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Regorafenib in hepatocellular carcinoma: latest evidence and clinical implications
Nicola Personeni MD1,2 , Tiziana Pressiani MD1, Armando Santoro MD1,2 , Lorenza Rimassa MD1
1Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center – IRCCS, Via Manzoni 56, 20089
Rozzano, Milan, Italy; 2Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 4, 20090 Pieve Emanuele, Milan, Italy

Abstract seems to be an attractive target for immunotherapy, a phase 1/2

Over the past ten years, sorafenib, a multikinase inhibitor, has trial reported promising efficacy signals from nivolumab, and
been the only systemic agent approved for first-line treatment results of a larger phase 3 trial with another checkpoint inhibitor,
of patients with unresectable hepatocellular carcinoma (HCC). namely, pembrolizumab, are still pending. After nearly a decade
Whereas only recently lenvatinib was shown to be noninferior of a certain degree of stagnation, we are now witnessing a
to sorafenib, in terms of survival, all other agents previously period of novel therapeutic advances with multikinase inhibitors
tested failed to prove noninferiority (or superiority) when and immunotherapy that will likely change the treatment
compared with sorafenib. Similarly, in a second-line setting, scenario of HCC.
most investigational drugs have failed to provide better survival
outcomes than placebo. However, in 2016, data from the Keywords: advanced, angiogenesis, hepatocellular carcinoma,
RESORCE trial, a phase 3 study evaluating regorafenib in HCC immunotherapy, metastatic, multikinase inhibition, regorafenib,
patients who experience disease progression after first-line second-line.
treatment with sorafenib, have shown a 2.8-month median
survival benefit over placebo (10.6 versus 7.8 months). Overall, Citation
side-effects were in line with the known safety profile of Personeni N, Pressiani T, Santoro A, Rimassa L. Regorafenib
regorafenib. More recently, the survival benefits of a sustained in hepatocellular carcinoma: latest evidence and clinical
anti-angiogenic inhibition were demonstrated also with implications. Drugs in Context 2018; 7: 212533.
cabozantinib in the frame of the phase 3 CELESTIAL trial. As HCC DOI: 10.7573/dic.212533

Introduction treatments are no longer available. Furthermore, no adjuvant

therapy has been demonstrated to improve recurrence-free
Hepatocellular carcinoma (HCC) is the most common primary survival after curative treatments [4]. Currently, treatment with
malignancy of the liver worldwide. It is the fifth most common the multikinase inhibitor sorafenib is the only approved first-line
cancer in men and seventh among women, and the third systemic therapeutic option in Western countries for patients
leading cause of cancer-related mortality in the world, with a with unresectable HCC and well-preserved liver function (Child–
rising incidence, particularly in Western countries [1,2]. Pugh class A) [5]. Sorafenib was approved in 2007 based on the
results of the Sorafenib Hepatocellular Carcinoma Assessment
Chronic liver disease due to hepatitis B virus (HBV) or hepatitis
Randomized Protocol (SHARP) trial, which reported a significant
C virus (HCV) accounts for the majority of HCC cases; alcohol
increase in overall survival (OS) and time to radiological
intake, steatosis, diabetes, exposures to toxic agents and
progression over placebo [5]. Similar results were achieved in
genetic and metabolic diseases are risk factors further
another double-blind, randomized, phase 3 trial in patients
increasing in incidence [1]. A common pathway for these varied
from the Asia-Pacific region [6]. The most frequent adverse
etiologies may involve chronic inflammation recognized as a
events (AEs) were diarrhea, hand-foot skin reaction (HFSR),
procarcinogenic condition [3].
fatigue, and weight loss, all of which were often manageable
Surgical resection, liver transplantation, and ablation are [5]. Recently, the REFLECT trial, a global randomized open-label
treatments that offer a high rate of complete excision of disease phase 3 noninferiority study, demonstrated that lenvatinib,
and, thus, potential for cure [2]. However, the disease frequently a different multikinase inhibitor, is noninferior compared to
relapses or is diagnosed at an advanced stage when curative sorafenib in terms of OS in untreated patients with advanced

