INTRODUCTION
Systemic therapy for hepatocellular carcinoma (HCC) has
changed markedly since 2007, with the approval of sorafenib.
Subsequently, a variety of molecular targeted agents (e.g., sunitinib,
erlotinib, brivanib, everolimus, and linifanib) have been
tested as first-line or second-line therapies but failed, and
sorafenib has been the only approved systemic agent for almost
10 years.1-6 Recently, the Food and Drug Administration
(FDA) approved regorafenib and nivolumab for the treatment of HCC in patients who have been previously treated
with sorafenib in the United States. In this article, the current
status and future perspectives of new agents for advanced
HCC will be reviewed.
MOLECULAR TARGETED THERAPY
1. Sorafenib
Sorafenib is an oral, multiple kinase inhibitor that blocks the
platelet derived growth factor receptor (PDGFR), Raf kinase,
and vascular endothelial growth receptor (VEGFR). Two multicenter
randomized placebo-controlled phase III trials were
conducted for patients with advanced HCC who had not received
any prior systemic therapy in Europe and America (SHARP trial) and in the Asia-Pacific region.7,8 The SHARP
trial demonstrated a significantly longer median overall survival
(OS) duration of 10.7 months in patients receiving sorafenib,
compared to an OS of 7.9 months for patients who received
placebos (hazard ratio [HR], 0.69; 95% confidence interval
[CI], 0.55–0.87; P<0.001).7 The disease control rate, defined as
the percentage of patients who achieved complete response,
partial response, and stable disease based on Response Evaluation
Criteria in Solid Tumors (RECIST) criteria, was 43% in
the sorafenib group compared with 32% in the placebo group
(P=0.002). The partial response rate was only 2% in the
sorafenib group, and no patients showed complete response.
The Asia-Pacific trial also showed a significantly superior median
OS of 6.5 months in patients receiving sorafenib, compared
with 4.2 months in patients receiving placebos (HR,
0.57; 95% CI, 0.42–0.79; P=0.014).8 The most common adverse
events were hand-foot syndrome, diarrhea, hair loss and
fatigue.7,8 Sorafenib became the standard 1st-line therapy for
advanced HCC through these two trials. Since then, substantial
studies have attempted to predict patient responses to
sorafenib; however, a clear conclusion has yet to be achieved.9-11
2. Regorafenib
Regorafenib inhibits multiple protein kinases, including
VEGFR and tyrosine kinase with immunoglobulin and epidermal
growth factor homology domain (TIE). A randomized,
double-blind, placebo-controlled phase 3 trial (RESORCE)
enrolled 573 patients who progressed on sorafenib.12 Patients
who had not tolerated sorafenib were excluded, because
regorafenib and sorafenib have similar toxicity profiles. Enrolled
patients were randomized, in a 2:1 ratio, to receive either
regorafenib (160 mg) or placebo once daily, during weeks
1–3 of each 4-week cycle. The study met the primary endpoint
of OS with a HR of 0.63 (95% CI, 0.50–0.79; one-sided
P<0.001). The median patient survival durations were 10.6
months with regorafenib and 7.8 months with placebo.12 The
disease control rate was 65% (complete response in 1% and
partial response in 10%).12 The most common clinically-relevant
grade 3 or 4 adverse events were hypertension (15%), handfoot
skin reaction (13%), fatigue (9%), and diarrhea (3%).12 Based on these results, regorafenib became the first approved
second-line agent for advanced HCC. However, whether patients
who were intolerant to sorafenib can tolerate and respond
well to regorafenib remains unclear, because such patients
were excluded from the RESORCE trial.
3. Lenvatinib
Lenvatinib is an oral, multi-kinase inhibitor that targets
VEGFR, fibroblast growth factor receptor (FGFR), PDGFR
alpha, rearranged during transfection gene (RET), and KIT.
Lenvatinib is approved for the treatment of radioactive iodine-refractory
differentiated thyroid cancer and advanced renal
cell carcinoma. A total of 954 patients with advanced HCC
who had not received systemic chemotherapy were randomized
to receive either lenvatinib (body weight ≥60 kg: 12 mg/
day; <60 kg: 8 mg/day) or sorafenib (400 mg twice daily) in a
1:1 ratio.13 This noninferiority phase III trial (REFLECT) indicated
that lenvatinib was noninferior to sorafenib in OS
(13.6 months for lenvatinib vs. 12.3 months for sorafenib; HR,
0.92; 95% CI, 0.79–1.06).13 Furthermore, the median time to
progression was significantly longer in patients receiving lenvatinib
(7.4 months for lenvatinib vs. 3.7 months for sorafenib;
HR, 0.63; 95% CI, 0.53–0.73; P<0.001).13 Objective response
rates were also significantly higher (24% for lenvatinib vs. 9%
for sorafenib; P<0.001), and the most common treatment-related
adverse events of lenvatinib were hypertension, diarrhea,
decreased appetite, and decreased weight. The approval of lenvatinib
as a first-line agent for advanced HCC is anticipated.
