinib is a non-selective FGFR inhibitor which also has effects on VEGFR, PDGFR, FGFR, c-KIT and
other targets. In HCC xenograft models, dovitinib inhibited tumour growth and angiogenesis, and reduced
[53]
the development of metastases and prolonged mouse survival . In other preclinical work, it also induced
[54]
apoptosis in sorafenib-resistant cell lines . When translated to the clinical setting however, the randomized
phase II study comparing dovitinib versus sorafenib as first-line treatment in advanced HCC in Asian-Pacif-