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Liver International ISSN 1478-3223


Novel molecular therapies in hepatocellular carcinoma
Sandrine Faivre, Mohamed Bouattour and Eric Raymond
                                                                                         ˆ
Department of Medical Oncology, Beaujon/Bichat University Hospital, Assistance Publique-Hopitaux de Paris, University INSERM U728, Paris 7, Clichy,
France



Keywords                                           Abstract
angiogenesis inhibitors – clinical trial –         The approval of sorafenib as the standard of care (SOC) for advanced
hepatocellular carcinoma – targeted therapies      hepatocellular carcinoma (HCC) fostered interest to further evaluate several
                                                   other targeted therapies and extend the positioning of sorafenib alone and in
Abbreviations                                      combination with other drugs and local therapies at earlier stages and in an
HCC, hepatocellular carcinoma; PDGFR,
                                                   adjuvant setting. This review highlights current research using targeted
platelet-derived growth factor receptor; SOC,
                                                   therapies in HCC. Information for this review was compiled by searching
standard of care; VEGF, vascular endothelial
                                                   PubMed and MEDLINE databases for articles published until September
growth factor.
                                                   2010. Several small molecules and humanized antibodies with anti-angiogenic
Correspondence                                     and antiproliferative properties are currently being investigated in preclinical
Eric Raymond, MD, PhD, Department of               and/or clinical trials. Results are awaited from these clinical trials and offer
Medical Oncology, Beaujon/Bichat University        promise for extending the current treatment options in HCC. Currently
                               ˆ
Hospital, Assistance Publique-Hopitaux de Paris,   published data suggest that substantial progress may be achieved in the
University INSERM U728, Paris 7 Diderot, 100       treatment of patients with HCC in the next 10 years.
                 ´ ´
boulevard du General Leclerc, 92110 Clichy,
France
Tel: 133 1 40 87 56 14
Fax: 133 1 40 87 54 87
e-mail: eric.raymond@bjn.aphp.fr

Received 10 November 2010
Accepted 26 November 2010

DOI:10.1111/j.1478-3231.2010.02395.x




Chemotherapy, including single agent doxorubicin, mul-                      Drug targets in hepatocellular carcinoma
tidrug regimens such as platinum–ifospahmide–adria-
mycin–5FU and more recently platinum-based doublets                         The carcinogenesis of HCC is heterogeneous and
such as GEMOX (gemcitabin and oxaliplatin) or FOL-                          complex (3). Several critical signalling pathways and
FOX (5fluorouracil and oxaliplatin), has long been the                       molecular disturbances involved in the development of
mainstay standard of care in patients with advanced                         HCC and tumour invasion have been described exten-
hepatocellular carcinoma (HCC). Although activity has                       sively. The genetic disturbances and disrupted signalling
been suggested in a number of case reports and small                        pathways involved in the proliferation, survival, differ-
clinical trials, none of those regimens has demonstrated                    entiation, invasion and metastasis of HCC cells have been
an improvement in overall survival (OS) (1). Only one                       reviewed elsewhere (4–7).
recent clinical study showed that FOLFOX improved the                          Hepatocellular carcinoma is one of the most vascular-
OS compared with doxorubicin in Asian patients (2).                         ized solid cancers, associated with a high tendency
Sorafenib is the first targeted therapy shown to improve                     towards vascular invasion. Immunohistochemical stu-
survival and has led to therapeutic options for HCC.                        dies showed that increased microvessel density was
Furthermore, improved understanding of tumour biol-                         associated with a poor outcome after surgery and corre-
ogy and critical signalling pathways in HCC have sug-                       lated with a risk of vascular invasion, metastasis and a
gested that several key kinases may be targets for novel                    poor prognosis (8). Vascular endothelial growth factor
anticancer agents.                                                          (VEGF) is the principal mediator of angiogenesis in HCC
   The aim of this review was to discuss the use of these                   (9–11). Most HCC overexpress VEGF and have an
emerging drugs in HCC and, in particular, the challenges                    aberrant VEGF expression (9–12). High VEGF expres-
of clinical development.                                                    sion has been associated with decreased survival (9).


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Targeted therapies in HCC                                                                                             Faivre et al.


Research has primarily targeted pro-angiogenic growth          advanced disease and in whom hepatitis B infection was
factors such as VEGF (using bevacizumab) or membrane           the prevalent cause of cirrhosis. The median OS was 6.5
tyrosine kinase receptors such as vascular endothelial         months in the sorafenib group versus 4.2 months in the
growth factor receptor (VEGFR) (using sorafenib, suni-         placebo group (HR = 0.68; 95% CI 0.500.93; P = 0.014)
tinib, brivanib and others). Other pro-angiogenic factors      (21). Tolerance to sorafenib in these two studies was
such as platelet-derived growth factor receptor (PDGFR)        generally good. The most common grade 3 drug-related
and basic fibroblast growth factor receptor FGF (bFGF;          adverse events in the Sorafenib HCC Assessment Rando-
FGF-2) have been shown to play crucial roles in HCC            mized Protocol and Asian-Pacific studies, including
angiogenesis, making them attractive candidates for            diarrhoea and hand–foot skin reaction, occurred in
targeted therapies.                                            o 10% of patients. Noticeably, the incidence of bleeding
   The epidermal growth factor receptor (EGFR) is over-        was similar in the experimental and the placebo arms
expressed in 40–70% of HCC, and proliferation was              (20). Based on these data, the United States (US) Food
shown to be dependent on stimulation of EGFR by                and Drug Administration (FDA), European Medicine
transforming growth factor (TGF)-a or EGF in several           Agency (EMA) and other regulatory authorities in the
HCC cells (13). Thus, targeting EGFR is a logical option       world approved sorafenib for advanced HCC.
for the treatment of HCC. The results of preclinical
models of therapeutic approaches using neutralizing
                                                               Anti-angiogenic agents in clinical development
antibodies against EGFR (cetuximab or panitumumab)
or small-molecule EGFR tyrosine kinase inhibitors              Sunitinib (SU011248, Pfizer Inc., New York, USA) –
(gefitinib, erlotinib and lapatinib) have been interesting      sunitinib malate is another oral multityrosine kinase
(14, 15).                                                      targeting the VEGFR-1, -2, PDGFR-a, -b, c-Kit, Flt-3
   The phosphatidylinositol 3-kinase (PI3K)/Akt/mam-           and RET. Sunitinib was identified in a drug discovery
malian target of the rapamycin (mTOR) pathway was              programme designed to identify more potent VEGFRs
shown to be crucial in HCC cell survival in several            and PDGFRs inhibitors (23), which, as described above,
preclinical models. This pathway was responsible for           play important roles in the angiogenesis of HCC. Suniti-
downstream cell signalling of various tyrosine kinase          nib has already been approved for the treatment of renal
receptors, such as VEGFR, EGFR, PDGFR and IGF-1R.              cell carcinoma as well as gastrointestinal stromal tu-
Genomic studies indicate that about 50% of patients            mours that are refractory or intolerant to imatinib.
with HCC have mTOR signalling disturbances (16). In            Recently, in a placebo-controlled randomized phase III
HCC, the activation of the PI3K/Akt/mTOR pathway is            trial, this compound was shown to exert a significant
associated with a poor prognosis (17). This pathway can        clinical benefit on progression-free survival (PFS) and
be targeted at various levels but at present, mTOR             safety in patients with advanced pancreatic endocrine
inhibitors such as rapamycin or its analogues (ever-           tumours, another hypervascularized tumour (24). In
olimus and temsirolimus) are the main available options.       xenograft models of HCC, sunitinib induced tumour
                                                               growth inhibition by increasing apoptosis, reducing
                                                               microvessel density and inhibiting cell proliferation
Sorafenib: a validated proof of concept for
                                                               (25). The results of three previous independent phase II
targeted therapy
                                                               studies on the efficacy and tolerance of sunitinib in
Sorafenib (Bayer Pharmaceuticals Corporation, Leverku-         patients with advanced HCC were encouraging (26–28).
sen, Germany) is an oral multityrosine kinase inhibitor        In the European/Asian study, a low response rate was
targeting the intracellular serine/threonine Raf kinase,       obtained despite the marked antitumour activity because
the VEGFR-2 and -3, PDGFR-b, Fms-like tyrosine kinase          35% of patients treated with 50 mg/day sunitinib
3 (Flt-3). In HCC cell lines and xenograft models,             (4 weeks on/2 weeks off) achieved stable disease for over
sorafenib has been shown to prevent tumour cell growth         3 months, resulting in disease control of 37.8% (26).
and induce apoptosis as well as anti-angiogenic effects        Similar results were observed with the use of sunitinib at
(18, 19). Sorafenib is the first and only drug so far shown     the dose of 37.5 mg/day with the same schedule because
to improve the OS in patients with advanced HCC in two         stable disease was reported in 50% of patients (27). The
large multicentre, double-blind, placebo-controlled ran-       median OS was 8 and 9.8 months respectively (26, 27).
domized phase III trials (20, 21). These two large trials      More recently, the results of a Swiss phase II study with a
were performed based on promising results from a phase         continuous daily dose of sunitinib of 37.5 mg showed a
II study (22). In the western trial, the benefit of sorafenib   PFS at 12 weeks in 33% of patients. The median OS was
in the European-American population was the result of          9.3 months (28). A multinational, phase III study
an increase in the median OS from 7.9 months in the            (NCT00699374) comparing sunitinib with sorafenib in
placebo group to 10.7 months in the sorafenib group            patients with advanced HCC was discontinued on 22
(HR = 0.69; 95% CI 0.55–0.87; P = 0.00058). Sorafenib          April 2010, because of a higher incidence of serious
extended the OS by 44%, and decreased the relative risk        adverse events in the sunitinib arm than the sorafenib
of death by 31% (20). The same increase in survival was        arm, and because sunitinib did not meet the primary
confirmed in the Asian-Pacific population that had more          endpoint in the overall population. The details of this