Personeni N, Pressiani T, Santoro A, Rimassa L. Drugs in Context 2018; 7: 212533. DOI: 10.7573/dic.212533 1 of 10
ISSN: 1740-4398
REVIEW – Regorafenib in hepatocellular carcinoma drugsincontext.com

HCC [7]. Furthermore, lenvatinib achieved statistically Tivantinib – a small-molecule, adenosine triphosphate (ATP)
significant improvement in progression-free survival (PFS), independent inhibitor of MET, the hepatocyte growth factor
time to progression (TTP), and overall response rate (ORR) (HGF) receptor – demonstrated statistically significant and
compared to sorafenib. The safety profile of the two drugs clinically meaningful increase in OS, PFS, TTP, and DCR over
was consistent with what observed in previous studies [7]. placebo in patients with high MET expression detected by
Based on these results, lenvatinib has been approved in Japan immunohistochemistry (IHC) on tumor cells in a second-
as a new therapeutic option for patients with unresectable line randomized double-blind placebo-controlled phase 2
HCC. Finally, in the first-line setting, two recently published study [25]. Initial tumor biomarker analysis from this study
phase 3 randomized studies, the European SARAH trial [8] and showed the prognostic value and the predictive value of MET
SIRveNIB study, conducted in the Asia-Pacific region [9], failed expression as a marker of benefit from tivantinib [25]. Further
to show an improvement in OS with selective internal radiation biomarker analyses from the same study suggested that tumor
therapy (SIRT) with yttrium-90 resin microspheres compared to MET levels were higher in patients previously treated with
sorafenib even if SIRT appeared to achieve a better local control sorafenib, circulating biomarkers such as MET and HGF might
and to be associated with less AEs. be prognostic in second-line HCC [26], and baseline neutrophil-
to-lymphocyte ratio was an independent prognostic biomarker
In the second-line setting, in the randomized double-blind
[27]. Based on the phase 2 results, tivantinib has been evaluated
phase 3 RESORCE trial, regorafenib achieved improved OS, PFS,
in two phase 3 trials in previously treated patients with
TTP, ORR and disease control rate (DCR) compared to placebo
high tumor MET expression, the METIV-HCC trial in western
[10]. In the second- and third-line setting, the CELESTIAL trial,
countries [21], and the JET-HCC trial in Japan [22]. To the best
a recently presented randomized double-blind phase 3 trial,
of our knowledge, these trials were the first biomarker-driven
demonstrated statistically significant improved OS, PFS and
trials in HCC. However, both studies were negative and did not
ORR with cabozantinib versus placebo [11].
confirm that tivantinib would improve OS and PFS compared to
However, in the last decade, 11 phase 3 trials, evaluating placebo in patients with high tumor MET expression detected
tyrosine-kinase inhibitors (TKIs), monoclonal antibodies by IHC. Although the METIV-HCC study was negative, with
(moAbs), chemotherapy and other molecules, as monotherapy more than 1100 biopsies analyzed, this trial demonstrated
or in combination, in first- and second-line setting, failed the feasibility of conducting large tissue biomarker studies in
to demonstrate any advantage over sorafenib or placebo, advanced HCC. Furthermore, paired biopsy results confirmed
respectively [12–22]. Even if safety was not a major problem in that MET expression is more frequently high in patients treated
the development of some new agents, for other compounds with sorafenib (35% of patients were MET-high when biopsied
toxicities related to the concomitant liver cirrhosis may before sorafenib, and 69% of patients were MET-high when
represent a significant hurdle for clinical development. biopsied after sorafenib), highlighting MET plasticity and the
Furthermore, efficacy may also depend on patient’s importance to biopsy at the appropriate time.
characteristics and geographical region.

