GIST靶向治療進(jìn)展

胃腸間質(zhì)瘤(GIST)概述北京腫瘤醫(yī)院消化腫瘤內(nèi)科齊長松2013-10-17胃腸道(GI)最常見的間葉源性瘤間葉源（結(jié)締組織）性腫瘤占所有胃腸道腫瘤的1-2%高發(fā)年齡為50-60歲男、女發(fā)病率相當(dāng)，但有些報道提示男性發(fā)病率略高，兒童少見最近GIST被確認(rèn)為具有獨立臨床和組織病理學(xué)特征的腫瘤以往曾誤診為平滑肌肉瘤/其他梭形細(xì)胞癌GIST的年發(fā)病率為10-20/100萬CancerFacts&Figures.2003.Fletcheretal.HumPathol.2002;33:459.Miettinenetal.PolJPathol.2003;54:3.Joensuuetal.LancetOncol.2002;3:655.

Kindblometal.AnnOncol.2002;13:157.Abstract577O.Kindblom.At:.GIST的形態(tài)學(xué)特征梭形細(xì)胞型(60%-80%)上皮樣細(xì)胞型(10%-30%）混合細(xì)胞型(少見)形態(tài)學(xué)特征（圖示）上皮樣細(xì)胞型梭形細(xì)胞型GIST的免疫組化分析DOG1：＞95%(~100%).CD117(KIT)：＞95%(~100%).CD34：60%-70%.SMA：30%-40%.S-100：5%.Desmin：1%-2%.

GIST的診斷標(biāo)準(zhǔn)來源于消化道間葉組織形態(tài)學(xué)特征：梭形細(xì)胞型或上皮細(xì)胞型CD117(＋)

發(fā)病部位

食管5-10%胃40-60%小腸20-35%結(jié)直腸5-15%腸系膜10%臨床特征腹痛(20-50%)消化道出血(20-50%)消化道梗阻(10%)腹部腫物及其它常見轉(zhuǎn)移部位

肝臟: 54to65%腹膜: 20to21%淋巴結(jié): 2to6%骨: 6%肺: 2%abdomen-pelvic

GIST的傳統(tǒng)治療手術(shù)對于可根治性切除的GIST患者仍是首選治療

根治性切除術(shù)后5年生存率:35～65%

中位復(fù)發(fā)時間：7ms～2yr；二次手術(shù)后復(fù)發(fā)率:接近100%

由于極少出現(xiàn)區(qū)域淋巴結(jié)轉(zhuǎn)移，故不推薦區(qū)域淋巴結(jié)清掃放療、化療:

有效率<7%術(shù)前活檢：對于大多數(shù)可完整切除的GIST，手術(shù)前不推薦常規(guī)活檢或穿刺；

？GIST：惡性潛能的評估（NIH）不同惡性潛能的GIST總生存期比較RiskGroups00.10.20.30.40.50.60.70.80.91.0Estimatedproportionsurviving01234567891011121314151617YearssincediagnosisIntermediateHighVerylowLowGIST姑息治療

甲磺酸伊馬替尼（Glivec、Gleevec、STI571

）小分子選擇性酪氨酸激酶抑制劑Bcr-Abl、PDGFR和KIT伊馬替尼在GIST治療中的應(yīng)用2000.3.首例患者使用（芬蘭）2000.7.phaseⅡtrial(B2222)2001.Aug.phaseⅢtrials(S0033,EORTC)2002.2.FDA、CPMP2002.3.ChinaPhaseIclinictrial(EORTC)36例：

PR19case（53％）

MR6case（17％）

SD7case（19％）

PD4case（11％）

RD：400mgQd

DLT－－－500mgBidVanOosteromAT,etal.ProcAmSocClin

Oncol,2001,20:1a(abstract2)

phaseIIstudy(B2222)C.D.Blanke,etal.2006ASCOPartI.Vol24,No.18S(June20Supplement),2006:9528B2222:ResponseRateC.D.Blanke,etal.2006ASCOPartI.Vol24,No.18S(June20Supplement),2006:9528B2222TimetoResponse(到達(dá)反應(yīng)的時間)C.D.Blanke,etal.2006ASCOPartI.Vol24,No.18S(June20Supplement),2006:9528B2222:OSC.D.Blanke,etal.2006ASCOPartI.Vol24,No.18S(June20Supplement),2006:9528OSbybestresponseC.D.Blanke,etal.2006ASCOPartI.Vol24,No.18S(June20Supplement),2006:9528Safety:mostcommonGrade?AdverseEvents**

研究證實格列衛(wèi)治療進(jìn)展期GIST出現(xiàn)的副作用較少伊馬替尼耐藥以及治療策略GIST耐藥機制Imatinib治療開始后6月內(nèi)未能達(dá)到疾病穩(wěn)定發(fā)生率10%-26%與無KIT/PDGFRA突變或含PDGFRAD842V突變有關(guān)