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Faivre et al.                                                                                   Targeted therapies in HCC


trial will soon be available. The dosing and schedules of      OS of 10.4 months. The benefit appears to be limited in
sunitinib seem to be complex in patients with HCC (29).        patients with CP class B because the median TTP was 3.7
Frequent underlying liver disease generate a narrow            months and the median OS was 2.5 months (37). Based
therapeutic index and the routine daily dose of 50 mg          on these encouraging results, the efficacy and tolerance of
used in other tumour types does not seem to be suitable        a daily dose of 17.5 mg linifanib is now being compared
in these patients (30).                                        with that of sorafenib in an international randomized
   Brivanib (BMS-582664; Bristol-Meyers Squibb, New            non-blinded phase III study in patients CP class A and
York, USA) – brivanib alaninate is a potent, oral, selective   advanced HCC (NCT01009593).
inhibitor of VEGFR-2, -3 and FGFR-2, -3, tyrosine                 Axitinib (AG-013736; Pfizer Inc.) – axitinib is a potent
kinases. FGFR inhibition could provide an add-on ben-          inhibitor of VEGFR tyrosine kinase, PDGFR and Kit.
efit in HCC compared with VEGFR/PDGFR inhibitors.               Axitinib had been shown to have potent preclinical
In derived HCC xenografts, brivanib significantly sup-          activity in various models (38). Interestingly, no cross-
pressed tumour growth, resulting in decreased mean             resistance has been found between axitinib and other
blood microvessel density as well as increased apoptosis       agents because the antitumour activity of axitinib was
and a reduction in microvessel density (31). Similar           reported in patients with metastatic RCC in whom
results were reported in a broad range of human tumour         treatment with sunitinib, sorafenib and cytokines thera-
xenografts, encompassing models of chemoresistant dis-         pies were unsuccessful (39). A combined phase II/III trial
ease. Assessment of angiogenesis by dynamic contrast-          evaluating axitinib as a second-line agent in advanced
enhanced MRI showed a significant reduction in tumour           HCC is being planned.
vascular density and in blood flow (32). Brivanib                  Cediranib (AZD2171, AstraZeneca, Wilmington, USA)
(800 mg daily) as either a first-line or a second-line          – AZD2171, a potent oral small-molecule pan-VEGFR
therapy was evaluated in a phase II open-label study in        inhibitor that blocks PDGFR and c-Kit, has been shown
patients with advanced HCC. Interim efficacy and safety         to have antitumour activity in a broad range of human
results were reported at ASCO 2009 (33) and updated at         tumour xenograft models. Oral daily doses of 45 mg or
ILCA 2009 (34). The median OS was 10 months in the             less of AZD2171 were generally well tolerated and
first-line treated group and 9.8 months in the second-line      associated with encouraging antitumour activity in a
treated group (including prior treatment with sorafenib).      wide variety of advanced solid tumours (40). AZD2171
Major grade Z3 toxicities were fatigue (16%), hypona-          has been tested in a two-stage phase II study in patients
traemia (15%) and hypertension (11%). Based on these           with non-resectable HCC. At the dose of 45 mg/day, 84%
results and evidence of antitumour activity, brivanib is       of the evaluated patients experienced grade 3 toxicities
currently being evaluated in phase II trials in patients       including fatigue, hypertension and anorexia (41). Poor
with advanced HCC as a first-line treatment compared            tolerance to this agent could be due in part to underlying
with sorafenib (NCT00858871) as a second-line therapy          cirrhosis because liver metabolism could be impaired by
compared with placebo (NCT00825955) and also com-              liver dysfunction. Thus, another phase II study was
pared with placebo as an adjuvant therapy to transarter-       planned with a reduced dose of AZD2171. However, this
ial chemo-embolization (NCT00908752).                          study has been suspended (NTC00427973).
   Linifanib (ABT-869, Abbott, Abbott Park, USA) –                TSU-68 (SU6668, Taiho Pharmaceutical Co. Ltd,
linifanib is a novel, orally bioavailable, small-molecule      Tokyo, Japan) – TSU-68 is an oral multikinase inhibitor
receptor tyrosine kinase inhibitor that targets VEGF and       of VEGFR-2, PDGFR and FGFR. This compound has
PDGF receptor families. In a phase I study, linifanib was      been assessed in 35 Japanese patients with CP classes A/B
found to be well tolerated at doses  0.25 mg/kg daily.        HCC in a coupled phase I/II study (42). Two hundred
After 17 months in the cohort of 33 patients with HCC,         milligrams of STU-68 was administered twice a day. In
prolonged stable disease was achieved in two patients          this study, 11.4% of patients experienced grade 3/4
with HCC. Dynamic radiological assessment showed               adverse events including elevated AST/ALT levels and
reduced vascular permeability of the tumour and vascu-         thrombocytopenia. An objective response was observed
larity correlated to drug exposure (35). Recently, interim     in 9.6% of patients (complete response: 2.9% and partial
results of an open-label multicentre phase II trial of ABT-    response: 5.7%). Stable disease was achieved in 42.8% of
869 in patients with advanced HCC were reported (34).          patients. The median PFS was 2.1 months compared with
ABT-869 was administered at 0.25 mg/kg daily to Child-         a surprising median OS of 13.1 months (42).
Pugh (CP) class A patients or every other day in CP class         Pazopanib (GW786034, GlaxoSmithKline, Brentford,
B patients. Thirty-four patients could be evaluated in this    UK) – pazopanib is an oral, multitargeted tyrosine kinase
cohort, and an objective response was achieved in 8.7%         inhibitor that targets VEGFRs, PDGFR and c-Kit. This
of CP class A patients but in none of the CP class B           compound recently obtained US FDA approval for the
patients. The median TTP was 112 days and the median           treatment of advanced renal cell carcinoma. Pazopanib
OS was 295 days. The most common grade Z3 toxicities           was evaluated in a phase I study in patients with
were hypertension (20.6%) and fatigue (11.8%). Up-             advanced HCC (43). The maximum tolerated dose
dated results showed a clinical benefit in CP class A           was established as 600 mg twice a day. The main grade
patients with a median TTP of 5.4 months and a median          3/4-related side effects were diarrhoea (4%) and

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Targeted therapies in HCC                                                                                            Faivre et al.


