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1、Authors Accepted ManuscriptBiomarker-Driven and Molecular Targeted Therapiesfor Hepatobiliary CancersWilliam P.Harris,Kit Man Wong,Supriya Saha,Imane El Dika,Ghassan K.Abou-AlfaPII:S0093-7754(17)30127-6DOI:https:/doi.org/10.1053/j.seminoncol.2018.03.002Reference:YSONC52043To appear in:Seminars in On

2、cologyCite this article as:William P.Harris,Kit Man Wong,Supriya Saha,Imane ElDika and Ghassan K.Abou-Alfa,Biomarker-Driven and Molecular TargetedTherapies for Hepatobiliary Cancers,Seminars inOncology,doi:10.1053/j.seminoncol.2018.03.002This is a PDF file of an unedited manuscript that has been acc

3、epted forpublication.As a service to our customers we are providing this early versionof the manuscript.The manuscript will undergo copyediting,typesetting,andreview of the resulting galley proof before it is published in its final citableform.Please note that during the production process errors ma

4、y be discoveredwhich could affect the content,and all legal disclaimers that apply to thejournal and Molecular Targeted Therapies for Hepatobiliary Cancers Authors and Affiliations First Author:William P.Harris,M.D.University of Washington,Department of Medicine,Division of Medical Oncology Fred Hut

5、chinson Cancer Research Center,Clinical Research Division Second Author:Kit Man Wong,M.D.University of Washington,Department of Medicine,Division of Medical Oncology Fred Hutchinson Cancer Research Center,Clinical Research Division Third Author:Supriya Saha,M.D.,PhD University of Washington,Departme

6、nt of Medicine,Division of Medical Oncology Fred Hutchinson Cancer Research Center,Human Biology Division Fourth Author:Imane El Dika,M.D.Memorial Sloan Kettering Cancer Center,Department of Medicine Last Author/Corresponding Author:Ghassan K.Abou-Alfa,M.D.,MBA Memorial Sloan Kettering Cancer Center

7、,Department of Medicine Corresponding author address:300 East 66th St.,New York,NY,10065 Telephone:(646)888-4184 Email:abou-algmskcc.org Dr.Harris reports grants from Halozyme,Eisai,Arqule,BMS,Agio,other from Bayer,Eisai outside the submitted work.Dr.Abou-Alfa reports grants from Agios,Array,Astra Z

8、eneca,Bayer,BMS,Casi,Celgene,Exelixis,Genentech,Incyte,Lilly,Mabvax,Medimmune,Momenta,OncoMed Pharmaceuticals,Roche,other from Agios,Amgen,Aptus,Aslan,Astellas,Astra Zeneca,Bayer,BMS,Boston Scientifc,Carsgen,Celgene,Casi,CytomX,Daiichi,Debio,Delcath,Gilead,Halozyme,Inovio,Ipsen,Merck,Medimmune,Onxeo

9、,PCI Biotech,Roche,Sanofi,Servier,Silenseed,Sillajen,Sirtex,Yakult during the conduct of the study.Drs.Wong,Saha and El Dika have nothing to disclose.Abstract:The recent accumulation of molecular profiling data for primary hepatobiliary malignancies including hepatocellular carcinoma and biliary tra

10、ct cancers has led to a proliferation of promising therapeutic investigations in recent years.Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results.Key molecular alterations in common hepatobiliary cancers and ongoing inte

11、rventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.Keywords:hepatobiliary,hepatocellular carcinoma,HCC,biliary tract cancer,cholangiocarcinoma,intrahepatic cholangiocarcinoma,ICC,immuno-oncology,immunotherapy,

12、targeted therapeutics,clinical trials,molecular therapy,liver cancer,systemic therapy.Introduction Hepatocellular carcinoma(HCC)and biliary tract cancers(BTC)represent the first and second most common hepatobiliary tumors.To date,development of successful systemic therapeutics has been hampered by a

13、n incomplete understanding of tumor biology and by comorbidities associated with a patient population typically affected by underlying hepatic dysfunction,symptoms secondary to presentation at a late clinical stage,or both.Recent efforts focused on deciphering the molecular alterations for each dise

14、ase can increasingly be leveraged for patient benefit,especially in the context of a rapidly expanding armamentarium of molecularly targeted therapeutics.Recent and ongoing efforts to identify targeted therapeutics for HCC and BTC,with a focus on the rapidly developing treatment of intrahepatic chol

15、angiocarcinoma(ICC),are reviewed here.Targeted therapy in hepatocellular carcinoma Current systemic therapy in advanced hepatocellular carcinoma HCC is the second-leading cause of global cancer-related mortality with rising incidence in the United States population.1,2 Despite current therapeutic op

16、tions,patients in the United States with locally advanced or metastatic disease achieve 5-year survival rates of 11%and 3%from time of presentation,respectively.2 Standard cytotoxic chemotherapy has failed to demonstrate significant benefit in advanced disease,while clinical benefits were shown in t

