Liver International 2011

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Liver International 2011

  1. 1. Liver International ISSN 1478-3223Novel molecular therapies in hepatocellular carcinomaSandrine Faivre, Mohamed Bouattour and Eric Raymond ˆDepartment of Medical Oncology, Beaujon/Bichat University Hospital, Assistance Publique-Hopitaux de Paris, University INSERM U728, Paris 7, Clichy,FranceKeywords Abstractangiogenesis inhibitors – clinical trial – The approval of sorafenib as the standard of care (SOC) for advancedhepatocellular carcinoma – targeted therapies hepatocellular carcinoma (HCC) fostered interest to further evaluate several other targeted therapies and extend the positioning of sorafenib alone and inAbbreviations combination with other drugs and local therapies at earlier stages and in anHCC, hepatocellular carcinoma; PDGFR, adjuvant setting. This review highlights current research using targetedplatelet-derived growth factor receptor; SOC, therapies in HCC. Information for this review was compiled by searchingstandard of care; VEGF, vascular endothelial PubMed and MEDLINE databases for articles published until Septembergrowth factor. 2010. Several small molecules and humanized antibodies with anti-angiogenicCorrespondence and antiproliferative properties are currently being investigated in preclinicalEric Raymond, MD, PhD, Department of and/or clinical trials. Results are awaited from these clinical trials and offerMedical Oncology, Beaujon/Bichat University promise for extending the current treatment options in HCC. Currently ˆHospital, Assistance Publique-Hopitaux de Paris, published data suggest that substantial progress may be achieved in theUniversity INSERM U728, Paris 7 Diderot, 100 treatment of patients with HCC in the next 10 years. ´ ´boulevard du General Leclerc, 92110 Clichy,FranceTel: 133 1 40 87 56 14Fax: 133 1 40 87 54 87e-mail: eric.raymond@bjn.aphp.frReceived 10 November 2010Accepted 26 November 2010DOI:10.1111/j.1478-3231.2010.02395.xChemotherapy, including single agent doxorubicin, mul- Drug targets in hepatocellular carcinomatidrug regimens such as platinum–ifospahmide–adria-mycin–5FU and more recently platinum-based doublets The carcinogenesis of HCC is heterogeneous andsuch as GEMOX (gemcitabin and oxaliplatin) or FOL- complex (3). Several critical signalling pathways andFOX (5fluorouracil and oxaliplatin), has long been the molecular disturbances involved in the development ofmainstay 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 signallingbeen 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 beenan 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 tendencySorafenib 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 wasFurthermore, 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 agested that several key kinases may be targets for novel poor prognosis (8). Vascular endothelial growth factoranticancer 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 anemerging 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. 2. Targeted therapies in HCC Faivre et al.Research has primarily targeted pro-angiogenic growth advanced disease and in whom hepatitis B infection wasfactors such as VEGF (using bevacizumab) or membrane the prevalent cause of cirrhosis. The median OS was 6.5tyrosine kinase receptors such as vascular endothelial months in the sorafenib group versus 4.2 months in thegrowth 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 wassuch as platelet-derived growth factor receptor (PDGFR) generally good. The most common grade 3 drug-relatedand 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, includingangiogenesis, making them attractive candidates for diarrhoea and hand–foot skin reaction, occurred intargeted 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 armsexpressed in 40–70% of HCC, and proliferation was (20). Based on these data, the United States (US) Foodshown to be dependent on stimulation of EGFR by and Drug Administration (FDA), European Medicinetransforming growth factor (TGF)-a or EGF in several Agency (EMA) and other regulatory authorities in theHCC cells (13). Thus, targeting EGFR is a logical option world approved sorafenib for advanced HCC.for the treatment of HCC. The results of preclinicalmodels of therapeutic approaches using neutralizing Anti-angiogenic agents in clinical developmentantibodies 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 discoverymalian target of the rapamycin (mTOR) pathway was programme designed to identify more potent VEGFRsshown 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 renalreceptors, 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 IIIHCC, the activation of the PI3K/Akt/mTOR pathway is trial, this compound was shown to exert a significantassociated with a poor prognosis (17). This pathway can clinical benefit on progression-free survival (PFS) andbe targeted at various levels but at present, mTOR safety in patients with advanced pancreatic endocrineinhibitors such as rapamycin or its analogues (ever- tumours, another hypervascularized tumour (24). Inolimus 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 proliferationSorafenib: a validated proof of concept for (25). The results of three previous independent phase IItargeted