1、晚期肠癌靶向治疗进展晚期肠癌靶向治疗进展徐瑞华徐瑞华 MD&PhD中山大学肿瘤医院内科中山大学肿瘤医院内科主要内容主要内容 以分子指标为指导的靶向治疗时代的来临以分子指标为指导的靶向治疗时代的来临 多个靶向药物联合的重新定位多个靶向药物联合的重新定位 靶向药物治疗的广泛研究靶向药物治疗的广泛研究ERBITUX in first-line treatment of mCRCPhase III CRYSTAL study:Study designStratification factors:Region ECOG performance statusPopulations:Randomized p
2、atients(n=1217)Safety population(n=1202)ITT population(n=1198)FOLFIRIIrinotecan(180 mg/m2)+5-FU(400 mg/m2 bolus+2400 mg/m2 as 46-h continuous infusion)+LV(every 2 weeks)ERBITUX+FOLFIRIERBITUX(IV 400 mg/m2 on day 1,then 250 mg/m2 weekly)+irinotecan(180 mg/m2)+5-FU(400 mg/m2 bolus+2400 mg/m2 as 46-h c
3、ontinuous infusion)+LV(every 2 weeks)REGFR-expressing mCRC Van Cutsem E,et al.ASCO 2007(Abstract No.4000)1.00.80.90.00.10.20.30.40.50.60.702468101214161820Primary endpoint:PFS(ITT population)PFS estimate Van Cutsem E,et al.ASCO 2007(Abstract No.4000)PFS time(months)1-year PFS rate:23%vs 34%FOLFIRI(n
4、=599)ERBITUX+FOLFIRI(n=599)PFS ITT:HR=0.85;p=0.048mPFS ERBITUX+FOLFIRI:8.9 monthsmPFS FOLFIRI:8.0 monthsIndependent assessment of response OutcomeCRPRSDPDORR95%CIDCRFOLFIRI(n=599)(%)0.338.446.7 9.038.734.842.8 85.4ERBITUX+FOLFIRI(n=599)(%)0.546.437.4 8.846.942.951.0 84.3 Van Cutsem E,et al.ECCO 2007
5、(Abstract No.3001)39%47%Response rate(%)p=0.0038aaCochranMantelHaenszel testKRAS analysis:Objective and methodology To retrospectively investigate the impact of the KRAS mutation status of tumors on PFS and RR in the first-line treatment of mCRC with FOLFIRI ERBITUX Efficacy analyses repeated on KRA
6、S evaluable population Genomic DNA isolated from archived tumor material Paraffin-embedded,formalin-fixed tissue KRAS mutation status of codons 12/13 determined using quantitative PCR-based assay Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)KRAS evaluable population587 subjects analysed
7、for KRAS mutation status540(45%)subjects:KRAS evaluable population348(64.4%)KRAS wild-type192(35.6%)KRAS mutant171 subjects with events(49.1%)Group A:105(54.7%)Group B:87(45.3%)101 subjects with events(52.6%)1198 subjects(ITT)Group A:172(49.4%)Group B:176(50.6%)FOLFIRIERBITUX+FOLFIRI Van Cutsem E,et
8、 al.J Clin Oncol 2008;26(Suppl.abstract 2)Relating KRAS status to efficacyPrimary endpoint:PFS KRAS wild-type0.00.10.20.30.40.50.60.70.80.91.0024681012141618MonthsProgression-free survival estimateERBITUX+FOLFIRIFOLFIRIKRAS wild-type(n=348)HR=0.68;p=0.017 mPFS ERBITUX+FOLFIRI:9.9 months mPFS FOLFIRI
9、:8.7 months1-year PFS rate25%vs 43%Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)Relating KRAS status to efficacyPrimary endpoint:PFS KRAS mutantKRAS mutant (n=192)HR=1.07;p=0.75mPFS ERBITUX+FOLFIRI:7.6 months mPFS FOLFIRI:8.1 months0246810121416MonthsERBITUX+FOLFIRIFOLFIRI0.00.10.20.30.4
10、0.50.60.70.80.91.0Progression-free survival estimate Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)Relating KRAS status to efficacy:PFSERBITUX+FOLFIRI HR=0.63(p=0.007)Median PFS:Wild-type(n=172)9.9 months vs mutant(n=105)7.6 monthsFOLFIRI HR=0.97(p=0.87)Median PFS:Wild-type(n=176)8.7 mont