hypertension (26%). Partial response and stable disease      isoforms, has emerged as an important therapeutic agent.
were observed in 7.5 and 41% of patients respectively.       It has been approved for the treatment of several carci-
Thus, pazopanib appears to be a promising active drug        nomas including colorectal, non-small-cell lung, breast
for further clinical development in HCC.                     cancer and metastatic renal cell carcinoma. In preclinical
   Vandetanib (ZD6474, AstraZeneca, Wilmington,              models of HCC, bevacizumab induced a significant
USA) – ZD6474 is an orally active inhibitor of VEGFR,        decrease in vessel density and prolonged time to progres-
EGFR and RET tyrosine kinases. In preclinical models         sion of tumour-bearing mice (53). Bevacizumab was
and under experimental conditions, ZD6474 was shown          evaluated as a single agent for the treatment of advanced
to inhibit HCC cell proliferation adhesion, migration        HCC in two phase II trials. In the first study in 46
and invasion (44). ZD6474 is currently being evaluated       patients with locally advanced HCC, partial responses
in a phase II trial in patients with advanced HCC            were observed in 13% and disease stabilization for at least
(NCT00508001).                                               6 months was obtained in 65% of patients, with a median
   Vatalanib (PTK787/ZK, Novartis, Basel, Switzerland        PFS of 6.9 months (54). The OS rate at 1, 2 and 3 years
and Bayer Schering Pharma) – PTK787 is an orally active,     was 53, 28 and 23% respectively. Comparable results were
selective inhibitor of all VEGFR tyrosine kinases. At        reported in the interim results of a French study, because
higher concentrations, this compound also inhibits other     partial response and stable disease for at least 16 weeks
tyrosine kinases such as PDGFR and Kit. PTK787 in-           were observed in 12.5 and 29 % respectively (55).
duced tumour cell apoptosis and reduced vessel forma-        Updated data presented at ASCO 2009 showed that
tion. Its effect was enhanced by the induction of hypoxia    bevacizumab induced 16% partial response and 47%
through ligation of the hepatic artery (45), which sug-      stable disease in 38 patients (56). Despite these promising
gests that this compound might be interesting in combi-      results, it should be noted that patients with a CLIP score
nation with transarterial chemoembolization. In the          4 3 (55), liver involvement of the tumour of 4 50%
phase I study, the maximum tolerated dose was 750 mg         and/or with vascular invasion and/or extrahepatic spread
daily and stable disease was observed in 50% of patients     disease (54) were excluded from trials. Therefore, it is
(46). For pharmacological and marketing reasons, the         difficult to compare these results with those obtained
development of PTK787/ZK was not pursued in HCC.             with sorafenib and probably only well-selected patients
   BIBF 1120 (Vargatef, Boehringer Ingelheim, Ridge-         can benefit from this therapy. Moreover, these results
field, Germany) – BIBF 1120 is an oral triple angiokinase     were accompanied by a high incidence of adverse drug-
inhibitor targeting VEGF, FGFR and PDGF receptors            related events, in particular, severe bleeding, which
that showed antitumour activity in preclinical models        occurred in 11% of patients in the American study (54)
(47). Its activity on FGFR was considered to be a            and required withdrawal of the drug in 20% of patients in
potential advantage to broaden its activity over other       the French study (55). Other serious side effects included
VEGFR inhibitors. This compound is being compared            arterial thrombosis (6%) and hypertension (15%).
with sorafenib in two different phase II studies to             The combination of bevacizumab with cytotoxic agents
evaluate the safety and the efficacy for advanced HCC in      was also evaluated in phase II studies and was shown to be
European patients (NCT01004003) and Asian patients           reasonably safe, with a moderate clinical benefit (57–59).
(NCT00987935).                                               The combination of bevacizumab and GEMOX was eval-
   Foretinib (GSK1363089, EXEL-2880; XL-880, Exelixis,       uated in a phase II study. Twenty per cent of the 33 patients
San Francisco, USA) – foretinib is an orally bioavailable    enrolled showed an objective response. The median OS was
selective inhibitor of c-Met and VEGFR-2 tyrosine ki-        9.6 months (57). Adding bevacizumab did not markedly
nases. Targeting the c-Met pathway could be a potential      improve the clinical benefit because results with GEMOX
therapy in HCC because dysregulation of c-MET as well        alone were similar in a phase II study, with a response rate
as its ligand HGF are frequent (48) and overexpression of    of 18% and a median OS of 11.5 months (60).
c-Met correlates with more advanced HCC (49). The
exact role of this pathway in the pathogenesis of HCC has
                                                             Anti-epidermal growth factor receptor under
not been clearly elucidated. Blocking the HGF/c-MET
                                                             clinical development
pathway during the orthotopic transplant of HCC mod-
els induced growth suppression and a decrease in angio-      Cetuximab (C225, ImClone Systems, New York, USA
genesis (50). Foretinib was found to be potentially active   and Merck Serono, Darmstadt, Germany), a chimeric
in preclinical HCC models with inhibition of tumour          monoclonal antibody directed against EGFR, is already
angiogenesis, tumour cell proliferation and metastasis       part of standard therapy in patients with metastatic
(51). Although several molecules targeting MET path-         colorectal cancer and head neck cancer. Cetuximab was
ways are under development (52), only foretinib is being     evaluated as a single agent in two phase II studies (61,
investigated for safety and tolerance in patients with       62). In the first study, no clinical responses were observed
advanced HCC in a phase I/II study (NCT00920192).            and stable disease was achieved in 17% of patients. The
   Bevacizumab (Genentech Inc., San Francisco, USA           median OS was 9.6 months and the median PFS was 1.4
and Roche, Basel, Switzerland), a recombinant, huma-         months (61). In the second open-label study, stable
nized monoclonal antibody directed against all VEGF          disease was observed for at least 8 weeks in 44.4% of the

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Faivre et al.                                                                                      Targeted therapies in HCC