Negative studies for second-line Regorafenib for second-line

treatment of HCC treatment of HCC
Regorafenib has been studied in the advanced HCC setting
Previous studies with several drugs designed to inhibit different
in a multicenter single-arm phase 2 study that enrolled 36
pathways important in HCC pathogenesis and progression have
patients with well-preserved liver function (Child–Pugh class A)
been evaluated for second-line treatment with disappointing
who progressed on prior sorafenib therapy [28]. Patients who
results. Phase 3 trials of brivanib, a small-molecule TKI targeting
discontinued sorafenib for toxicity were not eligible for the
vascular endothelial growth factor receptor (VEGFR) and
study, due to the partially overlapping safety profiles. Patients
fibroblast growth factor receptor (FGFR) [17], everolimus, a
received regorafenib at the dose of 160 mg orally once daily
mammalian target of rapamycin (mTOR) inhibitor [18], pegylated
in cycles of 3 weeks on/1 week off treatment. The primary
arginine deiminase (ADI-PEG) 20, an arginine degrading enzyme
endpoint was safety, the secondary endpoints were efficacy,
[19], and ramucirumab, a moAb against VEGFR2 [20], did not
according to modified Response Evaluation Criteria in Solid
meet their primary endpoint of improved OS versus placebo.
Tumors (mRECIST) [29], and pharmacokinetics (PK). The median
Noteworthy, in the ramucirumab study the predefined subgroup
duration of treatment was 19.5 weeks (range 2–103). Thirty-five
of patients with elevated baseline alpha-fetoprotein (AFP) levels
patients (97%) required dose reductions, interruptions, and/
showed a statistically significant benefit in terms of OS, and it has
or delays, in most of cases due to AEs. All patients reported at
been recently announced that a phase 3 trial enrolling patients
least one treatment-emergent AE (TEAE), graded according to
with high baseline AFP levels met its primary endpoint of OS [23].
the National Cancer Institute Common Terminology Criteria
While prognostic and predictive biomarkers are already used for Adverse Events (NCI-CTCAE) version 3.0. Most common
in clinical practice in several tumor types, biomarker research AEs included diarrhea (53%), fatigue (53%), HFSR (53%),
has still to produce conclusive results in the field of HCC [24]. hypothyroidism (42%), anorexia (36%), hypertension (36%),

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Table 1.  Efficacy results of the RESORCE phase 3 trial [10].

Outcome Regorafenib Placebo Hazard ratio p-value

(n=379) (n=194) (95% CI)
Response
 Complete 2 (1%) 0 - NR
 Partial 38 (10%) 8 (4%) - NR
Overall response rate 40 (11%) 8 (4%) - 0.0047
Stable disease 206 (54%) 62 (32%) - NR
Disease control rate 247 (65%) 70 (36%) - <0.0001
Overall survival (months) 0.63 (0.50–0.79) <0.0001
 Median 10.6 7.8
  95% CI 9.1–12.1 6.3–8.8
Progression-free survival (months) 0.46 (0.37–0.56) <0.0001
 Median 3.1 1.5
  95% CI 2.8–4.2 1.4–1.6
Time to progression (months) 0.44 (0.36–0.55) <0.0001
 Median 3.2 1.5
  95% CI (2.9–4.2) (1.4–1.6)
CI, confidence interval; NR, not reported.