11、hsvs mutant(n=87)8.1 months0.51.00.40.30.20.10.00.60.70.80.9802461016PFS estimateTime(months)ERBITUX+FOLFIRI wild-typeERBITUX+FOLFIRI mutant12140.51.00.40.30.20.10.00.60.70.80.9Time(months)FOLFIRI wild-typeFOLFIRI mutant8024610161214PFS estimate Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract
12、 2)Relating KRAS status to efficacySecondary endpoint:Responsep=0.0025aFOLFIRIERBITUX+FOLFIRIaCochran-Mantel-Haenszel(CMH)testKRAS wild-type(n=348)KRAS mutant(n=192)p=0.46aFOLFIRIERBITUX+FOLFIRI Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)Relating KRAS status to outcome:Most common grad
13、e 3/4 adverse eventsAdverse events,%Any Neutropenia Febrile neutropenia DiarrheaVomitingFatigueAcne-like rashaInfusion-related reactionsKRAS wild-typeFOLFIRI(n=176)50.616.50.69.12.84.500ERBITUX+FOLFIRI(n=173)78.025.40.617.34.62.316.21.7KRAS mutantFOLFIRI(n=87)55.223.0012.66.92.300ERBITUX+FOLFIRI(n=1
14、05)72.421.93.813.32.99.517.13.8aThere was no grade 4 acne-like rash Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)Conclusions:CRYSTAL study Adding ERBITUX to FOLFIRI in mCRC leads to a significant increase in PFS(HR=0.85;p=0.048)The benefit of ERBITUX+FOLFIRI is greater in patients with K
15、RAS wild-type tumors:PFS(HR=0.68;p=0.017)Response rate 59%vs 43%(p=0.0025)The grade 3/4 adverse-event profile was similar in the KRAS wild-type and mutant populationsOPUS:Study design Primary endpointOverall confirmed response rate(as assessed by independent review)Secondary endpointsPFS time OS tim
16、e Rate of curative surgery for metastases SafetyERBITUX+FOLFOX4a400 mg/m2 initial IV infusion(day 1)then 250 mg/m2 weekly+oxaliplatin 85 mg/m2+5-FU/LV every 2 weeksFOLFOX4aOxaliplatin 85 mg/m2+5-FU/LV every 2 weeksEGFR-detectablemCRCRStratification by:ECOG PS 0/1,2 Bokemeyer C,et al.J Clin Oncol 200
17、8;26(Suppl.abstract 4000)aTreatment until progression,symptomatic deterioration or unacceptable toxicityKRAS evaluable population233(69%)subjects:KRAS evaluable population134(58%)KRAS wild-type99(42%)KRAS mutantGroup A:52(53%)Group B:47(47%)337 subjects(ITT)Group A:61(46%)Group B:73(54%)FOLFOXERBITU
18、X+FOLFOX Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)KRAS wild-type:n=134(58%)KRAS mutant:n=99(42%)p=0.011p=0.16Role of KRAS status in response rate Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)37614933Relating KRAS status to efficacySecondary endpoint:PFS KRAS wild-type
19、0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsKRAS wild-type:HR=0.57;p=0.016 mPFS ERBITUX+FOLFOX:7.7 monthsmPFS FOLFOX:7.2 monthsProgression-free survival estimateFOLFOXERBITUX+FOLFOX Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Relating KRAS status to efficacySecondary endpoint:PFS