cases and the median PFS was 1.8 months (62). The               pathways could be developed by the tumour to bypass
results of these two studies are inconsistent; hence, the       the EGF signal for its survival and cell proliferation (67,
role and activity of this compound in HCC must still be         68). A possible solution to avoid this resistance mechan-
clarified. Currently, anti-EGFR-based approaches are             ism is to combine IGF-1R inhibitors and EGFR blockers
being tested in clinical trials (NCT00142428), especially       and enhance the antitumour activity of the respective
in combination with conventional chemotherapy                   monotherapies (69, 70).
(NCT00483405).                                                     Lapatinib (GW572016, GlaxoSmithKline) is a selective
   Erlotinib (OSI-774, Genentech Inc. and Roche) is a           dual inhibitor of both EGFR and Human EGFR type 2
potent oral and specific inhibitor of the EGFR/HER1-             (HER-2/NEU) signalling pathways. Although HER-2/
related tyrosine kinase domain. Erlotinib is already ap-        NEU overexpression is rare in HCC, this compound has
proved for the treatment of metastatic or locally advanced      also been evaluated in advanced HCC. Twenty-six patients
non-small-cell lung cancer and pancreatic cancer. The           with advanced HCC were treated with daily lapatinib
safety and efficacy of erlotinib as a single agent in Child-     orally at a dose of 1500 mg in a phase II study (71). No
Pugh class A and B patients with advanced HCC were              objective responses were obtained. Approximately 40% of
reported in two phase II clinical studies. The first report      patients achieved their best response. The median PFS and
showed that 32% of patients were progression-free at 6          OS were 1.9 and 12.6 months respectively. Only three
months, with disease control in 59% of cases. The median        patients experienced grade 3 drug-related toxicities in-
OS for this cohort was 13 months (63). The most frequent        cluding diarrhoea, rash and acute renal failure. Interest-
grade 3/4 toxicities were skin rash, diarrhoea and fatigue.     ingly, patients who developed a rash (an effect of EGFR/
Treatment was significantly less well tolerated in CP class B    HER1 inhibition) had a more favourable outcome with
patients (63). These results are limited by the fact that 42%   longer survival compared with the overall study popula-
of enrolled patients had no underlying liver disease. In the    tion (71). In another phase II study, a cohort of 40 patients
second study, erlotinib was evaluated in 40 patients with CP    with advanced HCC was treated with lapatinib. Moderate
class A or B cirrhosis and advanced HCC. There was no           antitumoral activity was observed because an objective
partial or complete response to erlotinib. However, the PFS     response was observed in 5% of patients. The median PFS
at 4 months was 43%, and the median OS was 10.75                was 2.3 and the median OS was 6.2 months (72).
months. No correlation was found in this trial between
EGFR expression and OS (64). A phase III clinical trial is
                                                                mTOR inhibitors
ongoing to evaluate the benefit of combining erlotinib with
sorafenib compared with sorafenib plus placebo as a first-       Rapamycin (sirolimus) is an mTOR kinase inhibitor with
line therapy in patients with advanced HCC                      antiproliferative (by inhibiting tumour cell growth and
(NCT00901901). The results of a phase II study combining        proliferation) and anti-angiogenesis activities (by both
bevacizumab and erlotinib were interesting, with a median       direct effects on vascular cell proliferation and indirect
time to progression of 9 months and a median OS of 15.65        effects on growth factor production). Rapamycin also
months. Major side effects included fatigue (20%), hyper-       inhibits VEGF secretion and signal transduction induced
tension (15%) and gastrointestinal bleeding (12.5%) (65).       by VEGF in endothelial cells ultimately altering tumour
Patients included in this study had slightly less advanced      growth by an anti-angiogenic mechanism. Even if the
disease than the populations in other published phase II        PI3K/AKT/mTOR pathway could be inhibited at various
trials in this setting. Further studies are needed to confirm    levels, the most promising target in this pathway is
the potential synergistic activity of this combination. This    mTOR. Rapamycin and its derivatives such as everolimus
combination is being compared with sorafenib as a first-         (RAD001, Novartis) yielded interesting antitumour ac-
line therapy in a phase 2 study (NCT00881751) as well as a      tivity in preclinical studies and xenograft models of HCC
second-line therapy (NCT01180959).                              (73, 74). Two small pilot studies showed promising
   Gefitinib (ZD1839, AstraZeneca), another EGFR tyr-            results on the efficacy of sirolimus in HCC patients with
osine kinase inhibitor, was also evaluated in a two-stage       a safe profile (75, 76). The efficacy of sirolimus was
design, single-arm phase 2 study in patients with HCC           evaluated in a single-arm study in 21 advanced HCC
(66). Thirty-one patients were recruited in the first stage.     patients (75). Sirolimus induced a partial response and
Gefitinib induced an objective response of 3% and                tumour stabilization for at least 3 months in 5 and 24%
disease stabilization of 22.6%. The median PFS was 2.8          of patients respectively. The median OS was 6.5 months.
months and the median OS was 6.5 months. Because the            No major sirolimus-related side effects were observed in
criterion for the second stage of the study was not met,        this study (75). In the French pilot study, 14 patients
the authors hypothesized that gefitinib was not active as a      were treated with 30 mg oral sirolimus once a week (76).
single agent in patients with advanced HCC (66).                A complete or a partial response according to the
These results could be explained by the possible cross-         RECIST criteria was observed in 7 and 33% of patients
talk between insulin-like growth factor 1 receptor              respectively. Sirolimus also seemed to be safe because no
(IGF-1R) and EGF signalling pathways (67). Gefitinib             grade 4 toxicity was observed and only two patients
resistance may be associated with alternative activation of     experienced grade 3 mucositis. Sirolimus did not affect
the IGF-2/IGF-1R survival pathway. Substitution                 liver function (76). Several phase I and phase II studies

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c  2011 John Wiley  Sons A/S                                                                                            155
Targeted therapies in HCC                                                                                               Faivre et al.


are currently testing mTOR inhibitors as single agents       about 30% of HCC and b-catenin mutations in around
(NCT00390195 and NCT00516165), in combination                20% of cases (86). Although the clinical and therapeutic
with sorafenib (NCT01008917) or with bevacizumab             relevance of the Wnt-b-catenin pathway in HCC has not
(NTC00775073). Based on the safety profile in patients        been elucidated, drugs targeting this pathway are in
with cirrhosis temsirolimus (CCI-779, Pfizer Inc.) is also    the early stages of evaluation for HCC. Effective ther-
being evaluated in a phase II study in CP class B patients   apeutic inhibition of this pathway seems to be fairly
with advanced HCC (NCT01079767). Everolimus is               complex (87).
being evaluated in patients with advanced HCC with
progressive disease or as a second-line therapy in a phase   Transforming growth factor-b inhibitors
III study compared with placebo either following sorafe-
nib or in patients who cannot tolerate sorafenib.            Although TGF-b inhibits hepatocyte cell growth in the
                                                             normal liver, HCC mainly occurs in injured livers
                                                             including those with activated TGF-b signalling (88,
MEK/ERK inhibitors                                           89). Previous studies have shown that the disruption of
The Raf/MEK/ERK pathway appears to be one of the             TGF-b signalling in mice through dominant-negative
most significant cellular signalling sequences in the         transforming growth factor receptor 2 accelerates chemi-
development and maintenance of HCC (77). AZD6244             cally induced hepatocarcinogenesis (90). In preclinical
(ARRY-142886, AstraZeneca) is an oral, new MEK in-           models, treatment with TGF-b induced senescence in
hibitor. This compound combined with rapamycin had           well-differentiated HCC cell lines with preliminary evi-
been shown to have antitumour and anti-angiogenic            dence for antitumour activity. This effect was associated
effects in preclinical models of human HCC (78).             with in vivo senescence-associated b-galactosidase activ-
Furthermore, pharmacological inhibition of the MEK/          ity in tumour cells (91). Further investigations and
ERK pathway by the MEK inhibitor AZD6244 enhanced            clinical studies could clarify the role of TGF-b signalling
the antitumour effect of sorafenib in both orthotopic and    as a potential target for HCC.
ectopic models of HCC (79). However, AZD6244 as a
single agent did not show any clinical benefit. Indeed,       Conclusion
this compound was evaluated in 19 patients with ad-
vanced HCC in a phase II study with a two-stage design       Several novel anticancer agents are currently under
and the results are disappointing because the median         investigation for HCC. These drugs were investigated
TTP was 8 weeks (80). This suggests that exclusive           based on current knowledge on hepatocellular carcino-
inhibition of the MAPK pathway is insufficient and            genesis, and the results have been encouraging in pre-
ineffective for HCC treatment (81). AZD6244 is under         clinical evaluations. Although none of these agents have
evaluation in HCC patients with moderate liver dysfunc-      yet demonstrated significant clinical benefits, it is likely
tion and normal liver function in a phase II study           that based on current trials, patients will have access to
(NCT00604721) and in association with sorafenib in an        more therapeutic options in the next few years.
Asian phase I/II study (NCT01029418).
                                                             Acknowledgements
Insulin growth factor 1 receptor inhibitors
                                                             This work was funded in part by AAREC (Association
Great interest has been shown in exploring IGFR inhibi-             `
                                                             d’Aide a la Recherche et l’Enseignement en Cancerologie).
tors in HCC. Deregulation of the IGF axis and its
activation have been involved in hepatocarcinogenesis        Conflicts of interest
(82, 83). Around 30% of HCCs overexpress the IGF–1R.
Preclinical studies suggest that inhibition of the IGF       Sandrine Faivre is a consultant for Pfizer Inc. and Bayer.
receptors suppresses HCC cell growth (69–84). Small          Eric Raymond is a consultant for Pfizer Inc., Bayer
molecules and monoclonal antibodies targeting IGF-1R         and Novartis. Mohamed Bouattour has no conflicts to
(such as the monoclonal antibody A12, cixutumumab            declare.
and AVE 1642) are under early clinical development. In a
phase I study, we showed that AVE 1642 (Sanofi-Avantis,            Notes: Information for this review was compiled by
Paris, France) can be safely combined with active doses of   searching PubMed and MEDLINE databases for articles
sorafenib without interaction between their respective       published until September 2010. Only articles published
pharmacokinetics. Long-lasting stabilization was ob-         in English were considered. The search terms used
tained in most patients because the mean time to             included ‘hepatocellular carcinoma’ in association with
progression was 13.3 weeks (85).                             the search terms: ‘angiogenesis’, ‘VEGFR’, ‘PDGFR’, ‘su-
                                                             nitinib’, ‘sorafenib’, ‘bevacizumab’, ‘thalidomide’, ‘mTOR
                                                             inhibitors’, ‘rapamycin’, ‘rapalogues’, ‘oxaliplatin’, ‘doxor-
Novel drugs targeting the Wnt-b-catenin pathway
                                                             ubicin’, ‘PIAF’, ‘IGF1-R inhibitor’, ‘natural product’, ‘me-
The Wnt-b-catenin pathway plays an important role in         tastatic’, ‘clinical trial’, ‘antiangiogenic agents’, ‘brivanib’,
HCC. Activation of the Wnt cascade had been shown in         ‘targeted therapy’, ‘cytotoxic therapy’ ‘and’ ‘drug