4. Cabozantinib
Cabozantinib is an oral, multi-tyrosine kinase inhibitor that
targets VEGFR, mesenchymal-epithelial transition (MET),
growth arrest-specific 6 gene receptor (AXL), RET, KIT and
FMS-like tyrosine kinase 3 (FLT3); however, cabozantinib has
most potent activity against VEGFR and MET. A phase II trial
was conducted for 41 patients with advanced HCC, all of
whom had received up to one prior systemic anticancer therapy
for more than four weeks before receiving an initial 12-
week lead-in cabozantinib treatment.14 Patients with a partial response could continue open-label cabozantinib, while patients
with stable disease were randomized into either cabozantinib
or placebo cohorts, and patients with progressive disease
discontinued therapy at or before week 12. At week 12,
two of the 41 patients achieved partial responses (5%), the disease
control rate was 66%, and no patients showed complete
response.14 A randomized, double-blind, placebo-controlled phase III
trial (CELESTIAL) enrolled 707 patients with advanced HCC
who had received up to two lines of prior systemic therapies
(including sorafenib) and progressed on at least one.15 Patients
were randomized 2:1 to receive cabozantinib (60 mg)
or placebo once daily. At the second planned interim analysis,
the primary endpoint was met with longer OS in the cabozantinib-treated
group (10.2 months for cabozantinib vs. 8.0
months for placebo; HR, 0.76; 95% CI, 0.63–0.92; P=0.0049).15 The objective response rate was also significantly better in the
cabozantinib cohort (4% for cabozantinib vs. 0.4% for placebo,
P=0.0086).15 The most common grade 3/4 adverse events
were hand-foot skin reaction (17%) and hypertension (16%).15 The response rate of 4% seems slightly lower compared to
other potential drugs; however, approval awaits.
5. Other agents
Tivantinib is an oral c-MET inhibitor. A randomized, placebo-controlled
phase II study demonstrated that the median
time-to-progression was longer with tivantinib as second-line
therapy in patients with advanced HCC (1.6 months vs. 1.4
months; HR, 0.64; 95% CI, 0.43–0.94; P=0.04).16 For patients
with high MET expression, the magnitude of the time-to-progression
benefit when taking tivantinib was more significant
than in patients without high MET expression (2.7 months vs.
1.4 months; HR, 0.43; 95% CI, 0.19-0.97; P=0.03).16 Therefore, a
randomized, placebo-controlled phase III trial was conducted for
MET-high patients who had shown progression or intolerance
while taking sorafenib; however, in this trial, tivantinib failed to
improve OS or progression-free-survival over placebo.17 Ramucirumab is a recombinant immunoglobulin G 1
(IgG1) monoclonal antibody that binds to VEGFR-2 and is
approved for colorectal cancer, non-small cell lung cancer, and gastric or gastroesophageal junction adenocarcinoma. A
randomized, placebo-controlled, phase III trial (REACH) for
patients with HCC who had previously received sorafenib
demonstrated that ramucirumab did not significantly improve
OS (9.2 months vs. 7.6 months; HR, 0.87; 95% CI,
0.72–1.05; P=0.14).18 However, subgroup analysis suggested
that ramucirumab improved OS of patients with baseline alpha-fetoprotein
levels ≥ 400 ng/mL (7.8 months vs. 4.2
months; HR, 0.67; 95% CI 0.51–0.90). Currently, the
REACH-2 study of ramucirumab in patients with advanced
HCC with baseline alpha-fetoprotein levels of 400 ng/mL or
more is underway (NCT02435433).19
IMMUNOTHERAPY
Immune checkpoints are co-inhibitory proteins that prevent
T cells from attacking other cells in the body. Immune
checkpoint inhibitors can release the brakes on the immune
system and restore the immune response against cancer cells.
Targets of immune checkpoint inhibitors include cytotoxic
T-lymphocyte protein 4 (CTLA-4), programmed cell death
protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1).