20、KRAS mutantKRAS mutant HR=1.83;p=0.0192 mPFS ERBITUX+FOLFOX:5.5 monthsmPFS FOLFOX:8.6 monthsFOLFOXERBITUX+FOLFOX0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsProgression-free survival estimate Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Relating KRAS status to efficacy:Progression-f
21、ree survival0.51.00.40.30.20.10.00.60.70.80.9802461012PFS estimateTime(months)ERBITUX+FOLFOX wild-typeERBITUX+FOLFOX mutant0.51.00.40.30.20.10.00.60.70.80.9802461012Time(months)FOLFOX wild-typeFOLFOX mutantERBITUX+FOLFOX HR=0.45;p=0.0009 mPFS Cet+FOLFOX wild-type(n=61):7.7 monthsmPFS Cet+FOLFOX muta
22、nt(n=52):5.5 monthsFOLFOX HR=1.40;p=0.1655 mPFS FOLFOX wild-type(n=73):7.2 monthsmPFS FOLFOX mutant(n=47):8.6 monthsPFS estimate Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Most common grade 3/4 AEsAdverse event,%Any Neutropenia Febrile neutropenia DiarrheaPeripheral sensory neuropath
23、yAcne-like rashaInfusion-related reactionsKRAS wild-typeFOLFOX(n=73)63.032.91.45.58.200ERBITUX+FOLFOX(n=61)83.641.0011.54.914.81.4KRAS mutantFOLFOX(n=47)78.744.74.312.82.100ERBITUX+FOLFOX(n=52)67.325.005.83.811.57.7aThere was no grade 4 acne-like rash Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abs
24、tract 4000)Conclusions:OPUS study The addition of ERBITUX to FOLFOX increased the response rate by 10%(46%vs 36%)In patients with KRAS wild-type tumors,addition of ERBITUX to FOLFOX resulted in a significant and relevant improvement in:Response rate(61%vs 37%;p=0.011)PFS(HR=0.57;p=0.016)1.Van Cutsem
25、 E,et al.J Clin Oncol 2008;26(Abstract No.2);2.Bokemeyer C,et al.J Clin Oncol 2008;26(Abstract No.4000)ERBITUX+CT in KRAS wild-type:Consistent resultsResponse rate(%)5937010203040506070CRYSTAL1(n=348)OPUS2(n=134)4361FOLFIRIFOLFOXERBITUX+FOLFIRIERBITUX+FOLF0XCRYSTALKRAS wild-type:HR=0.68p=0.01732%ris
26、k reductionfor progressionOPUSKRAS wild-type:HR=0.57p=0.01643%risk reductionfor progression0.00.10.20.30.40.50.60.70.80.91.0024681012141618Time(months)PFS estimate0.00.10.20.30.40.50.60.70.80.91.0024681012Time(months)PFS estimateERBITUX in pretreated mCRCEvidence of correlation between KRAS wild-typ
27、e and EGFR inhibitor efficacy in chemorefractory CRC:ResponseReference Livre A,et al.(J Clin Oncol 2008)Benvenuti S,et al.(Cancer Res 2007)DeRoock W,VanCutsem E,Tejpar S et al.(Ann Onc 2008)Finocchiaro G et al.(ASCO Proceedings 2007)Di Fiore F et al.(Br J Cancer 2007)Khambata-Ford S et al.(J Clin On
28、col 2007)Amado R,Van Cutsem E et al.(J Clin Oncol 2008)Treatment ERBITUX CT Panitumumab or ERBITUX or ERBITUX+CTERBITUX or ERBITUX+irinotecanERBITUX CTERBITUX+CTERBITUXPanitumumabNo.of patients(wild-type:mutant)114(78:36)48(32:16)113(67:46)81(49:32)59(43:16)80(50:30)208(124:84)Objective response,n(%
29、)Wild-type34(44)10(31)27(41)13(26)12(28)5(10)21(17)Mutant0(0)1(6)0(0)2(6)0(0)0(0)0(0)NCIC CTG CO.17 Karapetis C,et al.WCGIC 2008 June 28 10:45 Session XVIIRole of KRAS mutations in predicting response,progression-free survival and overall survival in irinotecan-refractory patients treated with cetux