nausea (33%), and voice change (28%); most frequent grade 160 mg regorafenib (four 40 mg tablets) orally or matching
3/4 AEs were fatigue (17%) and HFSR (14%); 5 patients (14%) placebo once daily for 21 consecutive days, followed by 7
experienced serious AEs (SAEs) considered related to the study days off treatment in 28-day cycles. Treatment continued until
drug. DCR was achieved in 72% of patients, with stable disease disease progression according to mRECIST, clinical progression,
in 25 patients (69%) and partial response in 1 (3%). Median death, unacceptable toxicity, or decision by the investigator.
TTP was 4.3 months (95% CI: 2.9–13.1). The 3-month PFS rate The primary endpoint of the study was OS in the intent-to-treat
was 65% (95% CI: 45–79) and the 6-month PFS rate 44% (95% population, further endpoints included PFS, TTP, ORR, and
CI: 26–60). Median OS was 13.8 months (95% CI: 9.3–18.3). The DCR assessed by the investigators using mRECIST and RECIST
3-month OS rate was 88% (95% CI: 72–95) and the 6-month OS v.1.1, safety, and quality of life. Of the patients who started
rate 79% (95% CI: 61–89) [28]. treatment, 309 (83%) in the regorafenib arm and 183 (95%)
in the placebo arm discontinued study treatment. The most
Based on the phase 2 results, regorafenib has been further
common reason for discontinuation was disease progression.
evaluated in the multicenter, randomized, double-blind,
Median treatment duration was 3.6 months with regorafenib
placebo-controlled RESORCE phase 3 trial [10]. The RESORCE
and 1.9 months with placebo.
trial enrolled HCC patients with Barcelona clinic liver cancer
(BCLC) stage B or C, preserved liver function (Child–Pugh class After a median follow-up of 7 months, median OS was 10.6
A), and good performance status (PS) (Eastern Cooperative months in the regorafenib arm versus 7.8 months in the
Oncology Group [ECOG] 0 or 1). Patients had to have tolerated placebo arm, with a hazard ratio (HR) of 0.63 (95% CI: 0.50–0.79;
treatment with sorafenib ≥400 mg daily for at least 20 of p<0.0001). Regorafenib was superior to placebo in all the efficacy
the last 28 days of treatment, and the reason for permanent endpoints (Table 1). An updated OS analysis, performed almost
discontinuation of sorafenib had to be documented 1 year after the primary analysis, confirmed the previously
radiological progression. Patients had to be enrolled in the trial reported results (10.7 versus 7.9 months, HR 0.61, p<0.0001)
within 10 weeks after the end of sorafenib treatment. Patients [30]. Both predefined and exploratory analyses confirmed
who discontinued sorafenib due to toxicity were not allowed the superiority of regorafenib compared to placebo in all
to be enrolled in the study. Between May 2013 and December subgroups of patients. The efficacy of regorafenib was confirmed
2015, 573 patients were randomized (2:1 ratio) to receive regardless of the pattern of progression on prior sorafenib [31]
regorafenib (n=379) or placebo (n=194). Randomization was and regardless of last sorafenib dose [32]. The development of
stratified by geographical region (Asia versus rest of world), new distant metastases or vascular invasion was confirmed to
macrovascular invasion (yes versus no), extrahepatic disease be associated with worse survival. However, despite the strong
(yes versus no), AFP levels (<400 versus ≥400 ng/mL), and ECOG prognostic impact, regorafenib provides significant survival
PS (0 versus 1). The percentage of patients enrolled from Asia benefits irrespective of the pattern of disease progression
was 38% (n=216). Baseline patient characteristics were well- on prior sorafenib [31]. Further exploratory data showed that
balanced between the two treatment groups. Patients received in the selected population for the study, treatment with the

