Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy that arises
in the context of progressive underlying liver dysfunction. Given the asymptomatic
nature of early disease and the limited use of surveillance, the majority of HCC cases
present at advanced or incurable stages. The prognosis of advanced-stage HCC is poor,
with an overall survival (OS) rate of < 5%,[1] and in earlier stages, 5-year recurrence rates of over 70% have been reported despite
surgical or locoregional therapies.[2]
[3]
[4] The treatment options for patients with recurrent or de novo advanced HCC are limited,
and until recently there were no systemic treatment options that provided a clear
survival benefit for these patients. Systemic chemotherapy and hormone therapies have
not been effective in HCC, partly owing to the inherent hepatic dysfunction and the
chemoresistance of the tumor.[5]
[6] However, in the last decade, a better understanding of the molecular pathogenesis
of HCC has led to the evaluation of molecular targeted therapies in this setting.
Although the exact molecular mechanisms for hepatocarcinogenesis have still not been
defined, angiogenesis has been found to have an integral role in HCC pathogenesis,
making this a rational therapeutic target in this disease.
Sorafenib is an antiangiogenic multikinase inhibitor that targets the vascular endothelial
growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor
receptor- (PDGFR-) β, RAF kinase, and stem cell factor receptor (c-kit). It was the
first systemic therapy to demonstrate a significant improvement in OS in patients
with advanced HCC. Two positive pivotal phase III trials (the Sorafenib HCC Assessment
Randomized Protocol [SHARP] trial and the Asia-Pacific trial), and its subsequent
approval represent a major breakthrough in the treatment of advanced HCC.[7]
[8] However, given the limitations of sorafenib therapy, such as resistance and tolerability,
there are still unmet medical needs in the treatment of HCC. Our knowledge of the
diverse etiologies and the genetic heterogeneity of HCC and the multiple molecular
pathways implicated in HCC pathogenesis are now being evaluated as potential targets
for therapeutic interventions, including the VEGF, fibroblast growth factor (FGF),
PDGFR, epidermal growth factor receptor (EGFR), and mammalian target of rapamycin
(mTOR) pathways. This review will examine our current understanding of these pathways,
the efficacy and safety data pertaining to the most promising targeted agents beyond
sorafenib, and novel treatment combinations in clinical testing for HCC. There are
many other novel agents and targets in development, including histone deacetylase
inhibitors (HDAC), c-Met inhibitors, MEK kinase inhibitors, insulin-like growth factor
receptor (IGFR), arginine deiminase, and the anti-VEGF monoclonal antibody bevacizumab.
In this article, we will focus on those agents currently in advanced phase III trials.
Signaling Pathways Involved in HCC Pathogenesis
Hepatocellular carcinoma is a highly vascularized tumor, and the central role of angiogenesis
in its initiation, growth, and subsequent dissemination to other tissues is well recognized.
Angiogenesis in HCC is dependent on endothelial cell activation, proliferation, and
migration, which occur in response to angiogenic cues (e.g., hypoxia and inflammation)
and involves several molecular effectors such as growth factors, extracellular matrix
proteins, and proteases.[9]
[10] Vascular endothelial growth factor and its receptors are known to be key mediators
of HCC neovascularization, primarily through their stimulation of endothelial cell
growth and induction of vascular permeability.[9]
[10] Supporting the major role of VEGF in hepatocarcinogenesis are reports of its increased
expression from low-grade to high-grade dysplastic nodules to early HCC, which correlates
directly with increased neoangiogenesis and cell proliferation activity.[11] Additionally, high serum levels of VEGF have been shown to significantly correlate
with advanced tumor stage, recurrence of HCC following resection, and presence of
intrahepatic metastasis and venous invasion.[12] Overexpression of VEGF and its receptors in tumor tissue is also reportedly associated
with worse OS and recurrence-free survival after surgical resection.[13]
[14]
[15] Similarly, a prospective study showed that pretreatment serum elevations in VEGF
were associated with progressive disease and poor survival in patients with inoperable
HCC who underwent transarterial chemoembolization (TACE) treatment.[16]
In addition to the VEGF pathway, FGF and its family of receptors have been implicated
also in augmenting HCC growth, invasion, and angiogenesis, making it an attractive
candidate for therapeutic intervention.[17] Activation of the FGF pathway induces neovascularization through various mechanisms,
including stimulation of endothelial cell proliferation, migration, invasion, and
capillary formation.[18]
[19] Increased serum levels of FGF and concomitant activation of FGF receptors are associated
with tumor invasion and recurrence, treatment resistance, and poor prognosis in HCC.[20]
[21] Synergistic interactions between FGF and VEGF have been shown to drive HCC development
and angiogenesis.[22]
[23] Compelling evidence indicates that induction of the FGF signaling pathways might
represent a resistance mechanism to the antiangiogenic effects of VEGF-targeted agents
in HCC.[23]
[24] In addition, alterations in ligand expression has been identified as a potential
driver in HCC.[25] Together, these data indicate that concomitant inhibition of both the VEGF and FGF
pathways might be more efficient at controlling disease and overcoming resistance
to anti-VEGF therapies than targeting either factor alone.