30、imab plus irinotecan for a metastatic colorectal cancer:Analysis of 281 individual data from published seriesAbstract O-018 World Congress GI Cancer Barcelona 2008Di Fiore F(1),Van Cutsem E(1),Laurent-Puig P(2),Siena S(3),Frattini M(4),De Roock W(1),Lievre A(2),Sartore-Bianchi A(3),Bardelli A(5),Tej
31、par S(1)(1)Digestive Oncology Unit,University Hospital Gasthuisberg,Leuven-Belgium;(2)Institut National de la Sant et de la Recherche Mdicale U775,Universit Paris-Descartes,Paris-France;(3)Divisione Oncologia Medica Falck,Ospedale Niguarda Ca Granda,Milan-Italy;(4)Institute Of Pathology,Locarno-Swit
32、zerland;(5)Laboratory of Molecular Genetics Institute for Cancer Research and Treatment,University of Torino Medical School,Torino-ItalyResponsenKRAS mutation(n)KRAS WT(n)Complete response(CR)30(0)3(1.6)Partial response(PR)740(0)74(40.6)Stable disease(SD)10741(41.4)66(36.3)Progressive disease(PD)975
33、8(58.6)39(21.5)Response to cetuximab-Irinotecan according to KRAS status(n=281)Di Fiore F,Van Cutsem E et al,WCGIC Barcelona,Ann Oncol,2008 abstract O-018Meta-analysis in chemorefractory CRC6Meta-analysis in chemorefractory CRCPFS according to KRAS statusDi Fiore F,Van Cutsem E et al,WCGIC Barcelona
34、,Ann Oncol,2008 abstract O-018Meta-analysis in chemorefractory CRC OS according to KRAS statusDi Fiore F,Van Cutsem E et al,WCGIC Barcelona,Ann Oncol,2008 abstract O-018Overall survival according to KRAS mutation and skin toxicityTime(months)1.000.750.500.250.000102030p=0.000815.6 months(95%CI:10.92
35、2)10.7 months(95%CI:8.316.3)5.6 months(95%CI:2.810.6)Survival probability2 good prognostic factors(wild-type and grade 2/3 skin toxicity)0 good prognostic factors(KRAS mutant and grade 0/1 skin toxicity)1 good prognostic factor(wild-type or grade 2/3 skin toxicity)Livre A,et al.J Clin Oncol 2008NCIC
36、 CO.17:randomized phase III trialEGFR testing by IHC Disease progression orUnacceptable toxicityStratification:Center ECOG PS(0 or 1 vs 2)REGISTERRANDOMI ZE1:1ERBITUX+BSCBSC aloneFailed or intolerant to all recommended therapiesJonker D,et al.N Engl J Med 2008ERBITUX+BSCCENSOREDBSCCENSOREDSubjects a
37、t riskERBITUX+BSC 2872171367837144000BSC285197854426128210Proportion alive00.10.20.30.40.50.60.70.80.91.0Months0369121518212427 HR 0.77(95%CI:0.64,0.92)Stratified log-rank p=0.0046Study armMS95%CIERBITUX+BSC6.1 months5.4,6.7BSC alone4.6 months4.2,4.9Jonker D,et al.N Engl J Med 2008NCIC CTG CO.17:Ove
38、rall SurvivalERBITUX+BSCCENSOREDBSCCENSOREDProportion progression-free00.10.20.30.40.50.60.70.80.91.0Months03691215 HR 0.68(95%CI:0.570.80)Stratified log-rank p10mConclusions KRAS is the first molecular marker used to select a targeted therapy in combination with a standard chemotherapy regimen ERBI