17、he positive randomized phase 3 trials of the multi-tyrosine kinase inhibitors(TKIs)sorafenib and lenvatinib in the first-line setting and regorafenib as second-line therapy.3-5 Ongoing barriers to optimization of systemic therapeutics in HCC include the lack of validated predictive biomarkers for ex

18、isting agents and the requirement to account for the competing risk of underlying hepatic dysfunction in this patient population.An increased understanding of the molecular alterations associated with hepatocarcinogenesis and tumor progression,in conjunction with the development of targeted therapeu

19、tics and well-designed clinical trials,holds promise in advancing the field of systemic therapeutic intervention in HCC.Molecular characteristics of hepatocellular carcinoma HCC is increasingly recognized as demonstrating significant genetic heterogeneity and complexity.Multiple genomic profiling st

20、udies have shown that distinct molecular pathways are implicated in its pathogenesis and progression,and are associated with different etiologies.6-8 It is estimated that up to 28%of identified mutations from exome sequencing of HCC could be potentially targetable with currently available targeted a

21、gents.6 Several prior genome-wide association studies and a recent multi-platform integrative analysis by the Cancer Genome Atlas Research Network have documented critical insights into the molecular characteristics of HCC9.Common somatic mutations include TERT promoter mutations(often an early mole

22、cular event present in up to 60%of cases),and high rates of recurrent somatic mutations in chromatin-remodeling factors including ARID1A,ARID2 and BAP(25-60%),alterations in the WNT pathway including CTNNB1 oncogenic mutations(25-40%)or related inactivation of AXIN1 and APC,and finally TP53 inactiva

23、ting mutations(25-40%).8-13 Somatic copy number alterations of relevance include recurrent focal amplifications of chromosome 11q(including oncogenes CCND1 and FGF19),7q(MET),and 6p(VEGFA)among others9.A small cluster of samples with extensive hypermethylation was identified,associated with IDH1 or

24、IDH2 mutations,suggesting a potential molecular shift toward a biliary phenotype.Moreover,overexpression has been documented to occur in EGFR,TOPO1,PD-1,TOP2A,SPARC and c-MET(25-83%).14 Finally,gene expression cluster analysis suggests that 44%of all tumors demonstrated dysregulated WNT axis signali

25、ng,and that generally mutations within the receptor tyrosine kinase/RAS/PI3K pathway were implicated in tumor progression although specific mutations did not occur at high frequency.9 Additional observations include that tumors harboring CTNNB1 mutations more likely overexpressed PD-L1 in one study(

26、29%vs 0%,p=0.026)and TP53 mutations were more frequently associated with HBV-related HCC.6,15 VEGF-targeted multikinase inhibitors for advanced HCC Sorafenib showed an improvement in overall survival(OS)versus placebo in patients with advanced HCC.This TKI targets RAF,VEGFR1-2,and PDGFR among multip

27、le other targets and exerts its effects by inhibiting cellular proliferation,increasing apoptosis,and inhibiting neoangiogenesis.16 Two independent randomized Phase 3 trials have documented the OS advantage of sorafenib 400 mg twice daily in comparison to placebo in patients with Child-Pugh A hepati

28、c function and advanced HCC.3,17 While RECIST response rates were only 2%,patients experienced a median OS benefit of 2.8 months in the Western populations,and 2.3 months in Asian populations.Subgroup analyses suggested that patients with underlying hepatitis C infection may derive more benefit from

29、 sorafenib in comparison to those with hepatitis B or no viral etiology of cirrhosis.18 This observation may be explained by differences in the somatic mutational composition of tumors depending upon the etiology of cirrhosis,or by direct activity of sorafenib on cellular RAF,a factor known to be up

30、regulated by hepatitis C infection.19 While effective in advanced disease,sorafenib failed to improve outcomes when administered after surgical resection or radiofrequency ablation(RFA)in the adjuvant setting,leaving adjuvant therapy as a highly unmet need.20 Lenvatinib targets VEGFR1-3,FGFR1-4,PDGF

31、R,RET,and cKIT.5,21 This TKI was compared to sorafenib in the first-line treatment setting in a randomized non-inferiority Phase 3 trial.Median OS was non-inferior but not superior to sorafenib therapy(13.6 vs.12.3 months).There was a significant improvement in secondary endpoints including progress

32、ion-free survival(PFS,7.4 vs.3.7 months),time to progression,and response rate as assessed by mRECIST criteria(24.1%vs.9.2%).To date,no prospectively validated biomarker can guide selection of sorafenib versus lenvatinib,and selection of first-line therapy may ultimately be determined by other facto

33、rs,including genetic,that are yet to be discovered.Of interest,a subset analysis suggested benefit favoring lenvatinib in patients with elevated baseline AFP levels,a generally poorer prognostic subgroup.Further studies to elucidate clinical factors or biomarkers that might influence selection of fi