Several other signaling pathways have been shown to be involved in HCC pathogenesis;
the most studied are the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, EGFR, Ras/Raf/mitogen-activated
protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK), and IGFR
pathways.[26] The PI3K/Akt/mTOR pathway is a major intracellular signaling cascade that is involved
in the regulation of cell growth, proliferation, and survival.[27] Mammalian target of rapamycin is a potent inducer of angiogenesis through upregulation
of the hypoxia-induced gene HIF1-α.[28] The mTOR pathway mediates its effects through activation of various tyrosine kinase
receptors, such as VEGFR, EGFR, PDGFR, and IGFR.[29] Nearly 50% of patients with HCC have shown activation of the mTOR pathway, which
may be partially attributable to activation signals from receptor tyrosine kinases
such as IGFR and/or EGFR pathways.[30] The activation of the mTOR pathway in HCC is associated with aggressive tumor behavior
and decreased survival, supporting efforts to target this pathway for therapeutic
interventions.[31] The Ras/Raf/MEK/ERK signaling cascade is another important intracellular pathway.
Ras activation and subsequent downstream signaling may be mediated by hepatitis C
virus (HCV) infection. As Raf is a potential target for sorafenib, this observation
may be another explanation for sorafenib's clinical activity in HCC.[32]
[33] In addition, the aberrant activation of the Wnt pathway may also play a role in
HCC pathogenesis and is another potential target in HCC.[34]
cMET is a tyrosine kinase receptor, with its ligand hepatocyte growth factor (HGF),
that has been implicated in liver cancer. Most recently, randomized phase II data
of the cMET inhibitor, tivantinib, has demonstrated activity in a subset of patients
with advanced HCC that have progressed on sorafenib and had elevated expression of
cMET by immunohistochemistry.[35]
There has been considerable interest in targeting peptide growth factor signaling
via the EGFR and IGFR axis, which is suggested by elevated levels of these receptors
in HCC.[36]
[37] The increasing awareness of the association of insulin resistance, diabetes, obesity,
and nonalcoholic steatohepatitis (NASH) in the development of cirrhosis and HCC also
is evidence that the IGFR pathway might have a causal role in this process.[38] Given the molecular heterogeneity of HCC, the challenge is identifying in which
patients any given alteration is critical. It is unlikely that any of these targeted
agents will yield clinical success without selecting the patients whose tumors are
most dependent on these pathways and therefore most likely to benefit, and the identification
of predictive markers of response is essential for successful development of new targeted
agents.