起初治療有效或疾病穩(wěn)定之后發(fā)生的疾病進(jìn)展中位進(jìn)展時間20～24個月與KIT/PDGFRA繼發(fā)突變、基因擴增、新的酪氨酸激酶活化等因素有關(guān)

原發(fā)耐藥繼發(fā)耐藥1.TrentJC,etal.Curr

Opin

Oncol2006,18:386-95

2.HohenbergerP,etal.2006ASCOPartI2006,24(18S):9500.3.AgaramNP,etal.ClinCancerRes2007,13(1),170-181VEGFR-1

VEGFR-2

FLT4

FmsSplitKinaseDomainRTKs舒尼替尼(索坦):多靶點酪氨酸激酶抑制劑IC50(mM)[1]VEGFR2: 4PDGFRβ: 39KIT: 1FLT3(WT): 8EGFR: >10,000ChowLQ,etal.JClinOncol.2007;25:884-896.PDGFR-a

PDGFR-b

CSF1R

KIT

FLT3有效抑制VEGFR,PDGFR,KIT和FLT3抑制靶點腫瘤增殖和血管生成GIST,腎細(xì)胞癌等新生血管形成

蘋果酸舒尼替尼（sunitinib）

－藥物結(jié)構(gòu)&作用機制外膜細(xì)胞血管內(nèi)皮細(xì)胞腫瘤細(xì)胞抗增殖效應(yīng)抑制腫瘤生長，周細(xì)胞增殖，內(nèi)皮細(xì)胞增殖Sunitinib

inimatinib-resistantGISTinhibitoroftyrosinekinase,multi-target：

KIT，PDGFR,VEGFR，F(xiàn)LT397cases,imatinibresistant：

PR8%，SD37%,SD>6m,mTTP7.9m,mOS19.8mSideeffect:fatigue,diarrhea,nauseaMutationsmOSKITexon9mutation31mKITexon11mutation5mDemetrietal：ASCO2004Abstr3001Makietal:ASCOAbstr9001(sunitinib:

placebo)Placebo(n=105)SunitinibPhaseIIITrialinImatinib-resistantor-intolerantGISTSunitinib(n=207)50mg/d,4weekson,2weeksoffSunitinibImatinib-refractoryor

-intolerantGIST

patientsConductedat56sitesinEurope,USA,AustraliaandAsia(Singapore)Randomisation2:1Placebo4weekson,2weeksoffCrossoverto

sunitinibat

progressionContinueaslongasclinical

benefitSunitinibTreatmentSignificantly

IncreasedControlofDisease(TTP)Sunitinib(N=207)

Placebo(N=105)Median

27.3weeks

6.4weeksHazardratio=0.3395%CI(0.23,0.47)

P<0.00001061218243036424854Time(weeks)0102030405060708090100EstimatedTTPprobability(%)SunitinibTreatmentSignificantly

ImprovedOverallSurvivalSunitinib(N=207)

Placebo(N=105)Hazardratio=0.4995%CI(0.29,0.83)

P=0.007

Sunitinib

Placebo6-monthsurvival 79.4% 56.9%Totaldeaths 14.0% 25.7%061218243036424854Time(weeks)0102030405060708090100Estimatedsurvivalprobability(%)SunitinibisReasonablyWellTolerated:

MostCommonTreatment-relatedAEs*Incidence(%)Sunitinib(n=202)*Placebo(n=102)*AEGr1–2Gr3–4Gr1–2Gr3–4Fatigue295202Diarrhoea26380Skindiscolouration25060Nausea231101Anorexia19051Dysgeusia18020Stomatitis15120Vomiting15151*As-treatedpopulation;AE=adverseeventsoccurringin

10%ofpatients;

Gr=maximumNCICTCAEgradeSunitinibisReasonablyWellTolerated:

MostCommonTreatment-relatedAEs(cont’d)*Incidence(%)Sunitinib(n=202)*Placebo(n=102)*AEGr1–2Gr3–4Gr1–2Gr3–4Hand–footsyndrome9420Rash12150Anaemia7510Asthenia9322Mucosalinflammation12000Dyspepsia11110Hypertension7340*As-treatedpopulation;AE=adverseeventsoccurringin

10%ofpatients;

Gr=maximumNCICTCAEgradeSunitinibPhaseI/IIStudy

TTPbyOriginalMutationStatusKITexon9(N=19)KITWT(N=9)KITexon11(N=42)KIT(exon9orWT)vs.11:P≤0.01KITexon9vs.WT:NSTime(Months)EstimatedTTPprobability(%)1009080706050403020100 0 6 12 18 24 30Sunitinib

治療GIST多靶點抗腫瘤藥物作為GIST耐藥患者首選二線治療推薦給藥為：50mgQdd1-28，每6w為1周期

37.5mgQd

服藥至腫瘤進(jìn)展或不良反應(yīng)無法耐受對exon-9突變患者效果更佳GIST新輔助治療及輔助治療

ImatinibinadjuvanttreatmentACOSOGZ9000:PhaseII400mg/dⅹ1Y(T>10cm,rupture,multicenter)106cases,completedACOSOGZ9001PhaseIIIplacebo_400mg/dⅹ1Y(T≥3cm)672casesEORTC62024PhaseIIIplacebo_400mg/dⅹ2Y(intermediateandhighrisk)400casesSSG/AIOPhaseIII400mg/dⅹ1yvs3y(highandbeyondhighrisk)240casesChina：