therapy studies on the efficacy and tolerance of sunitinib inSorafenib (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 wastargeting the intracellular serine/threonine Raf kinase, obtained despite the marked antitumour activity becausethe VEGFR-2 and -3, PDGFR-b, Fms-like tyrosine kinase 35% of patients treated with 50 mg/day sunitinib3 (Flt-3). In HCC cell lines and xenograft models, (4 weeks on/2 weeks off) achieved stable disease for oversorafenib 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 becauseto improve the OS in patients with advanced HCC in two stable disease was reported in 50% of patients (27). Thelarge 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 awere performed based on promising results from a phase continuous daily dose of sunitinib of 37.5 mg showed aII study (22). In the western trial, the benefit of sorafenib PFS at 12 weeks in 33% of patients. The median OS wasin the European-American population was the result of 9.3 months (28). A multinational, phase III studyan increase in the median OS from 7.9 months in the (NCT00699374) comparing sunitinib with sorafenib inplacebo 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 seriousextended the OS by 44%, and decreased the relative risk adverse events in the sunitinib arm than the sorafenibof death by 31% (20). The same increase in survival was arm, and because sunitinib did not meet the primaryconfirmed 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. 3. Faivre et al. Targeted therapies in HCCtrial will soon be available. The dosing and schedules of OS of 10.4 months. The benefit appears to be limited insunitinib seem to be complex in patients with HCC (29). patients with CP class B because the median TTP was 3.7Frequent underlying liver disease generate a narrow months and the median OS was 2.5 months (37). Basedtherapeutic index and the routine daily dose of 50 mg on these encouraging results, the efficacy and tolerance ofused in other tumour types does not seem to be suitable a daily dose of 17.5 mg linifanib is now being comparedin 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 andYork, 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 potentkinases. 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 preclinicalIn 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 otherblood microvessel density as well as increased apoptosis agents because the antitumour activity of axitinib wasand a reduction in microvessel density (31). Similar reported in patients with metastatic RCC in whomresults 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 trialease. Assessment of angiogenesis by dynamic contrast- evaluating axitinib as a second-line agent in advancedenhanced 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-VEGFRtherapy was evaluated in a phase II open-label study in inhibitor that blocks PDGFR and c-Kit, has been shownpatients with advanced HCC. Interim efficacy and safety to have antitumour activity in a broad range of humanresults were reported at ASCO 2009 (33) and updated at tumour xenograft models. Oral daily doses of 45 mg orILCA 2009 (34). The median OS was 10 months in the less of AZD2171 were generally well tolerated andfirst-line treated group and 9.8 months in the second-line associated with encouraging antitumour activity in atreated group (including prior treatment with sorafenib). wide variety of advanced solid tumours (40). AZD2171Major grade Z3 toxicities were fatigue (16%), hypona- has been tested in a two-stage phase II study in patientstraemia (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 toxicitiescurrently being evaluated in phase II trials in patients including fatigue, hypertension and anorexia (41). Poorwith advanced HCC as a first-line treatment compared tolerance to this agent could be due in part to underlyingwith sorafenib (NCT00858871) as a second-line therapy cirrhosis because liver metabolism could be impaired bycompared with placebo (NCT00825955) and also com- liver dysfunction. Thus, another phase II study waspared with placebo as an adjuvant therapy to transarter- planned with a reduced dose of AZD2171. However, thisial 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 inhibitorreceptor tyrosine kinase inhibitor that targets VEGF and of VEGFR-2, PDGFR and FGFR. This compound hasPDGF receptor families. In a phase I study, linifanib was been assessed in 35 Japanese patients with CP classes A/Bfound to be well tolerated at doses 0.25 mg/kg daily. HCC in a coupled phase I/II study (42). Two hundredAfter 17 months in the cohort of 33 patients with HCC, milligrams of STU-68 was administered twice a day. Inprolonged stable disease was achieved in two patients this study, 11.4% of patients experienced grade 3/4with HCC. Dynamic radiological assessment showed adverse events including elevated AST/ALT levels andreduced vascular permeability of the tumour and vascu- thrombocytopenia. An objective response was observedlarity correlated to drug exposure (35). Recently, interim in 9.6% of patients (complete response: 2.9% and partialresults of an open-label multicentre phase II trial of ABT- response: 5.7%). Stable disease was achieved in 42.8% of869 in patients with advanced HCC were reported (34). patients. The median PFS was 2.1 months