Emerging Molecular Therapies in Phase III Development
There are currently a historic number of investigational agents being tested in HCC,
most of which are targeting the previously described VEGF axis, FGF, EGFR, and mTOR
signaling pathways ([Fig. 1]).[39] The most recent clinical data relating to these novel agents, their combinations,
and ongoing trials are outlined in [Tables 1] and [2].[35]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
Table 1
Early efficacy results of novel targeted therapies in advanced development in hepatocellular
carcinoma[35]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
|
Agent
|
Phase
|
N
|
Efficacy
|
|
Tivantinib[35]
|
Randomized Phase II
|
|
|
|
Tivantinib vs placebo
|
|
|
|
ITT population
|
71 vs 36
|
Median TTP: 6.9 weeks vs 6.0 weeks
Median OS: 6.6 months vs 6.2 weeks
|
|
c-Met high
|
22 vs 15
|
Median TTP: 11.7 weeks vs 6.1 weeks
Median OS: 7.2 months vs 3.8 weeks
|
|
Sunitinib
|
Phase II[40]
|
34
|
Median PFS: 3.9 months
Median OS: 9.8 months
|
|
Phase III[41]
Sunitinib vs sorafenib
|
1073
|
Median OS: 7.9 vs 10.2 months;
|
|
Brivanib
|
Phase II[42]
|
55
|
Median PFS: 2.7 months
Median OS: 10 months
|
|
Phase III (BRISK-PS)[43]
Brivanib vs placebo
|
395
|
Median OS: 9.4 months vs 8.3 months
TTP: 4.2 months vs 2.7 months
RR: 12% vs 2%
|
|
Linifanib[44]
|
Phase II
|
44
|
TTP: 5.4 months
Median OS: 10.4 months
|
|
Erlotinib
|
Phase II[45]
|
38
|
Median OS: 13.0 months
|
|
Phase II[46]
|
40
|
Median OS: 10.8 months
|
|
Phase III (SEARCH)[47]
Sorafenib/erlotinib vs sorafenib/placebo
|
362
|
Median OS: 9.5 months vs 8.5 months
TTP: 3.2 months vs 4.0 months
|
|
Bevacizumab[48]
|
Phase II
|
46
|
Median PFS: 6.9 months
Median OS: 12.4 months
|
|
Ramucirumab[49]
|
Phase II
|
42
|
Median PFS: 3.9 months
Median OS: 14.9 months
|
|
Everolimus[50]
|
Phase I/II
|
20
|
Median PFS: 3.8 months
Median OS: 8.4 months
|
|
Pegylated arginine deiminase[51]
|
II
|
80
|
Mean OS: 15.8 months
|
Abbreviations: ITT, intent to treat; OS, overall survival; PFS, progression-free survival.
Table 2
Phase III trials in hepatocellular carcinoma[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
|
Study
|
Agent
|
Proposed accrual
|
Primary end point
|
|
First-line therapy
|
|
CALGB-80802
(NCT01015833)[52]
|
Sorafenib/doxorubicin vs sorafenib
|
480
|
OS
|
|
BOOST
(NCT01405573)[53]
|
Sorafenib vs placebo
(Child-Pugh B only)
|
320
|
OS
|
|
Linifanib
(NCT01009593)[54]
|
Linifanib vs sorafenib
|
900
|
OS
|
|
BRISK-FL[a]
(NCT00858871)[55]
[56]
|
Brivanib vs sorafenib
|
1050
|
OS
|
|
Second-line therapy
|
|
BRISK-APS
(NCT01108705)[57]
|
Brivanib + BSC vs placebo + BSC
|
252
|
OS
|
|
EVOLVE-1
(NCT01035229)[58]
|
Everolimus + BSC vs placebo + BSC
|
531
|
OS
|
|
REACH
(NCT01140347)[59]
|
Ramucirumab + BSC vs placebo + BSC
|
544
|
OS
|
|
POLARIS 2009–001
(NCT01287585)[60]
|
Pegylated arginine deiminase vs placebo
|
633
|
OS
|
|
Adjuvant targeted therapy following surgical resection or local ablation
|
|
STORM
(NCT00692770)[61]
|
Sorafenib vs placebo
|
1115
|
RFS
|
|
Targeted therapy in combination or following TACE
|
|
ECOG
(NCT01004978)[62]
|
Sorafenib/TACE[b] vs placebo/TACE
|
400
|
PFS
|
|
TACE-2
(NCT01324076)[63]
|
Sorafenib/DEB-TACE vs placebo/ DEB-TACE
|
412
|
PFS
|
|
BRISK-TA
(NCT00908752)[64]
|
Brivanib vs placebo
|
870
|
OS
|
|
ORIENTAL
(NCT01465464)[65]
|
Orantinib/TACE vs placebo/TACE
|
880
|
OS
|
Abbreviations: BSC, best supportive care; DEB-TACE, doxorubicin-eluting beads TACE;
OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival;
TACE, transarterial chemoembolization.
