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Page 6 of 13 Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21

Regorafenib
Regorafenib is an oral multikinase inhibitor, targeting angiogenic, stromal and oncogenic receptors
[48]
VEGFR1-3, TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR . Besides, studies in vivo
reported that the drug can inhibit the factor CSF1R and to reduce levels of tumor associated macrophages,
[48]
a factor implicated in the tumor-specific immune response and in tumor growth . The drug was initially
approved for colorectal cancer and for gastrointestinal stromal tumor by the main health authorities.

A phase 2 study conducted on 36 patients with intermediate or advanced HCC resistant to sorafenib
[49]
reported that regorafenib presented acceptable tolerability and antitumour activity . In the pivotal phase 3
study (RESORCE), more than 500 patients affected by advanced HCC with liver function Child-Pugh A and
with ECOG PS 0-1, were randomised (2:1) to receive 160 mg oral regorafenib or placebo plus best supportive
[50]
care once daily for 1-3 of each four week cycle . Patients were stratified for region, ECOG PS score,
extrahepatic spread, vascular invasion and AFP.

Worth mentioning is that the study was designed with the aim to avoid enrolling patients potentially non-
responding to tyrosine kinase inhibitor (TKI). In fact, the RESORCE study admitted only patients with a
documented radiological progression to sorafenib and tolerant to the drug (defined as receiving sorafenib ≥
400 mg daily for at least 20 of the last 28 days of treatment).

The results indicated significant improvements in the primary endpoint of OS [10.6 months with regorafenib
vs. 7.8 months with placebo hazard ratio (HR) 0.63, P < 0.0001] besides the secondary endpoints PFS (3.1
vs. 1.5 months, HR 0.46; P < 0.001). These benefits were maintained across all subgroups. In addition,
patients treated with regorafenib had significantly better overall response and disease control rate than best
supportive care. After a median 3.8 months, patients treated with regorafenib presented a reduction of 38%
[50]
of the risk of death and a 54% reduction in the risk of progression or death compared to placebo .
The most common AEs grade ≥ 3 in patients of the regorafenib group were hypertension (15.2% regorafenib
vs. 4.7% of the placebo group), hand-foot skin reaction (12.6% vs. 0.5%), fatigue (9.1% vs. 4.7%), and diarrhea
[50]
(3.2% vs. 0%) .
Similarly to sorafenib, the survival subgroup analysis of RESORCE evaluating the incidence of skin lesions
proposed that hand-foot skin reaction may be a marker for regorafenib activity: infactamong regorafenib-
treated patients, OS was improved in patients who had HFSR at any time during the trial and who had
their first HFSR event within the first cycle compared with those without HFSR during those periods
[50]
(13.2 vs. 8.1 months, HR 0.66) .
An additional exploratory analysis evaluating the global benefit of the sequence sorafenib-regorafenib
showed that the median OS from the start of sorafenib was 26 months for the sequence sorafenib-regorafenib
[51]
(whereas resulted 19.2 months in the sequence sorafenib-placebo) .

Following this positive study, an indication expansion for regorafenib was approved in April 2017 in the
USA, in May 2017 in Japan and in August 2017 in EU, allowing its use in second-line therapy for HCC.

Lenvatinib
Lenvatinib is a multitargeted TKI of the VEGFRs 1, 2, and 3, FGFRs 1–4, PDGFR a, RET, and KIT signaling
[52]
involved in tumor angiogenesis and malignant transformation . Lenvatinib was approved at the dosage
24 mg daily to treat patients with differentiated thyroid cancer refractory to iodine-131 therapy, later the
drug was approved in combination with everolimus as a treatment for the second line of renal cell carcinoma
at dosage 10 mg daily [52,53] .