Personeni N, Pressiani T, Santoro A, Rimassa L. Drugs in Context 2018; 7: 212533. DOI: 10.7573/dic.212533 3 of 10
ISSN: 1740-4398
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sequence of sorafenib followed by regorafenib resulted in an pathways have provided encouraging results, which may
unprecedented median OS of 26 months [32]. Also, a negative potentially expand the landscape of second-line treatments.
correlation between baseline AFP and circulating MET levels and
In fact, HCC immunogenicity and the concomitant immune
prognosis was confirmed regardless of treatment [33]. Finally,
suppression represent the ideal frame for immunotherapy
HFSR has been shown to be associated with a better OS with
interventions aiming to restore the otherwise ‘exhausted’
regorafenib [34], and this result, even if retrospectively observed,
effector T cells functions. Several studies previously described
is in line with the prospectively demonstrated correlation
different oncofetal and cancer/testis proteins, which in turn
between HFSR and OS with sorafenib [35]. Significantly, more
make up the so-called tumor-associated antigens able to
patients on regorafenib compared to placebo experienced
elicit CD8+ T-cell responses, though often impaired in HCC
an objective response by mRECIST criteria. However, similar
patients [37]. Furthermore, the appearance of neo-antigens
outcomes, in terms of PFS and TTP, were observed using
resulting from nonsynonymous tumor mutations might itself
mRECIST and RECIST v.1.1. The prognostic impact of the
contribute to HCC immunogenicity. Nevertheless, immune
objective response as a surrogate marker of outcome and the
surveillance is generally eluded by diverse mechanisms,
best radiological criterion to assess responses are still matters
including programmed cell death ligand 1 (PD-L1)
of debate. Indeed, in a retrospective analysis of patients treated
upregulation [38], that eventually lead to HCC progression
with sorafenib, the survival associated with disease control was
[39]. In this context, the immunotherapy armamentarium
not significantly different from the survival associated with
currently available with antiprogrammed cell death 1 receptor
progressive disease according to RECIST criteria [36].
(PD-1), anti-PD-L1, and anticytotoxic T lymphocyte antigen-4
Of the 573 randomized patients, 567 patients (99%) started (CTLA-4) blocking antibodies constitutes a rational strategy
treatment (374 in the regorafenib group and 193 in the placebo to efficiently stimulate anticancer immune responses. This
group) and were included in the safety analysis. All patients who approach has been proven successful in several tumor types,
received regorafenib and 93% of patients who received placebo including melanoma, refractory Hodgkin’s lymphoma,
had at least one TEAE (graded using NCI-CTCAE version 4.03), renal cell carcinoma, nonsmall cell lung cancer, Merkel cell
considered possibly related to the study drug in 93% of patients carcinoma, urothelial carcinoma, head and neck cancers,
on regorafenib and 52% of patients on placebo (Table 2). Most and in a broad group of cancers displaying microsatellite
commonly reported grade 3/4 AEs were hypertension (15% of instability.
patients on regorafenib versus 5% of patients on placebo), HFSR Early results with immune checkpoint blockade in HCC stem
(13 versus 1%), fatigue (9 versus 5%), and diarrhea (3% versus from a pilot study with an anti-CTLA-4 antibody, namely,
none). When analyzed by the last sorafenib dose during prior tremelimumab, where 43% of the patients were Child–
treatment, only grade ≥3 HFSR, fatigue, anorexia, and increased Pugh class B. Despite these poor prognostic characteristics,
bilirubin were slightly higher in the group that received <800 tremelimumab, even though administered at a dose that
mg compared with 800 mg, while no difference was observed is now considered subtherapeutic, exhibited a satisfactory
in rates of other TEAEs. Therefore, the last sorafenib dose may safety profile, and the survival outcomes were in line with
not predict the onset of TEAEs occurring with regorafenib [32]. other contemporary studies for second-line treatment of HCC
SAEs and death rates were similar in the two study arms; SAEs enrolling only Child–Pugh A patients [40].
were deemed related to the study drug in 10% of patients on
regorafenib and 3% of patients on placebo. Interruptions/dose More recent studies have been also focusing on the PD-1/
reductions and discontinuations due to AEs were reported in PD-L1 immune checkpoint pathway, which is felt to contribute
68 and 25% of patients on regorafenib and in 31 and 19% of to liver immune tolerance. Specifically, nivolumab, which is a
patients on placebo, respectively. Drug-related AEs leading to fully human IgG4 moAb blocking the PD-1 interaction with
interruptions/dose reductions and to discontinuations were PD-L1 and PD-L2, is currently investigated in a HCC-specific
reported in 54 and 10% of patients on regorafenib and 10 and multicohort phase 1/2 trial (CheckMate 040, NCT01658878). The
4% of patients on placebo, respectively. Of note, quality of life first two phases of this trial consist in a dose-escalation phase
was similar in the two treatment groups [10]. Based on the results and a dose-expansion phase designed to estimate ORR and
of the phase 3 RESORCE study, regorafenib has been approved duration of response with nivolumab monotherapy, according
by the United States Food and Drug Administration (FDA) and to patients’ viral status and prior sorafenib exposure. The final
the European Medicines Agency (EMA) for the treatment of results pertaining to these two phases of the CheckMate 040
patients with advanced HCC previously treated with sorafenib. study were reported in The Lancet, in 2017 [41]. With more than
60% of patients being previously exposed to sorafenib, a major
finding emerging from the dose-escalation and the dose-
Other second-line trials with expansion phases was an impressive median OS reaching 28.6
months in sorafenib-naïve patients and 15.6 months in patients
positive results who were previously exposed to sorafenib [42]. Based on these
In addition to the RESORCE study, recent second-line trials findings, the FDA has granted the approval of nivolumab as
investigating checkpoint inhibitors and multikinase inhibition second-line treatment agent for HCC on September 22, 2017.

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Table 2. Treatment-emergent adverse events in the RESORCE phase 3 trial – safety population.
Adapted from: Bruix J et al. Lancet 2017 [10].