a Did not meet primary end point.
b TACE might comprise doxorubicin, mitomycin, and cisplatin; doxorubicin alone; or
doxorubicin-eluting beads.
Fig. 1 Molecular targets and targeted agents in hepatocellular carcinoma.[39] EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase;
FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; MEK, mitogen-activated
protein kinase/ERK kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived
growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
(Reprinted with permission from Siegel B et al. Hepatology 2010;52:360–369. Copyright
John Wiley and Sons).
Sunitinib
Similar to sorafenib, sunitinib is an oral, multitargeted inhibitor of several tyrosine
kinases, such as VEGF-receptors, PDGFR, and c-KIT, which are involved in regulation
of tumor growth, angiogenesis, and metastatic invasion. Sunitinib showed promising
antitumor activity in phase II HCC studies, though there were significant toxicities
seen, such as bone marrow suppression and a small number of grade 5 events.[40]
[66] In addition, no one consistent dosing scheme was used in these studies. With this
in mind, it may not be surprising that a phase III study comparing sunitinib to sorafenib
in patients with advanced HCC was terminated early due to higher incidence of drug-related
serious adverse events and failure to demonstrate noninferiority of OS benefit (median
OS in the intent-to-treat population: 7.9 months vs 10.2 months; hazard ratio [HR] = 1.30;
95% confidence interval [CI], 0.99–1.30; p = 0.001).[41] In an exploratory analysis, sorafenib substantially improved median OS in comparison
to sunitinib in patients with HCV infection (17.6 months vs 9.2 months; HR = 1.52;
95% CI, 1.09–2.13; p = 0.0165), whereas in patients with HBV infection, both agents were equally effective
(8.0 months vs 7.6 months; HR =1.10; 95% CI, 0.92–1.33; p = 0.1714).[41] Further analyses of this dataset are ongoing, but the increased toxicity profile
of sunitinib as compared with sorafenib likely played an important role in the results.
Brivanib
Brivanib is a selective dual inhibitor of the FGF and VEGF receptors that is currently
in late-stage clinical development. In preclinical models, brivanib was shown to decrease
tumor growth and neovascularization, induce apoptosis, and decrease tumor cell proliferation.[67] Brivanib entered several phase III studies including testing in patients with HCC
in both the first-line and second-line settings.[42]
[68] An initial phase II open-label study evaluated brivanib monotherapy in two patient
cohorts with unresectable, locally advanced, or metastatic HCC; 55 patients received
brivanib as first-line therapy and 46 patients received brivanib as second-line therapy
(having received one prior regimen of antiangiogenic therapy). Patients that received
first-line brivanib therapy had a median progression-free survival (PFS) of 2.7 months
and a median OS of 10 months ([Table 1]).[42] The disease control rate was 47%, including a complete response in 1 patient and
partial responses in 3 patients; 22 patients achieved disease stabilization. As second-line
therapy, brivanib therapy resulted in a tumor response rate of 4.3% (all partial responses)
and a disease control rate of 45.7%. Median OS was 9.8 months and the median time
to progression (TTP) was 2.7 months.[68] Most common grade 3/4 adverse events (AEs) were fatigue and hypertension, which
were experienced by < 17% of patients, while only < 2% experienced grade 3 hand–foot
skin reactions.[42]
[68]
The promising results from the phase II study prompted the BRISK (Brivanib Study in
Patients at Risk) HCC program that includes four large randomized phase III trials,