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156                                                                                                   
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Faivre et al.                                                                                                Targeted therapies in HCC


resistance’. Full articles were obtained and references were            16. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of
checked for additional material when appropriate.                           mTOR signaling in hepatocellular carcinoma. Gastroenter-
                                                                            ology 2008; 135: 1972–83.
                                                                        17. Schmitz KJ, Wohlschlaeger J, Lang H, et al. Activation
                                                                            of the ERK and AKT signalling pathway predicts poor
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Liver International 2011

  • 1. Liver International ISSN 1478-3223 Novel molecular therapies in hepatocellular carcinoma Sandrine Faivre, Mohamed Bouattour and Eric Raymond ˆ Department of Medical Oncology, Beaujon/Bichat University Hospital, Assistance Publique-Hopitaux de Paris, University INSERM U728, Paris 7, Clichy, France Keywords Abstract angiogenesis inhibitors – clinical trial – The approval of sorafenib as the standard of care (SOC) for advanced hepatocellular carcinoma – targeted therapies hepatocellular carcinoma (HCC) fostered interest to further evaluate several other targeted therapies and extend the positioning of sorafenib alone and in Abbreviations combination with other drugs and local therapies at earlier stages and in an HCC, hepatocellular carcinoma; PDGFR, adjuvant setting. This review highlights current research using targeted platelet-derived growth factor receptor; SOC, therapies in HCC. Information for this review was compiled by searching standard of care; VEGF, vascular endothelial PubMed and MEDLINE databases for articles published until September growth factor. 2010. Several small molecules and humanized antibodies with anti-angiogenic Correspondence and antiproliferative properties are currently being investigated in preclinical Eric Raymond, MD, PhD, Department of and/or clinical trials. Results are awaited from these clinical trials and offer Medical Oncology, Beaujon/Bichat University promise for extending the current treatment options in HCC. Currently ˆ Hospital, Assistance Publique-Hopitaux de Paris, published data suggest that substantial progress may be achieved in the University INSERM U728, Paris 7 Diderot, 100 treatment of patients with HCC in the next 10 years. ´ ´ boulevard du General Leclerc, 92110 Clichy, France Tel: 133 1 40 87 56 14 Fax: 133 1 40 87 54 87 e-mail: eric.raymond@bjn.aphp.fr Received 10 November 2010 Accepted 26 November 2010 DOI:10.1111/j.1478-3231.2010.02395.x Chemotherapy, including single agent doxorubicin, mul- Drug targets in hepatocellular carcinoma tidrug regimens such as platinum–ifospahmide–adria- mycin–5FU and more recently platinum-based doublets The carcinogenesis of HCC is heterogeneous and such as GEMOX (gemcitabin and oxaliplatin) or FOL- complex (3). Several critical signalling pathways and FOX (5fluorouracil and oxaliplatin), has long been the molecular disturbances involved in the development of mainstay standard of care in patients with advanced HCC and tumour invasion have been described exten- hepatocellular carcinoma (HCC). Although activity has sively. The genetic disturbances and disrupted signalling been suggested in a number of case reports and small pathways involved in the proliferation, survival, differ- clinical trials, none of those regimens has demonstrated entiation, invasion and metastasis of HCC cells have been an improvement in overall survival (OS) (1). Only one reviewed elsewhere (4–7). recent clinical study showed that FOLFOX improved the Hepatocellular carcinoma is one of the most vascular- OS compared with doxorubicin in Asian patients (2). ized solid cancers, associated with a high tendency Sorafenib is the first targeted therapy shown to improve towards vascular invasion. Immunohistochemical stu- survival and has led to therapeutic options for HCC. dies showed that increased microvessel density was Furthermore, improved understanding of tumour biol- associated with a poor outcome after surgery and corre- ogy and critical signalling pathways in HCC have sug- lated with a risk of vascular invasion, metastasis and a gested that several key kinases may be targets for novel poor prognosis (8). Vascular endothelial growth factor anticancer agents. (VEGF) is the principal mediator of angiogenesis in HCC The aim of this review was to discuss the use of these (9–11). Most HCC overexpress VEGF and have an emerging drugs in HCC and, in particular, the challenges aberrant VEGF expression (9–12). High VEGF expres- of clinical development. sion has been associated with decreased survival (9). Liver International (2011) c 2011 John Wiley & Sons A/S 151
  • 2. Targeted therapies in HCC Faivre et al. Research has primarily targeted pro-angiogenic growth advanced disease and in whom hepatitis B infection was factors such as VEGF (using bevacizumab) or membrane the prevalent cause of cirrhosis. The median OS was 6.5 tyrosine kinase receptors such as vascular endothelial months in the sorafenib group versus 4.2 months in the growth factor receptor (VEGFR) (using sorafenib, suni- placebo group (HR = 0.68; 95% CI 0.500.93; P = 0.014) tinib, brivanib and others). Other pro-angiogenic factors (21). Tolerance to sorafenib in these two studies was such as platelet-derived growth factor receptor (PDGFR) generally good. The most common grade 3 drug-related and basic fibroblast growth factor receptor FGF (bFGF; adverse events in the Sorafenib HCC Assessment Rando- FGF-2) have been shown to play crucial roles in HCC mized Protocol and Asian-Pacific studies, including angiogenesis, making them attractive candidates for diarrhoea and hand–foot skin reaction, occurred in targeted therapies. o 10% of patients. Noticeably, the incidence of bleeding The epidermal growth factor receptor (EGFR) is over- was similar in the experimental and the placebo arms expressed in 40–70% of HCC, and proliferation was (20). Based on these data, the United States (US) Food shown to be dependent on stimulation of EGFR by and Drug Administration (FDA), European Medicine transforming growth factor (TGF)-a or EGF in several Agency (EMA) and other regulatory authorities in the HCC cells (13). Thus, targeting EGFR is a logical option world approved sorafenib for advanced HCC. for the treatment of HCC. The results of preclinical models of therapeutic approaches using neutralizing Anti-angiogenic agents in clinical development antibodies against EGFR (cetuximab or panitumumab) or small-molecule EGFR tyrosine kinase inhibitors Sunitinib (SU011248, Pfizer Inc., New York, USA) – (gefitinib, erlotinib and lapatinib) have been interesting sunitinib malate is another oral multityrosine kinase (14, 15). targeting the VEGFR-1, -2, PDGFR-a, -b, c-Kit, Flt-3 The phosphatidylinositol 3-kinase (PI3K)/Akt/mam- and RET. Sunitinib was identified in a drug discovery malian target of the rapamycin (mTOR) pathway was programme designed to identify more potent VEGFRs shown to be crucial in HCC cell survival in several and PDGFRs inhibitors (23), which, as described above, preclinical models. This pathway was responsible for play important roles in the angiogenesis of HCC. Suniti- downstream cell signalling of various tyrosine kinase nib has already been approved for the treatment of renal receptors, such as VEGFR, EGFR, PDGFR and IGF-1R. cell carcinoma as well as gastrointestinal stromal tu- Genomic studies indicate that about 50% of patients mours that are refractory or intolerant to imatinib. with HCC have mTOR signalling disturbances (16). In Recently, in a placebo-controlled randomized phase III HCC, the activation of the PI3K/Akt/mTOR pathway is trial, this compound was shown to exert a significant associated with a poor prognosis (17). This pathway can clinical benefit on progression-free survival (PFS) and be targeted at various levels but at present, mTOR safety in patients with advanced pancreatic endocrine inhibitors such as rapamycin or its analogues (ever- tumours, another hypervascularized tumour (24). In olimus and temsirolimus) are the main available options. xenograft models of HCC, sunitinib induced tumour growth inhibition by increasing apoptosis, reducing microvessel density and inhibiting cell proliferation Sorafenib: a validated proof of concept for (25). The results of three previous independent