1. Nivolumab
Nivolumab is a humanized monoclonal IgG4 antibody to
human PD-1. A phase I/II, open-label dose escalation and expansion
trial (CHECKMATE-040) was conducted for patients
with advanced HCC and included patients who experienced
disease progression while on at least one prior systemic therapy
or who were intolerant of or refused sorafenib.20 The dose
escalation phase confirmed the manageable safety profile and
acceptable tolerability of nivolumab. At the dose expansion
phase, 214 patients with advanced HCC received intravenous
nivolumab at 3 mg/kg every 2 weeks.20 The objective response
and disease control rates were 20% and 64%, respectively (3
complete responses, 39 partial responses, and 96 stable diseases).20
The 9-month overall survival rate was 74%,20 and grade
3 or 4 treatment-related adverse events were observed in 25%
(increased lipase in 13% and increased aspartate aminotransferase
in 10%) of the patients.20 In 2017, the CHECKMATE-040 study enabled nivolumab to achieve accelerated approval for
the treatment of HCC in patients who have been previously
treated with sorafenib. This approval was based on the outstanding
overall response (14.3%; 3 complete response and 19
partial response) and duration of response of a 154-patient
subgroup who progressed on or were intolerant to sorafenib.21 Among the 22 responders, 91% had responses of six months
or longer, and 55% had responses of 12 months or longer. A
phase III trial of nivolumab versus sorafenib as first-line treatment
is ongoing (CHECKMATE-459, NCT02576509).22
2. Other immune checkpoint inhibitors
Pembrolizumab is an anti-PD-1 antibody that has been approved
for melanoma, non-small cell lung cancer, head and
neck squamous cell carcinoma, Hodgkin lymphoma, urothelial
carcinoma, gastric cancer, and any solid tumor with high
microsatellite instability or deficient mismatch repair. Pembrolizumab
was the first approval based on a certain genetic
feature, without regard to original tumor location. Recently, a
phase II study of pembrolizumab (KEYNOTE-224) reported
the efficacy and safety of this drug in patients with advanced
HCC who were previously treated with sorafenib.23 Out of
the 104 treated patients, one patient (1.0%), 16 (15.4%), and
47 (45.2%) showed complete response, partial response, and
stable disease, respectively. The disease control rate was 61.5%,23 and the 6-month progression-free survival and overall survival
rates were 43.1% and 77.9%, respectively.23 Of the responders,
94% had durable responses of six months or longer.23 Common adverse events included fatigue (21.2%) and
increased aspartate aminotransferase levels (12.5%).23 Hepatitis
B or hepatitis C virus flares were not observed when immune-mediated
hepatitis occurred in 2.9% of the patients.23 A randomized, placebo-controlled phase III study of pembrolizumab
as a second-line therapy for advanced HCC (KEYNOTE-240)
is currently ongoing (NCT02702401), and promising
results are anticipated.24 Durvalumab is a human IgG1 monoclonal antibody that
blocks the interactions of PD-L1 with PD-1 and CD80 and has
been approved for urothelial carcinoma. Tremelimumab is a
human monoclonal antibody against CTLA-4 that has been
approved for malignant mesothelioma. Tremelimumab has
shown a partial response rate of 17.6% and a disease control
rate of 76.4% in patients with HCC and chronic hepatitis C virus
infection.25 PD-1 and CTLA-4 have been suggested as nonredundant
pathways for the regulation of T cell responses; and
therefore, simultaneous inhibition of PD-1 and CTLA-4 pathways
may have the potential for synergism.26 According to the
results of a phase I part of a phase I/II, open-label, randomized
study of durvalumab and tremelimumab for unresectable HCC,
the response rate was 20% and the disease control rate at week
16 was 57.5% across 40 enrolled patients.27 A phase III trial of
durvalumab and tremelimumab as first-line therapy is currently
ongoing (NCT03298451).
ONGOING CLINICAL TRIALS
Agents other than those mentioned above are also under investigation. Phase III clinical trials of apatinib, a VEGFR-2
inhibitor, and vaccinia, a virus-based immunotherapy, are ongoing
for patients with advanced HCC, as shown in Table 1.
Table 1. Ongoing phase III clinical trials for patients with advanced HCC

HCC, hepatocellular carcinoma.
CONCLUSIONS
In 2007, there was a breakthrough with sorafenib as a treatment
for advanced HCC. These have been hard times, with
many failures that may be attributable to heterogeneity of patient
populations, deficits in trial designs, marginal antitumor
activity of investigational drugs, or absence of biomarkers.28,29 Currently, we have two additional approved drugs (regorafenib
and nivolumab) and another two with positive results
in phase III trials (lenvatinib and cabozantinib), although none
of these therapeutics have clear biomarkers. Molecular targeted
agents have shown improved OS, with limited response
rates. On the contrary, immune checkpoint inhibitors are
drawing attention due to remarkable response rates and durable
responses. Results based on conventional RECIST criteria
alone may underestimate the efficacy of immune checkpoint
inhibitors since pseudoprogression and immune-related
patterns of mixed response have been reported.30 Immune
checkpoint inhibitors might lead the way for future HCC
therapies, and warrant further studies.
AUTHOR CONTRIBUTIONS
BH Kim and JW Park were responsible for the acquisition
and interpretation of the data, and the drafting of the
manuscript.
ACKNOWLEDGEMENT
This work was supported by National Cancer Center, Korea
(NCC # 1510520).
Conflicts of Interest
The authors have no conflicts to disclose.
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