three of which evaluate the role of brivanib in advanced HCC (BRISK-FL, BRISK-PS,
and BRISK-APS).[55]
[56]
[57] The BRISK-PS trial evaluated brivanib versus placebo in 395 patients with Child-Pugh
A or Child-Pugh B HCC for which prior sorafenib therapy had failed or who were intolerant
to prior sorafenib therapy (NCT00825955). Although this study did not meet its primary
end point of improving OS (9.4 months vs 8.2 months; HR = 0.89; 95.8% CI, 0.69–1.15;
p = 0.3307), treatment with brivanib resulted in improvements in TTP (4.2 months vs
2.7 months; HR = 0.56; 95% CI, 0.42–0.78; p = 0.0001) and response rate (12% vs 2%; odds ratio = 5.75; 95% CI, 1.40–23.62; p = 0.0032), which were secondary end points of the study.[43] The toxicity profile of brivanib and median survival for the brivanib group were
very similar to that seen in the phase II study in this population. What was surprising
and unexpected in BRISK-PS was the median OS of 8.2 months in the control arm. This
survival would not be expected based on data from the SHARP or Asia-Pacific sorafenib
studies. Although there were some baseline imbalances in the 2:1 randomized study
that favored the control arm (significantly fewer patients with portal vein invasion
versus the treatment group, 12% vs 25%, respectively), this number also reflects the
changing natural history of HCC in the postsorafenib era. Similar to the BRISK-PS
study, the BRISK-APS trial is evaluating second-line brivanib in 252 patients of exclusively
Asian ethnicity (NCT01108705).[57] The BRISK-FL trial (NCT00858871) was directly comparing the clinical outcomes of
brivanib versus sorafenib in 1050 patients with advanced HCC who received no prior
systemic therapy.[55] According to a July 2012 press release, this study did not meet its primary end
point of OS.[56]
Linifanib
Linifanib is a potent multitargeted receptor tyrosine kinase inhibitor that selectively
blocks the activity of the VEGFR and PDGFR families. Preclinical evidence indicates
that linifanib inhibits tumor angiogenesis and vascular permeability in HCC experimental
models.[69] A phase II study was conducted in 44 patients with Child-Pugh A or Child-Pugh B
liver disease to evaluate linifanib activity in advanced HCC in the first-line and
second-line settings.[44] Thirty-four percent of patients with Child-Pugh A liver function remained progression-free
at 16 weeks, with median TTP and OS of 5.4 months and 9.7 months, respectively. Overall
survival was comparable to the results achieved in the SHARP study (median OS: 10.7
months).[8] The most common grade 3/4 AEs were hypertension (18%), fatigue (14%), and diarrhea
(4.5%). Based on these results, an ongoing randomized phase III study is investigating
linifanib as first-line therapy in > 1000 patients with Child-Pugh A advanced HCC
(NCT01009593).[54] Although final results are pending, this study was recently terminated by the independent
data monitoring committee (IDMC).
Ramucirumab
Ramucirumab is a recombinant humanized antibody that specifically targets the extracellular
domain of VEGFR2. In a phase II study of 42 patients with unresectable HCC who primarily
presented with Child-Pugh A disease (74%) and Barcelona-Clinic Liver Cancer (BCLC)
stage C (83%), first-line ramucirumab therapy resulted in a disease control rate of
69%.[49] The median OS for all patients was 14.9 months, and in patients with BCLC C/Child-Pugh
A and BCLC C/Child-Pugh B HCC, it was 18.0 months and 4.4 months, respectively. Grade
3/4 toxicities included gastrointestinal bleeding, hypertension, and fatigue. These
results may indicate a signal of activity for ramucirumab in the front-line setting,
though this was a relatively small population of clinically heterogeneous patients.