compared withABT-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 kinasecohort, and an objective response was achieved in 8.7% inhibitor that targets VEGFRs, PDGFR and c-Kit. Thisof CP class A patients but in none of the CP class B compound recently obtained US FDA approval for thepatients. The median TTP was 112 days and the median treatment of advanced renal cell carcinoma. PazopanibOS was 295 days. The most common grade Z3 toxicities was evaluated in a phase I study in patients withwere hypertension (20.6%) and fatigue (11.8%). Up- advanced HCC (43). The maximum tolerated dosedated results showed a clinical benefit in CP class A was established as 600 mg twice a day. The main gradepatients with a median TTP of 5.4 months and a median 3/4-related side effects were diarrhoea (4%) andLiver International (2011)c 2011 John Wiley Sons A/S 153
  4. 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, breastfor further clinical development in HCC. cancer and metastatic renal cell carcinoma. In preclinical Vandetanib (ZD6474, AstraZeneca, Wilmington, models of HCC, bevacizumab induced a significantUSA) – 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 wasand under experimental conditions, ZD6474 was shown evaluated as a single agent for the treatment of advancedto inhibit HCC cell proliferation adhesion, migration HCC in two phase II trials. In the first study in 46and invasion (44). ZD6474 is currently being evaluated patients with locally advanced HCC, partial responsesin 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 yearsand Bayer Schering Pharma) – PTK787 is an orally active, was 53, 28 and 23% respectively. Comparable results wereselective inhibitor of all VEGFR tyrosine kinases. At reported in the interim results of a French study, becausehigher concentrations, this compound also inhibits other partial response and stable disease for at least 16 weekstyrosine 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 thattion. 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 promisinggests that this compound might be interesting in combi- results, it should be noted that patients with a CLIP scorenation 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 spreaddaily 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 obtaineddevelopment 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 resultsfield, 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, whichthat 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 inpotential advantage to broaden its activity over other the French study (55). Other serious side effects includedVEGFR 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 agentsevaluate the safety and the efficacy for advanced HCC in was also evaluated in phase II studies and was shown to beEuropean 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 patientsSan Francisco, USA) – foretinib is an orally bioavailable enrolled showed an objective response. The median OS wasselective inhibitor of c-Met and VEGFR-2 tyrosine ki- 9.6 months (57). Adding bevacizumab did not markedlynases. Targeting the c-Met pathway could be a potential improve the clinical benefit because results with GEMOXtherapy in HCC because dysregulation of c-MET as well alone were similar in a phase II study, with a response rateas 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). Theexact role of this pathway in the pathogenesis of HCC has Anti-epidermal growth factor receptor undernot been clearly elucidated. Blocking the HGF/c-MET clinical developmentpathway during the orthotopic transplant of HCC mod-els induced growth suppression and a decrease in angio- Cetuximab (C225, ImClone Systems, New York, USAgenesis (50). Foretinib was found to be potentially active and Merck Serono, Darmstadt, Germany), a chimericin preclinical HCC models with inhibition of tumour monoclonal antibody directed against EGFR, is alreadyangiogenesis, 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 wasways 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 observedadvanced 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 1.4and Roche, Basel, Switzerland), a recombinant, huma- months (61). In the second open-label study, stablenized 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. 5. Faivre et al. Targeted therapies in HCCcases and the median PFS was 1.8 months (62). The pathways could be developed by the tumour to bypassresults 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 blockersbeing tested in clinical trials (NCT00142428), especially and enhance the antitumour activity of the respectivein 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 2potent 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 hasproved for the treatment of metastatic or locally advanced also been evaluated in advanced HCC. Twenty-six patientsnon-small-cell lung cancer and pancreatic cancer. The with advanced HCC were treated with daily lapatinibsafety and efficacy of erlotinib as a single agent in Child- orally at a dose of 1500 mg in a phase II study (71). NoPugh class A and B patients with advanced HCC were objective responses were obtained. Approximately 40% ofreported in two phase II clinical studies. The first report patients achieved their best response. The median PFS andshowed