Treatment-emergent Treatment-emergent drug-related

Regorafenib (n=374) Placebo (n=193) Regorafenib (n=374) Placebo (n=193)
Any Grade Grade Any Grade Grade Any Grade Grade Any Grade Grade
grade 3 4 grade 3 4 grade 3 4 grade 3 4
n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Any AE 374 208 40 (11) 179 61 (32) 14 (7) 346 173 14 (4) 100 31 (16) 1 (1)
(100) (56) (93) (93) (46) (52)
HFSR 198 47 (13) NA 15 (8) 1 (1) NA 196 47 (13) NA 13 (7) 1 (1) NA
(53) (52)
Diarrhea 155 12 (3) 0 29 (15) 0 NA 125 9 (2) 0 18 (9) 0 0
(41) (33)
Fatigue 151 34 (9) NA 61 (32) 9 (5) NA 110 24 (6) NA 37 (19) 3 (2) NA
(40) (29)
Hypertension 116 56 (15) 1 (<1) 12 (6) 9 (5) 0 87 (23) 48 (13) 1 (<1) 9 (5) 6 (3) 0
(31)
Anorexia 116 10 (3) 0 28 (15) 4 (2) 0 88 (24) 10 (3) 0 12 (6) 0 0
(31)
Increased bilirubin 108 37 (10) 2 (1) 34 (18) 15 (8) 6 (3) 70 (19) 24 (6) 1 (<1) 7 (4) 4 (2) 0
(29)
Increased AST 92 (25) 37 (10) 4 (1) 38 (20) 19 (10) 3 (2) 48 (13) 16 (4) 3 (1) 15 (8) 9 (5) 1 (1)
Fever 72 (19) 0 0 14 (7) 0 0 14 (4) 0 0 4 (2) 0 0
Nausea 64 (17) 2 (1) NA 26 (13) 0 NA 40 (11) 1 (<1) NA 13 (7) 0 NA
Increased ALT 55 (15) 10 (3) 2 (1) 22 (11) 5 (3) 0 29 (8) 6 (2) 2 (1) 8 (4) 2 (1) 0
Weight loss 51 (14) 7 (2) NA 9 (5) 0 NA 27 (7) 4 (1) NA 3 (2) 0 NA
Oral mucositis 47 (13) 4 (1) 0 6 (3) 1 (1) 0 42 (11) 4 (1) 0 5 (3) 1 (1) 0
Vomiting 47 (13) 3 (1) 0 13 (7) 1 (1) 0 27 (7) 1 (<1) 0 5 (3) 0 0
Cough 40 (11) 1 (<1) NA 14 (7) 0 NA 4 (1) 0 NA 2 (1) 0 NA
Hypophosphatemia 37 (10) 30 (8) 2 (1) 4 (2) 3 (2) 0 22 (6) 16 (4) 2 (1) 2 (1) 1(1) 0
Hoarseness 39 (10) 0 NA 1 (1) 0 NA 34 (9) 0 NA 0 0 NA
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HFSR, hand-foot skin reaction;
NA, not applicable.

Interestingly enough, response rates in PD-L1-positive and AE during sorafenib, roughly represent 30% of patients who
PD-L1-negative tumors were similar, as were according to have to discontinue first-line treatment [43].
viral and nonviral etiologies. Still pending are the results
Importantly, the PD-1 receptor and the CTLA-4 play together
from two other cohorts, respectively, evaluating nivolumab
complementary and nonredundant roles in regulating adaptive
plus an anti-CTLA-4 antibody (ipilimumab), and nivolumab
immunity and maintaining peripheral tolerance. In particular,
monotherapy in patients with Child–Pugh B7 or B8 scores.
whereas PD-1 contributes to T-cell anergy and exhaustion,
While the aforementioned cohorts have left the enrollment
the engagement of CTLA-4 rather inhibits T-cell activation. In
open to either patients sorafenib-naïve or previously exposed,
preclinical models, a combined blockade of PD-1 and CTLA-4
a ‘first-line only’ cohort has been designed for patients naïve
achieved more profound antitumor activity than blockade of
from systemic treatments, who are randomized in a 1:1 manner
either pathway alone [44]. Given these premises, a nivolumab plus
to receive sorafenib or nivolumab. Of note, results gained from
ipilimumab cohort in the CheckMate 040 study is of interest since it
nivolumab across these different cohorts might potentially
may provide useful results to gauge the value of such an additive to
expand treatment perspectives for patients usually excluded
synergistic approach, already tested in other disease settings [45].
from clinical trials due to their Child–Pugh score. It is also
predicted that sorafenib-intolerant patients, who therefore In the second-line setting, the RESORCE study has demonstrated
might not be optimal candidate for regorafenib, could derive the efficacy of multikinase inhibition mediated by regorafenib.
benefit from immunotherapy. Such patients, experiencing an Novel data now suggest a possible role even for another