Despite no clinical data supporting ramucirumab's activity in patients with HCC who
have progressed on sorafenib, an ongoing randomized placebo-controlled phase III study
(REACH) is evaluating second-line ramucirumab in comparison to best supportive care
(BSC) following failure of prior sorafenib therapy in patients with Child-Pugh score
<7 (NCT01140347).[59]
Everolimus
Mammalian target of rapamycin inhibitors, such as everolimus, have demonstrated antitumor
activity in several malignancies. In HCC, two early clinical studies have shown that
everolimus monotherapy was tolerable and had activity in patients who had received
prior systemic therapy.[50]
[70] Grade 3/4 AEs included lymphopenia, elevations in aspartate transaminase, and hyponatremia.
In both studies, the median PFS and OS were 3.8 months and 8.4 months, respectively.
Though both studies were single-arm and uncontrolled, their results suggested a potential
clinical benefit with everolimus in both patients who had received prior sorafenib
therapy and those who did not. An ongoing randomized, placebo-controlled, phase III
clinical trial (EVOLVE-1) is evaluating everolimus plus BSC in patients with Child-Pugh
A HCC pretreated with sorafenib (NCT01035229).[58]
ADI-PEG 20
ADI-PEG 20 is arginine deiminase (ADI) formulated with polyethylene glycol (PEG).
Its potential as an anticancer agent is based on the hypothesis that HCC is deficient
in argininosuccinate synthase and is, therefore, not capable of synthesizing arginine,
and the relative arginine deficiency resulting from ADI is toxic to cancer cells.
A randomized study comparing two doses of ADI-PEG-20 was performed in a heterogeneous
population of patients.[51] Median survival for all patients in this study was 15.8 months and the most common
events in this study related to the drug include transient and reversible encephalopathy,
skin irritation, or discomfort at the site of injection combined with low-grade fever.
A phase III study of ADI-PEG-20 versus placebo in the second-line setting is ongoing
(NCT01287585).[60]
Combination Strategies
Although single-agent therapy has demonstrated some success in the treatment of HCC,
intensive research is now focused on enhancing the clinical benefit of many therapies
through combination with other agents. The biologic rationale for combination approaches
might involve targeting the same pathway at different points to achieve complete blockade
of a given pathway or interrupting two different pathways simultaneously in hopes
of circumventing feedback loops.
Based on potential interplay between angiogenesis and the EGFR signaling pathways,
strategies targeting the VEGF and EGFR axis are being evaluated. In a single-arm,
single-institution, phase II study of 40 patients with advanced HCC, erlotinib plus
bevacizumab combination therapy was associated with a 16-week PFS of 62.5%, median
PFS of 9.0 months, and median OS of 15.65 months.[71] Treatment-related grade 3/4 toxicities were mostly reminiscent of those related
to bevacizumab. Despite the lack of similar data with sorafenib and erlotinib, a large
phase III study evaluating the combination was launched. However, recently presented
results of the SEARCH trial (NCT00901901) demonstrated that the addition of erlotinib
to sorafenib did not prolong OS (HR = 0.929; p = 0.204), which was the primary end point of the study.[47] A phase I study evaluating the combination of everolimus and sorafenib as front-line
therapy in advanced HCC did not move on to phase II development because of unexpected
toxicity (thrombocytopenia), which prevented dose escalation of the mTOR inhibitor.[72]
Although the role of chemotherapy has not been defined in HCC, several strategies
combining targeted and cytotoxic agents are being evaluated. In a randomized phase
II trial of 96 patients with advanced HCC, most of whom had Child-Pugh A liver disease,
the combination of sorafenib plus doxorubicin as first-line therapy yielded a significant
improvement in median OS, from 6.5 months to 13.7 months (HR = 0.49; 95% CI, 0.3–0.8;
p = 0.006), and prolonged PFS (6.0 months vs 2.7 months; 95% CI, 1.4–2.8; p = 0.006) compared with doxorubicin alone. Though this study was launched prior to
the results of the SHARP study, given sorafenib's proven single-agent activity, the
more appropriate control arm would have been sorafenib alone, not doxorubicin. Toxicity
profiles were similar to those observed with single agents; however, the combination
of sorafenib/doxorubicin increased bone marrow suppression and all grade left ventricular