34、rst-line TKI therapy will be required.Regorafenib binds to several targets,including VEGFR1-3,TIE2,c-KIT,RET,BRAF,PDGFR,and FGFR,exerting its effects on angiogenesis,cell proliferation,metastasis,and tumor immunity.22,23 Regorafenib was recently proven to confer an OS advantage of 2.8 months(10.6 vs

35、.7.8 months)in patients who received prior sorafenib,in comparison to placebo.4 Specifically,patients who tolerated sorafenib at least 400 mg daily for at least 20 of the last 28 days prior to discontinuation for disease progression and with Child-Pugh class A hepatic function were included in this

36、study,potentially selecting for a population who might better tolerate the agent.Based upon these findings,regorafenib represents the first FDA-approved agent for the second-line treatment of advanced HCC.The extended spectrum of activity against VEGFR1,RET,TIE2 and FGFR pathway signaling is one pot

37、ential explanation for the efficacy of regorafenib in sorafenib-refractory disease.22 cMET inhibitors The cMET pathway has been shown to be important in the pathogenesis of HCC.Hepatocyte growth factor(HGF)is secreted by stromal cells and binds to the cell surface receptor cMET,which normally plays

38、a role in hepatocyte survival and regeneration after acute injury by activating pathways such as the PI3K/AKT and MAPK pathways.24,25 In HCC,HGF-cMET signaling leads to tumor invasion and metastasis.26-28 Moreover,it has effects on angiogenesis and interacts with the VEGFR pathway.Hypoxia upregulate

39、s HIF,which increases HGF and cMET expression in tumor and stromal cells;increased cMET signaling induces VEGF secretion from tumor cells and expression of VEGFR2 on endothelial cells.29,30 Relative overexpression of cMET and HGF occurs in 20-48%and 33%of untreated HCC,respectively,although up to 60

40、%of patients may convert from low to high cMET expression after sorafenib exposure in advanced disease based upon immunohistochemical analysis(IHC).31,32 The expression of intratumoral cMET is associated with recurrence after hepatectomy and poorer prognosis.33,34 High circulating levels of cMET and

41、 HGF predict shorter OS.35 Moreover,preclinical and clinical data have demonstrated that cMET inhibition is a promising therapeutic strategy in HCC.31 Tivantinib,a cMET-selective oral TKI,was recently evaluated in the first biomarker-driven randomized phase 3 trial in advanced HCC,restricted to pati

42、ents with overexpression of cMET by IHC as defined by at least 2+staining in 50%of cells,in the second-line setting.The recently reported phase III study demonstrated no benefit in OS or PFS when compared with best supportive care.32,36 Tivantinib binds to the inactive form of cMET preventing activa

43、tion,but reports suggest an additional cMET-independent mechanism of microtubule disruption may play a role in its mechanism of action,thus limiting interpretation of this trial in the context of overall benefit of cMET inhibition in HCC.37 Cabozantinib,a TKI targeting cMET with additional activity

44、against cKIT,RET,VEGFR1-3,FLT3,AXL and TIE1,is being evaluated in a randomized placebo controlled phase 3 trial for patients in the second or third line setting based upon promising initial results from a phase 2 randomized discontinuation study.38,39 The Phase 2 study was designed irrespective of t

45、he level cMET expression of patients,as so far,there is no evidence of how much cMET expression may be needed.In this small patient population of patients with refractory disease,the median PFS and OS were 5.2 and 11.5 months,respectively.This trial will assess the role of combination cMET/VEGF inhi

46、bition in HCC,and will provide insight into the biologically relevant level of cMET expression through retrospective analyses.Additional cMET inhibitors including foretinib and tepotinib are currently being investigated in advanced HCC40.Of note,preclinical studies have suggested potential benefit o

47、f cMET inhibition in the adjuvant setting after resection of tumors with macroscopic vascular invasion in animal models.41 Additional preclinical studies suggest that inhibition of Focal Adhesion Kinase may supress cMET and B-catenin(CAT)driven hepatocarcinogenesis and delay progression in animal mo

48、dels in cMET/CAT driven tumors.42 Targeting of fibroblast growth factor receptor(FGFR)in HCC Inhibition of the Fibroblast Growth Factor Receptor(FGFR)represents a promising area of investigation.A subset of HCC demonstrates focal amplification of chromosome 11q13.3 including three genes:FGF19,CCND1

49、and ORAOV1.Such amplifications are associated with poorer prognosis,increased tumor size,and advanced stage.43 Preclinical models suggest that FGF19 binds to its receptor FGFR4 and drives hepatocyte proliferation,hepatocarcinogenesis,epithelial-mesenchymal transition,increased expression of prolifer

50、ative markers,and induces a shift to autocrine signaling in preclinical models.43-45 Activation of the FGF19/FGFR4 pathway also inhibits sorafenib-mediated apoptosis,suggesting a potential mechanism of resistance.43 Animal models driven by the FGF19/FGFR4 axis appear responsive to FGFR4 inhibition.T