phase II targeted therapy studies on the efficacy and tolerance of sunitinib in Sorafenib (Bayer Pharmaceuticals Corporation, Leverku- patients with advanced HCC were encouraging (26–28). sen, Germany) is an oral multityrosine kinase inhibitor In the European/Asian study, a low response rate was targeting the intracellular serine/threonine Raf kinase, obtained despite the marked antitumour activity because the VEGFR-2 and -3, PDGFR-b, Fms-like tyrosine kinase 35% of patients treated with 50 mg/day sunitinib 3 (Flt-3). In HCC cell lines and xenograft models, (4 weeks on/2 weeks off) achieved stable disease for over sorafenib has been shown to prevent tumour cell growth 3 months, resulting in disease control of 37.8% (26). and induce apoptosis as well as anti-angiogenic effects Similar results were observed with the use of sunitinib at (18, 19). Sorafenib is the first and only drug so far shown the dose of 37.5 mg/day with the same schedule because to improve the OS in patients with advanced HCC in two stable disease was reported in 50% of patients (27). The large multicentre, double-blind, placebo-controlled ran- median OS was 8 and 9.8 months respectively (26, 27). domized phase III trials (20, 21). These two large trials More recently, the results of a Swiss phase II study with a were performed based on promising results from a phase continuous daily dose of sunitinib of 37.5 mg showed a II study (22). In the western trial, the benefit of sorafenib PFS at 12 weeks in 33% of patients. The median OS was in the European-American population was the result of 9.3 months (28). A multinational, phase III study an increase in the median OS from 7.9 months in the (NCT00699374) comparing sunitinib with sorafenib in placebo group to 10.7 months in the sorafenib group patients with advanced HCC was discontinued on 22 (HR = 0.69; 95% CI 0.55–0.87; P = 0.00058). Sorafenib April 2010, because of a higher incidence of serious extended the OS by 44%, and decreased the relative risk adverse events in the sunitinib arm than the sorafenib of death by 31% (20). The same increase in survival was arm, and because sunitinib did not meet the primary confirmed in the Asian-Pacific population that had more endpoint in the overall population. The details of this Liver International (2011) 152 c 2011 John Wiley & Sons A/S
  • 3. Faivre et al. Targeted therapies in HCC trial will soon be available. The dosing and schedules of OS of 10.4 months. The benefit appears to be limited in sunitinib seem to be complex in patients with HCC (29). patients with CP class B because the median TTP was 3.7 Frequent underlying liver disease generate a narrow months and the median OS was 2.5 months (37). Based therapeutic index and the routine daily dose of 50 mg on these encouraging results, the efficacy and tolerance of used in other tumour types does not seem to be suitable a daily dose of 17.5 mg linifanib is now being compared in these patients (30). with that of sorafenib in an international randomized Brivanib (BMS-582664; Bristol-Meyers Squibb, New non-blinded phase III study in patients CP class A and York, USA) – brivanib alaninate is a potent, oral, selective advanced HCC (NCT01009593). inhibitor of VEGFR-2, -3 and FGFR-2, -3, tyrosine Axitinib (AG-013736; Pfizer Inc.) – axitinib is a potent kinases. FGFR inhibition could provide an add-on ben- inhibitor of VEGFR tyrosine kinase, PDGFR and Kit. efit in HCC compared with VEGFR/PDGFR inhibitors. Axitinib had been shown to have potent preclinical In derived HCC xenografts, brivanib significantly sup- activity in various models (38). Interestingly, no cross- pressed tumour growth, resulting in decreased mean resistance has been found between axitinib and other blood microvessel density as well as increased apoptosis agents because the antitumour activity of axitinib was and a reduction in microvessel density (31). Similar reported in patients with metastatic RCC in whom results were reported in a broad range of human tumour treatment with sunitinib, sorafenib and cytokines thera- xenografts, encompassing models of chemoresistant dis- pies were unsuccessful (39). A combined phase II/III trial ease. Assessment of angiogenesis by dynamic contrast- evaluating axitinib as a second-line agent in advanced enhanced MRI showed a significant reduction in tumour HCC is being planned. vascular density and in blood flow (32). Brivanib Cediranib (AZD2171, AstraZeneca, Wilmington, USA) (800 mg daily) as either a first-line or a second-line – AZD2171, a potent oral small-molecule pan-VEGFR therapy was evaluated in a phase II open-label study in inhibitor that blocks PDGFR and c-Kit, has been shown patients with advanced HCC. Interim efficacy and safety to have antitumour activity in a broad range of human results were reported at ASCO 2009 (33) and updated at tumour xenograft models. Oral daily doses of 45 mg or ILCA 2009 (34). The median OS was 10 months in the less of AZD2171 were generally well tolerated and first-line treated group and 9.8 months in the second-line associated with encouraging antitumour activity in a treated group (including prior treatment with sorafenib). wide variety of advanced solid tumours (40). AZD2171 Major grade Z3 toxicities were fatigue (16%), hypona- has been tested in a two-stage phase II study in patients traemia (15%) and hypertension (11%). Based on these with non-resectable HCC. At the dose of 45 mg/day, 84% results and evidence of antitumour activity, brivanib is of the evaluated patients experienced grade 3 toxicities currently being evaluated in phase II trials in patients including fatigue, hypertension and anorexia (41). Poor with advanced HCC as a first-line treatment compared tolerance to this agent could be due in part to underlying with sorafenib (NCT00858871) as a second-line therapy cirrhosis because liver metabolism could be impaired by compared with placebo (NCT00825955) and also com- liver dysfunction. Thus, another phase II study was pared with placebo as an adjuvant therapy to transarter- planned with a reduced dose of AZD2171. However, this ial chemo-embolization (NCT00908752). study has been suspended (NTC00427973). Linifanib (ABT-869, Abbott, Abbott Park, USA) – TSU-68 (SU6668, Taiho Pharmaceutical Co. Ltd, linifanib is a novel, orally bioavailable, small-molecule Tokyo, Japan) – TSU-68 is an oral multikinase inhibitor receptor tyrosine kinase inhibitor that targets VEGF and of VEGFR-2, PDGFR and FGFR. This compound has PDGF receptor families. In a phase I study, linifanib was been assessed in 35 Japanese patients with CP classes A/B found to be well tolerated at doses 0.25 mg/kg daily. HCC in a coupled phase I/II study (42). Two hundred After 17 months in the cohort of 33 patients with HCC, milligrams of STU-68 was administered twice a day. In prolonged stable disease was achieved in two patients this study, 11.4% of patients experienced grade 3/4 with HCC. Dynamic radiological assessment showed adverse events including elevated AST/ALT levels and reduced vascular permeability of the tumour and vascu- thrombocytopenia. An objective response was observed larity correlated to drug exposure (35). Recently, interim in 9.6% of patients (complete response: 2.9% and partial results of an open-label multicentre phase II trial of ABT- response: 5.7%). Stable disease was achieved in 42.8% of 869 in patients with advanced HCC were reported (34). patients. The median PFS was 2.1 months compared with ABT-869 was administered at 0.25 mg/kg daily to Child- a surprising median OS of 13.1 months (42). Pugh (CP) class A patients or every other day in CP class Pazopanib (GW786034, GlaxoSmithKline, Brentford, B patients. Thirty-four patients could be evaluated in this UK) – pazopanib is an oral, multitargeted tyrosine kinase cohort, and an objective response was achieved in 8.7% inhibitor that targets VEGFRs, PDGFR and c-Kit. This of CP class A patients but in none of the CP class B compound recently obtained US FDA approval for the patients. The median TTP was 112 days and the median treatment of advanced renal cell carcinoma. Pazopanib OS was 295 days. The most common grade Z3 toxicities was evaluated in a phase I study in patients with were hypertension (20.6%) and fatigue (11.8%). Up- advanced HCC (43). The maximum tolerated dose dated results showed a clinical benefit in CP class A was established as 600 mg twice a day. The main grade patients with a median TTP of 5.4 months and a median 3/4-related side effects were diarrhoea (4%) and Liver International (2011) c 2011 John Wiley Sons A/S 153