dysfunction (19% vs 2%, respectively).[73] Nevertheless, these results have led to an ongoing Cancer and Leukemia Group B (CALGB)
phase III trial evaluating the superiority of sorafenib plus doxorubicin versus current
standard of care, sorafenib, in a 480 patients with locally advanced or metastatic
HCC (NCT01015833).[74] Several single-arm studies combining bevacizumab with cytotoxic agents, including
capecitabine, oxaliplatin/capecitabine, and gemcitabine/oxaliplatin, have shown modest
clinical activity; however, bevacizumab-based combinations are not being pursued further
in phase III studies at this time.[75]
[76]
[77]
As previously discussed in this supplement, surgical resection and local ablation
are curative therapies for early-stage HCC, whereas TACE is the backbone of the management
of patients with intermediate-stage HCC. Preclinical evidence indicates that TACE
increases tumor hypoxic conditions, which then may elicit upregulation of proangiogenic
factors, such as VEGF and FGF, and ultimately stimulate angiogenesis.[78]
[79] It was found that patients with lower plasma VEGF levels following TACE have significantly
longer survival compared with those with higher levels following TACE (p = 0.008).[80] Taken together, these results suggest that coadministration of an antiangiogenic
agents with TACE may block angiogenesis and prevent local recurrence and potentially
distant metastasis. Several ongoing clinical trials are testing different combinations
of TACE (or other locoregional therapies) and antiangiogenic agents. In a single-center
phase II trial, combining TACE with doxorubicin-eluting beads (DEB-TACE) and sorafenib
showed promising efficacy with a disease control rate of 95% and objective response
of 58%.[81] Toxicity was manageable and mostly related to sorafenib; however, the authors noted
increased liver toxicity. Recently presented preliminary efficacy results from the
multicenter, randomized, placebo-controlled phase II SPACE trial (Sorafenib or Placebo
in Combination with TACE) are less impressive. This trial of 307 patients with intermediate-stage
HCC randomized patients to a combination of DEB-TACE/sorafenib or DEB-TACE/placebo
and showed a trend toward better objective response (35.7% vs 28.1%), but did not
significantly delay progression with sorafenib (TTP; HR = 0.797; 95% CI, 0.588–1.080;
p = 0.072).[82] A similar phase III study of sorafenib in combination with TACE versus TACE alone
performed in Japan and Korea likewise did not demonstrate any benefit with the combination.[83] This approach is being further evaluated in two ongoing phase III trials (NCT01004978
and NCT01324076).[62]
[63] Another important phase III trial in this population—with the primary end point
of improving OS—BRISK-TA is investigating brivanib versus placebo as adjuvant therapy
following TACE in 870 patients with intermediate HCC (NCT00908752).[64] TSU-68 (orantinib) is an oral small molecule inhibitor of VEGFR, PDGFR, and FGFR
also currently being evaluated in phase III study in combination with TACE vs TACE
alone (NCT01465464).[65]
Conclusion
Hepatocellular carcinoma is a heterogeneous disease, both in regard to its clinical
manifestation with underlying liver disease, and its complex pathogenesis involving
aberrant signaling in several molecular pathways. The introduction of sorafenib in
the treatment of advanced HCC saw a paradigm shift in its management. Based on new
molecular knowledge and recognition of the limitations of sorafenib, novel molecular
targeted therapies and combination strategies have been developed. Although early
phase data with these agents have looked promising, to date nothing has been shown
to be better than sorafenib in the front-line, and studies in the second-line have
been disappointing. Looking ahead, concerted research efforts must be focused, not
only on identifying new molecular targets and therapeutic agents, but also on understanding
mechanisms of resistance to targeted agents. In addition to a better understanding
of the natural history of HCC in the postsorafenib era, additional studies aimed at
identifying predictive markers for response to novel agents are necessary. Incorporating
these new agents into the presurgical or adjuvant setting also gives the opportunity
for tissue collection and correlative science that is pivotal for increasing our understanding
of these agents in HCC. Finally, the best method of assessing the activity of molecular
targeted agents in HCC remains to be determined.