Personeni N, Pressiani T, Santoro A, Rimassa L. Drugs in Context 2018; 7: 212533. DOI: 10.7573/dic.212533 5 of 10
ISSN: 1740-4398
REVIEW – Regorafenib in hepatocellular carcinoma drugsincontext.com

multikinase inhibitor with nonselective anti-MET activity, comparable to that observed in patients in the dose-escalation
namely, cabozantinib, that shares with regorafenib a certain and dose-expansion phase of the CheckMate 040, although a
degree of potent angiogenic inhibition [46]. A phase 3 double- full report is still pending. Currently, pembrolizumab plus best
blind placebo-controlled trial randomizing 773 HCC patients supportive care (BSC) is being studied against placebo plus BSC
to cabozantinib or placebo in the second- or third-line setting in a phase 3 trial as second-line therapy [49].
has been recently reported under the name of CELESTIAL
trial [11]. With primary endpoint OS, the trial was a positive Conclusions
one, since median OS was 10.2 months in the cabozantinib
group, as compared with 8.0 months in the placebo group, While previous efforts to develop new therapies for HCC have
and HR for death with cabozantinib versus placebo was 0.76 failed, both in first-line and in second-line setting, the results
(p=0.0049). Interestingly, MET overexpression as detected by of RESORCE definitely represent significant advances in the
IHC was a stringent inclusion criterion for enrollment onto treatment of HCC.
the HCC tivantinib trials [21,22] but not in CELESTIAL trial. However, the current landscape of available treatment options
Though cabozantinib is a MET inhibitor, this implies that MET is expanding and it is becoming increasingly more articulated.
expression, as detected by IHC at least, might not be necessary Despite such encouraging data, because of a lack of molecular
to select patients who might benefit from cabozantinib. Further and clinical predictors of efficacy, it remains currently unknown
developments of cabozantinib might be foreseen also in how to best select in the future a second-line treatment for
combination with checkpoints inhibitors. Indeed, in preclinical patients able to tolerate prior sorafenib. Similarly, the same
investigations, treatment of tumor cells with cabozantinib leads questions remain open also for patients intolerant to sorafenib,
to increased tumor-cell expression of major histocompatibility who nevertheless are logically excluded from further treatment
complex class 1 antigen and greater sensitivity of tumor cells with regorafenib.
to T-cell-mediated killing [47]. On these grounds, possible
From a clinical standpoint, several data gleaned in recent
synergistic activities of cabozantinib plus nivolumab (with or
years have turned the attention to patterns of progression
without ipilimumab) are currently explored within an additional
on sorafenib and reasons for sorafenib discontinuation
cohort of the aforementioned CheckMate 040 trial.
[43,50]. In fact, these data allow to dissect advanced HCC into
clinically defined categories and provide valuable prognostic
Ongoing phase 3 studies information that should be acknowledged for stratification
for second-line treatment within next trials for second-line treatment of HCC. For the time
being, additional considerations pertain to the optimization
of HCC: ramucirumab and of radiologic criteria currently used to assess tumor response,
pembrolizumab especially in view of mounting evidences highlighting the
discordance between TTP and OS [51]. In this context, a
Despite the negative results of the phase 3 REACH study thorough analysis of AFP kinetics would be still of interest,
in the intent-to-treat population [20], a test for interaction owing to earlier works [36] indicating a role for AFP response
indicated a significant and meaningful survival benefit from as a surrogate endpoint of survival, worth to be considered in
ramucirumab over placebo in the prespecified subgroup of conjunction with radiologic assessments.
patients with baseline AFP ≥400 ng/mL. Since the REACH
study did not stratify patients according to AFP concentration, Finally, as current data with regorafenib and cabozantinib
a prospective confirmation of these findings has been suggest a benefit from a sustained anti-angiogenic strategy, it
conducted in the frame of a new phase 3 trial. It has been is too early to define how this will compare in a clinical scenario
recently announced that this trial met its primary endpoint that is witnessing the emergence of immune-oncology.
of OS as well as the secondary endpoint of PFS, thus being Reasonably, in the absence of other decision-making parameters,
the first positive phase 3 biomarker-driven trial in HCC differences in tolerability and previous sorafenib exposure will be
[23]. However, in contrast to ramucirumab, in prespecified major drivers favoring the choice of a specific drug.
subgroup analyses of RESORCE, regorafenib equally Whereas for other solid malignancies, prognostic and predictive
benefitted patients with AFP levels ≥400 ng/mL as well as molecular biomarkers are ready for clinical practice, the METIV-
patients with lower AFP levels. HCC and CheckMate 040 trials indirectly teach that the quest
Consistent with findings from dose-escalation and dose- for reliable biomarkers in HCC is far from being concluded.
expansion phases of CheckMate 040 trial, the results of a phase Traditionally, the virtual lack of biological specimens from the
2 study (KEYNOTE-224) with another anti-PD-1 antibody, namely, majority of HCC patients has been one of the major hurdles
pembrolizumab, have confirmed the role of checkpoint blockade for biomarker discovery in this disease [24]. Although the
in HCC in patients progressing after sorafenib. Indeed, among search of predictive markers for anti-angiogenic therapies,
the most remarkable findings of this trial are an ORR as high as including regorafenib, has been rather elusive thus far, a novel
17% and a median OS not reached by the time of presentation generation of clinical trials is hopefully setting the stage for the
[48]. Moreover, the overall safety profile of pembrolizumab was development of precision medicine in the field of HCC.