PhaseII400mg/dⅹ1Y(intermediateandhighrisk)60cases,completedACOSOGZ9001:TrialSchema(PhaseIII)778patientsPlacebo(354randomised)(345treated)87discontinuedtreatmentearly

Imatinib(359randomised)(337treated)97discontinuedtreatmentearly

30events5GIST-unrelateddeaths713patientsrandomisedPhaseIII,randomised,double-blind,placebo-controlledmulti-centretrialIM400mg/dayorplacebofor1yr70events5GIST-relateddeaths3GIST-unrelateddeathsDeMatteoRPetal.Lancet.2009;373:1097-1104Medianfollow-up:19.7monthsEstimated1-yearRFS(95%CI):Imatinib:98%(96-100)Placebo:83%(78-88)HR=0.35(0.22-0.53)p<0.0001CI,confidenceinterval;HR,hazardratioEventsexperienced:Imatinib:8.0%(30)Placebo:20.0%(70)Recurrence-freeSurvival(RFS)**Allrandomisedpatientswereincludedintheanalysis;recurrence-freesurvivalwasdefinedasthetimefrompatientregistrationtothedevelopmentoftumourrecurrenceordeathfromanycause.Intention-to-treatanalysesweredoneforrecurrence-freesurvival(ie,analysedpatientsbyrandomisedgroup).

NodifferenceinOSbetweenimatinibandplaceboadjuvanttherapiesOverallSurvival(OS)**Allrandomisedpatientswereincludedintheanalysis;Overallsurvivalwasdefinedasthetimefrompatientregistrationtodeathfromanycause.Intention-to-treatanalysesweredoneforoverallsurvival(ie,analysedpatientsbyrandomisedgroup).Imatinib400mg/dfor12monthsAnopen-labelPhaseIIIstudy

Imatinib400mg/dfor36monthsFollow-upFollow-upSSGXVIII:StudydesignRandomassignment1:1Stratification:1)R0resection,notumorrupture2)R1resectionortumorrupture

SSGXVIII:Recurrence-freesurvival(ITT)No.atrisk(n=397)36Monthsofimatinib19818417313382398012Monthsofimatinib19917713788492710060.1%47.9%

86.6%65.6%36Months12MonthsHazardratio0.46(95%CI,0.32-0.65)P<.000101234567020406080100%Medianfollow-uptime54monthsYearsNo.atrisk(n=397)36Monthsofimatinib1981921841521005613012Monthsofimatinib1991881761408746200

SSGXVIII:Overallsurvival(ITT)Hazardratio0.45

(95%CI,0.22-0.89)P=.01996.3%92.0%94.0%81.7%36Months12Months01234567020406080100%YearsSubgroupNo.ofpatientsHazardratio(95%CI),RFSPvalueAge≤65 256 0.47(0.30-0.74) .001>65 141 0.49(0.28-0.85) .01SexMale 201 0.46(0.28-0.76) .002Female 196 0.46(0.28-0.76) .002TumorsiteStomach 202 0.42(0.23-0.78) .005Other 193 0.47(0.31-0.73) <.001Tumorsize≤10cm 219 0.40(0.23-0.69) <.001>10cm 176 0.47(0.29-0.76) .002Mitoses/50HPF(local)≤10mitoses209 0.76(0.43-1.32) .33>10mitoses154 0.29(0.17-0.49) <.001Mitoses/50HPF(central)≤10mitoses256 0.58(0.34-0.99) .04>10mitoses 137 0.37(0.23-0.61) <.001TumorruptureNo 318 0.43(0.28-0.66) <.001Yes 79 0.47(0.25-0.89) .02Tumormutationsite

KITexon9 26 0.61(0.22-1.68) .34

KITexon11 256 0.35(0.22-0.56) <.001Wildtype 33 0.41(0.11-1.51) .16Other 51 0.78(0.22-2.78) .700.11.010

36mobetter

12mobetter

0.11.010輔助治療——結(jié)論伊馬替尼輔助治療提高中高度復(fù)發(fā)風(fēng)險GIST的RFS中高危復(fù)發(fā)風(fēng)險患者建議輔助治療至少3年C-kit基因突變與療效及預(yù)后的相關(guān)性Heinrichetal.HumPathol.2002;33:484.Corlessetal.ProcAmAssocCancerRes.2003;44.AbstractR4447.GIST中KIT和PDGFRA突變細(xì)胞膜細(xì)胞質(zhì)外顯子11(67.5%)外顯子9(11%)外顯子13(0.9%)外顯子17(0.5%)外顯子12(0.9%)外顯子18(6.3%)KITPDGFRA總突變率:87.4%外顯子14(0.3%)3.HeinrichMC,etal.JClin

Oncol.2008Nov20;26(33):536