  • 4. Targeted therapies in HCC Faivre et al. hypertension (26%). Partial response and stable disease isoforms, has emerged as an important therapeutic agent. were observed in 7.5 and 41% of patients respectively. It has been approved for the treatment of several carci- Thus, pazopanib appears to be a promising active drug nomas including colorectal, non-small-cell lung, breast for further clinical development in HCC. cancer and metastatic renal cell carcinoma. In preclinical Vandetanib (ZD6474, AstraZeneca, Wilmington, models of HCC, bevacizumab induced a significant USA) – ZD6474 is an orally active inhibitor of VEGFR, decrease in vessel density and prolonged time to progres- EGFR and RET tyrosine kinases. In preclinical models sion of tumour-bearing mice (53). Bevacizumab was and under experimental conditions, ZD6474 was shown evaluated as a single agent for the treatment of advanced to inhibit HCC cell proliferation adhesion, migration HCC in two phase II trials. In the first study in 46 and invasion (44). ZD6474 is currently being evaluated patients with locally advanced HCC, partial responses in a phase II trial in patients with advanced HCC were observed in 13% and disease stabilization for at least (NCT00508001). 6 months was obtained in 65% of patients, with a median Vatalanib (PTK787/ZK, Novartis, Basel, Switzerland PFS of 6.9 months (54). The OS rate at 1, 2 and 3 years and Bayer Schering Pharma) – PTK787 is an orally active, was 53, 28 and 23% respectively. Comparable results were selective inhibitor of all VEGFR tyrosine kinases. At reported in the interim results of a French study, because higher concentrations, this compound also inhibits other partial response and stable disease for at least 16 weeks tyrosine kinases such as PDGFR and Kit. PTK787 in- were observed in 12.5 and 29 % respectively (55). duced tumour cell apoptosis and reduced vessel forma- Updated data presented at ASCO 2009 showed that tion. Its effect was enhanced by the induction of hypoxia bevacizumab induced 16% partial response and 47% through ligation of the hepatic artery (45), which sug- stable disease in 38 patients (56). Despite these promising gests that this compound might be interesting in combi- results, it should be noted that patients with a CLIP score nation with transarterial chemoembolization. In the 4 3 (55), liver involvement of the tumour of 4 50% phase I study, the maximum tolerated dose was 750 mg and/or with vascular invasion and/or extrahepatic spread daily and stable disease was observed in 50% of patients disease (54) were excluded from trials. Therefore, it is (46). For pharmacological and marketing reasons, the difficult to compare these results with those obtained development of PTK787/ZK was not pursued in HCC. with sorafenib and probably only well-selected patients BIBF 1120 (Vargatef, Boehringer Ingelheim, Ridge- can benefit from this therapy. Moreover, these results field, Germany) – BIBF 1120 is an oral triple angiokinase were accompanied by a high incidence of adverse drug- inhibitor targeting VEGF, FGFR and PDGF receptors related events, in particular, severe bleeding, which that showed antitumour activity in preclinical models occurred in 11% of patients in the American study (54) (47). Its activity on FGFR was considered to be a and required withdrawal of the drug in 20% of patients in potential advantage to broaden its activity over other the French study (55). Other serious side effects included VEGFR inhibitors. This compound is being compared arterial thrombosis (6%) and hypertension (15%). with sorafenib in two different phase II studies to The combination of bevacizumab with cytotoxic agents evaluate the safety and the efficacy for advanced HCC in was also evaluated in phase II studies and was shown to be European patients (NCT01004003) and Asian patients reasonably safe, with a moderate clinical benefit (57–59). (NCT00987935). The combination of bevacizumab and GEMOX was eval- Foretinib (GSK1363089, EXEL-2880; XL-880, Exelixis, uated in a phase II study. Twenty per cent of the 33 patients San Francisco, USA) – foretinib is an orally bioavailable enrolled showed an objective response. The median OS was selective inhibitor of c-Met and VEGFR-2 tyrosine ki- 9.6 months (57). Adding bevacizumab did not markedly nases. Targeting the c-Met pathway could be a potential improve the clinical benefit because results with GEMOX therapy in HCC because dysregulation of c-MET as well alone were similar in a phase II study, with a response rate as its ligand HGF are frequent (48) and overexpression of of 18% and a median OS of 11.5 months (60). c-Met correlates with more advanced HCC (49). The exact role of this pathway in the pathogenesis of HCC has Anti-epidermal growth factor receptor under not been clearly elucidated. Blocking the HGF/c-MET clinical development pathway during the orthotopic transplant of HCC mod- els induced growth suppression and a decrease in angio- Cetuximab (C225, ImClone Systems, New York, USA genesis (50). Foretinib was found to be potentially active and Merck Serono, Darmstadt, Germany), a chimeric in preclinical HCC models with inhibition of tumour monoclonal antibody directed against EGFR, is already angiogenesis, tumour cell proliferation and metastasis part of standard therapy in patients with metastatic (51). Although several molecules targeting MET path- colorectal cancer and head neck cancer. Cetuximab was ways are under development (52), only foretinib is being evaluated as a single agent in two phase II studies (61, investigated for safety and tolerance in patients with 62). In the first study, no clinical responses were observed advanced HCC in a phase I/II study (NCT00920192). and stable disease was achieved in 17% of patients. The Bevacizumab (Genentech Inc., San Francisco, USA median OS was 9.6 months and the median PFS was 1.4 and Roche, Basel, Switzerland), a recombinant, huma- months (61). In the second open-label study, stable nized monoclonal antibody directed against all VEGF disease was observed for at least 8 weeks in 44.4% of the Liver International (2011) 154 c 2011 John Wiley Sons A/S
  • 5. Faivre et al. Targeted therapies in HCC cases and the median PFS was 1.8 months (62). The pathways could be developed by the tumour to bypass results of these two studies are inconsistent; hence, the the EGF signal for its survival and cell proliferation (67, role and activity of this compound in HCC must still be 68). A possible solution to avoid this resistance mechan- clarified. Currently, anti-EGFR-based approaches are ism is to combine IGF-1R inhibitors and EGFR blockers being tested in clinical trials (NCT00142428), especially and enhance the antitumour activity of the respective in combination with conventional chemotherapy monotherapies (69, 70). (NCT00483405). Lapatinib (GW572016, GlaxoSmithKline) is a selective Erlotinib (OSI-774, Genentech Inc. and Roche) is a dual inhibitor of both EGFR and Human EGFR type 2 potent oral and specific inhibitor of the EGFR/HER1- (HER-2/NEU) signalling pathways. Although HER-2/ related tyrosine kinase domain. Erlotinib is already ap- NEU overexpression is rare in HCC, this compound has proved for the treatment of metastatic or locally advanced also been evaluated in advanced HCC. Twenty-six patients non-small-cell lung cancer and pancreatic cancer. The with advanced HCC were treated with daily lapatinib safety and efficacy of erlotinib as a single agent in Child- orally at a dose of 1500 mg in a phase II study (71). No Pugh class A and B patients with advanced HCC were objective responses were obtained. Approximately 40% of reported in two phase II clinical studies. The first report patients achieved their best response. The median PFS and showed that 32% of patients were progression-free at 6 OS were 1.9 and 12.6 months respectively. Only three months, with disease control in 59% of cases. The median patients experienced grade 3 drug-related toxicities in- OS for this cohort was 13 months (63). The most frequent cluding diarrhoea, rash and acute renal failure. Interest- grade 3/4 toxicities were skin rash, diarrhoea and fatigue. ingly, patients who developed a rash (an effect of EGFR/ Treatment was significantly less well tolerated in CP class B HER1 inhibition) had a more favourable outcome with patients (63). These results are limited by the fact that 42% longer survival compared with the overall study popula- of enrolled patients had no underlying liver disease. In the tion (71). In another phase II study, a cohort of 40 patients second study, erlotinib was evaluated in 40 patients with CP with advanced HCC was treated with lapatinib. Moderate class A or B cirrhosis and advanced HCC. There was no antitumoral activity was observed because an objective partial or complete response to erlotinib. However, the PFS response was observed in 5% of patients. The median PFS at 4 months was 43%, and the median OS was 10.75 was 2.3 and the median OS was 6.2 months (72). months. No correlation