Personeni N, Pressiani T, Santoro A, Rimassa L. Drugs in Context 2018; 7: 212533. DOI: 10.7573/dic.212533 6 of 10
ISSN: 1740-4398
REVIEW – Regorafenib in hepatocellular carcinoma drugsincontext.com

Contributions: All authors performed the research, writing, and review of all drafts of this manuscript and approved the final draft.
Disclosure and potential conflicts of interest: Dr Rimassa reports personal fees from Bayer, personal fees and non-financial support
from Arqule, personal fees from Lilly, personal fees from Sirtex medical, personal fees from Exelixis, personal fees and non-financial support
from Ipsen, personal fees from AstraZeneca, but not connected with the submitted work. Dr Santoro declares support from Bayer, Takeda Lilly,
Amgen, Arqule, Bristol-Myers Squibb, Cegene, Merck Sharp and Dohme, Novartis, Roche, Servier, Eisai, but not connected with the submitted
work. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for
download at http://www.drugsincontext.com/wp-content/uploads/2018/06/dic.212533-COI.pdf
Funding declaration: No funds were provided for this review nor for medical writing assistance.
Copyright: Copyright © 2018 Personeni N, Pressiani T, Santoro A, Rimassa L. Published by Drugs in Context under Creative Commons License
Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified
below. No commercial use without permission.
Correct attribution: Copyright © 2018 Personeni N, Pressiani T, Santoro A, Rimassa L. https://doi.org/10.7573/dic.212533. Published by Drugs
in Context under Creative Commons License Deed CC BY NC ND 4.0.
Article URL: https://www.drugsincontext.com/regorafenib-in-hepatocellular-carcinoma-latest-evidence-and-clinical-implications
Correspondence: Lorenza Rimassa, Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research
Center – IRCCS, Rozzano, Milan, Italy lorenza.rimassa@cancercenter.humanitas.it
Provenance: invited; externally peer reviewed.
Submitted: 5 April 2018; Peer review comments to author: 11 May 2018; Revised manuscript received: 25 May 2018; Accepted: 1 June 2018;
Publication date: 27 June 2018.
Drugs in Context is published by BioExcel Publishing Ltd. Registered office: Plaza Building, Lee High Road, London, England, SE13 5PT.
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ISSN: 1740-4398