that 32% of patients were progression-free at 6 OS were 1.9 and 12.6 months respectively. Only threemonths, 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 withpatients (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 patientssecond study, erlotinib was evaluated in 40 patients with CP with advanced HCC was treated with lapatinib. Moderateclass A or B cirrhosis and advanced HCC. There was no antitumoral activity was observed because an objectivepartial or complete response to erlotinib. However, the PFS response was observed in 5% of patients. The median PFSat 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 betweenEGFR expression and OS (64). A phase III clinical trial is mTOR inhibitorsongoing to evaluate the benefit of combining erlotinib withsorafenib compared with sorafenib plus placebo as a first- Rapamycin (sirolimus) is an mTOR kinase inhibitor withline 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 bothbevacizumab and erlotinib were interesting, with a median direct effects on vascular cell proliferation and indirecttime to progression of 9 months and a median OS of 15.65 effects on growth factor production). Rapamycin alsomonths. Major side effects included fatigue (20%), hyper- inhibits VEGF secretion and signal transduction inducedtension (15%) and gastrointestinal bleeding (12.5%) (65). by VEGF in endothelial cells ultimately altering tumourPatients included in this study had slightly less advanced growth by an anti-angiogenic mechanism. Even if thedisease than the populations in other published phase II PI3K/AKT/mTOR pathway could be inhibited at varioustrials in this setting. Further studies are needed to confirm levels, the most promising target in this pathway isthe potential synergistic activity of this combination. This mTOR. Rapamycin and its derivatives such as everolimuscombination 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 HCCsecond-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 withosine kinase inhibitor, was also evaluated in a two-stage a safe profile (75, 76). The efficacy of sirolimus wasdesign, 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 andGefitinib 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 incriterion for the second stage of the study was not met, this study (75). In the French pilot study, 14 patientsthe 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 theThese results could be explained by the possible cross- RECIST criteria was observed in 7 and 33% of patientstalk 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 patientsresistance may be associated with alternative activation of experienced grade 3 mucositis. Sirolimus did not affectthe IGF-2/IGF-1R survival pathway. Substitution liver function (76). Several phase I and phase II studiesLiver International (2011)c 2011 John Wiley Sons A/S 155
  6. 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 therapeuticwith 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 inwith 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 fairlywith advanced HCC (NCT01079767). Everolimus is complex (87).being evaluated in patients with advanced HCC withprogressive disease or as a second-line therapy in a phase Transforming growth factor-b inhibitorsIII 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 ofThe Raf/MEK/ERK pathway appears to be one of the TGF-b signalling in mice through dominant-negativemost 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 inhibitor. 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 associatedeffects 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 andERK pathway by the MEK inhibitor AZD6244 enhanced clinical studies could clarify the role of TGF-b signallingthe antitumour effect of sorafenib in both orthotopic and as a potential target for HCC.ectopic models of HCC (79). However, AZD6244 as asingle agent did not show any clinical benefit. Indeed, Conclusionthis 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 underand the results are disappointing because the median investigation for HCC. These drugs were investigatedTTP 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 haveevaluation in HCC patients with moderate liver dysfunc- yet demonstrated significant clinical benefits, it is likelytion 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). AcknowledgementsInsulin growth factor 1 receptor inhibitors This work was funded in part by AAREC (AssociationGreat 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 itsactivation 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., Bayermolecules 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 aphase I study, we showed that AVE 1642 (Sanofi-Avantis, Notes: Information for this review was compiled byParis, France) can be safely combined with active doses of searching PubMed and MEDLINE databases for articlessorafenib without interaction between their respective published until September 2010. Only articles publishedpharmacokinetics. Long-lasting stabilization was ob- in English were considered. The search terms usedtained in most patients because the mean time to included ‘hepatocellular carcinoma’ in association withprogression 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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