was found in this trial between EGFR expression and OS (64). A phase III clinical trial is mTOR inhibitors ongoing to evaluate the benefit of combining erlotinib with sorafenib compared with sorafenib plus placebo as a first- Rapamycin (sirolimus) is an mTOR kinase inhibitor with line therapy in patients with advanced HCC antiproliferative (by inhibiting tumour cell growth and (NCT00901901). The results of a phase II study combining proliferation) and anti-angiogenesis activities (by both bevacizumab and erlotinib were interesting, with a median direct effects on vascular cell proliferation and indirect time to progression of 9 months and a median OS of 15.65 effects on growth factor production). Rapamycin also months. Major side effects included fatigue (20%), hyper- inhibits VEGF secretion and signal transduction induced tension (15%) and gastrointestinal bleeding (12.5%) (65). by VEGF in endothelial cells ultimately altering tumour Patients included in this study had slightly less advanced growth by an anti-angiogenic mechanism. Even if the disease than the populations in other published phase II PI3K/AKT/mTOR pathway could be inhibited at various trials in this setting. Further studies are needed to confirm levels, the most promising target in this pathway is the potential synergistic activity of this combination. This mTOR. Rapamycin and its derivatives such as everolimus combination is being compared with sorafenib as a first- (RAD001, Novartis) yielded interesting antitumour ac- line therapy in a phase 2 study (NCT00881751) as well as a tivity in preclinical studies and xenograft models of HCC second-line therapy (NCT01180959). (73, 74). Two small pilot studies showed promising Gefitinib (ZD1839, AstraZeneca), another EGFR tyr- results on the efficacy of sirolimus in HCC patients with osine kinase inhibitor, was also evaluated in a two-stage a safe profile (75, 76). The efficacy of sirolimus was design, single-arm phase 2 study in patients with HCC evaluated in a single-arm study in 21 advanced HCC (66). Thirty-one patients were recruited in the first stage. patients (75). Sirolimus induced a partial response and Gefitinib induced an objective response of 3% and tumour stabilization for at least 3 months in 5 and 24% disease stabilization of 22.6%. The median PFS was 2.8 of patients respectively. The median OS was 6.5 months. months and the median OS was 6.5 months. Because the No major sirolimus-related side effects were observed in criterion for the second stage of the study was not met, this study (75). In the French pilot study, 14 patients the authors hypothesized that gefitinib was not active as a were treated with 30 mg oral sirolimus once a week (76). single agent in patients with advanced HCC (66). A complete or a partial response according to the These results could be explained by the possible cross- RECIST criteria was observed in 7 and 33% of patients talk between insulin-like growth factor 1 receptor respectively. Sirolimus also seemed to be safe because no (IGF-1R) and EGF signalling pathways (67). Gefitinib grade 4 toxicity was observed and only two patients resistance may be associated with alternative activation of experienced grade 3 mucositis. Sirolimus did not affect the IGF-2/IGF-1R survival pathway. Substitution liver function (76). Several phase I and phase II studies Liver International (2011) c 2011 John Wiley Sons A/S 155
  • 6. Targeted therapies in HCC Faivre et al. are currently testing mTOR inhibitors as single agents about 30% of HCC and b-catenin mutations in around (NCT00390195 and NCT00516165), in combination 20% of cases (86). Although the clinical and therapeutic with sorafenib (NCT01008917) or with bevacizumab relevance of the Wnt-b-catenin pathway in HCC has not (NTC00775073). Based on the safety profile in patients been elucidated, drugs targeting this pathway are in with cirrhosis temsirolimus (CCI-779, Pfizer Inc.) is also the early stages of evaluation for HCC. Effective ther- being evaluated in a phase II study in CP class B patients apeutic inhibition of this pathway seems to be fairly with advanced HCC (NCT01079767). Everolimus is complex (87). being evaluated in patients with advanced HCC with progressive disease or as a second-line therapy in a phase Transforming growth factor-b inhibitors III study compared with placebo either following sorafe- nib or in patients who cannot tolerate sorafenib. Although TGF-b inhibits hepatocyte cell growth in the normal liver, HCC mainly occurs in injured livers including those with activated TGF-b signalling (88, MEK/ERK inhibitors 89). Previous studies have shown that the disruption of The Raf/MEK/ERK pathway appears to be one of the TGF-b signalling in mice through dominant-negative most significant cellular signalling sequences in the transforming growth factor receptor 2 accelerates chemi- development and maintenance of HCC (77). AZD6244 cally induced hepatocarcinogenesis (90). In preclinical (ARRY-142886, AstraZeneca) is an oral, new MEK in- models, treatment with TGF-b induced senescence in hibitor. This compound combined with rapamycin had well-differentiated HCC cell lines with preliminary evi- been shown to have antitumour and anti-angiogenic dence for antitumour activity. This effect was associated effects in preclinical models of human HCC (78). with in vivo senescence-associated b-galactosidase activ- Furthermore, pharmacological inhibition of the MEK/ ity in tumour cells (91). Further investigations and ERK pathway by the MEK inhibitor AZD6244 enhanced clinical studies could clarify the role of TGF-b signalling the antitumour effect of sorafenib in both orthotopic and as a potential target for HCC. ectopic models of HCC (79). However, AZD6244 as a single agent did not show any clinical benefit. Indeed, Conclusion this compound was evaluated in 19 patients with ad- vanced HCC in a phase II study with a two-stage design Several novel anticancer agents are currently under and the results are disappointing because the median investigation for HCC. These drugs were investigated TTP was 8 weeks (80). This suggests that exclusive based on current knowledge on hepatocellular carcino- inhibition of the MAPK pathway is insufficient and genesis, and the results have been encouraging in pre- ineffective for HCC treatment (81). AZD6244 is under clinical evaluations. Although none of these agents have evaluation in HCC patients with moderate liver dysfunc- yet demonstrated significant clinical benefits, it is likely tion and normal liver function in a phase II study that based on current trials, patients will have access to (NCT00604721) and in association with sorafenib in an more therapeutic options in the next few years. Asian phase I/II study (NCT01029418). Acknowledgements Insulin growth factor 1 receptor inhibitors This work was funded in part by AAREC (Association Great interest has been shown in exploring IGFR inhibi- ` d’Aide a la Recherche et l’Enseignement en Cancerologie). tors in HCC. Deregulation of the IGF axis and its activation have been involved in hepatocarcinogenesis Conflicts of interest (82, 83). Around 30% of HCCs overexpress the IGF–1R. Preclinical studies suggest that inhibition of the IGF Sandrine Faivre is a consultant for Pfizer Inc. and Bayer. receptors suppresses HCC cell growth (69–84). Small Eric Raymond is a consultant for Pfizer Inc., Bayer molecules and monoclonal antibodies targeting IGF-1R and Novartis. Mohamed Bouattour has no conflicts to (such as the monoclonal antibody A12, cixutumumab declare. and AVE 1642) are under early clinical development. In a phase I study, we showed that AVE 1642 (Sanofi-Avantis, Notes: Information for this review was compiled by Paris, France) can be safely combined with active doses of searching PubMed and MEDLINE databases for articles sorafenib without interaction between their respective published until September 2010. Only articles published pharmacokinetics. Long-lasting stabilization was ob- in English were considered. The search terms used tained in most patients because the mean time to included ‘hepatocellular carcinoma’ in association with progression was 13.3 weeks (85). the search terms: ‘angiogenesis’, ‘VEGFR’, ‘PDGFR’, ‘su- nitinib’, ‘sorafenib’, ‘bevacizumab’, ‘thalidomide’, ‘mTOR inhibitors’, ‘rapamycin’, ‘rapalogues’, ‘oxaliplatin’, ‘doxor- Novel drugs targeting the Wnt-b-catenin pathway ubicin’, ‘PIAF’, ‘IGF1-R inhibitor’, ‘natural product’, ‘me- The Wnt-b-catenin pathway plays an important role in tastatic’, ‘clinical trial’, ‘antiangiogenic agents’, ‘brivanib’, HCC. Activation of the Wnt cascade had been shown in ‘targeted therapy’, ‘cytotoxic therapy’ ‘and’ ‘drug Liver International (2011) 156 c 2011 John Wiley Sons A/S
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