39、TUX brings a new era of tailored therapy to treatment of mCRC ERBITUX in combination with a standard first-line treatment for patients with mCRC is an important new option in patients with KRAS wild-type tumors主要内容主要内容 以分子指标为指导的靶向治疗时代的来临以分子指标为指导的靶向治疗时代的来临 多个靶向药物联合的重新定位多个靶向药物联合的重新定位 靶向药物治疗的广泛研究靶向药物治疗
40、的广泛研究Interim results from PACCE irinotecan+bevacizumab panitumumab for first-line treatment of mCRC study designHecht J,et al.Abstract 279SCREENINGRANDOMIZEOx-based CT(e.g.FOLFOX)N=800 inv choiceIn-based CT(e.g.FOLFIRI)N=200inv choicePanitumumab6mg/kg Q2WOx-CTBevacizumabPanitumumab6 mg/kg Q2WIri-CTB
41、evacizumabOx-CTBevacizumabIri-CTBevacizumab1:11:1Interim results from PACCE irinotecan+bevacizumab+/-panitumumab for first-line treatment of mCRC median PFS(central review)Hecht J,et al.Abstract 279100806040200PFS(%)0510152025Time(days)Panitumumab+Bevacizumab/Iri-CTBevacizumab/Iri-CT*PFS events(%)54
42、(47)43(37)Median(95%CI months10.1(8.213.1)11.1(9.013.2)HR=1.2(95%CI:0.801.82)*Descriptive onlyBACKInterim results from PACCE irinotecan+bevacizumab panitumumab for first-line treatment of mCRC response by KRAS statusHecht J,et al.Abstract 279Wild-type KRASMutant KRASN115 85Pmab+Bev/iri-CTn/N(%)31/57
43、(54)14/46(30)Bev/iri-CTn/N(%)27/58(47)15/39(38)Odds ratio(95%CI)1.42(0.633.21)0.59(0.231.55)BACK0510152025Interim results from PACCE oxaliplatin+bevacizumab+/-panitumumab for first-line treatment of mCRC PFS(central review)Hecht JR,et al.Abstract 273100806040200pmab+bev/Ox-CTbev/Ox-CTPFSevents(%)595
44、2Median(95%CI)months9.6(8.810.9)11.1(10.311.9)HR=1.27(95%CI:1.051.53)*Descriptive onlyTime(months)PFS(%)BACKSurviving(%)Interim results from PACCE oxaliplatin+bevacizumab+/-panitumumab for first-line treatment of mCRC OS(central review)Hecht JR,et al.Abstract 27306121824100806040200Time(months)pmab+
45、bev/Ox-CTbev/Ox-CTDeathevents n(%)143(35)108(26)Median(95%CI),months19.4(18.420.8NEHR=1.43(95%CI:1.111.83)*Descriptive only.Statistical significance is limited by the lackof a prespecified significance boundaryInterim results from PACCE oxaliplatin+bevacizumab+/-panitumumab for first-line treatment
46、of mCRC OS by ageHecht JR,et al.Abstract 27310080604020006121824Time(months)Age 80 years10080604020006121824Time(months)Age 80 yearsbev/Ox-CTpmab+bev/Ox-CTSurviving(%)Surviving(%)BACKInterim results from PACCE oxaliplatin+bevacizumab+/-panitumumab for first-line treatment of mCRC response rates(cent
47、ral review)Hecht JR,et al.Abstract 273Tumour response,n(%)Best ORRComplete responsePartial responseStable diseaseProgressive diseasebNot done or unevaluablecPmab+bev/OX-CT(N=413)187(45)0(0)187(45)121(29)28(7)78(19)Bev/OX-CT(N=410)189(46)2(1)189(46)138(34)17(4)64(16)BACKMetastatic CRC Trial:CAIRO 275
48、0 Previously untreated patientsPFS+3 monthsArm B：XELOX+Bevacizumab+CetuximabArm A:XELOX+BevacizumabCAIRO 2:ResultsArm A:Chemo+BevArm B:Chemo+Bev+C225CAIRO 2:TTPCAIRO 2:Overall SurvivalCAIRO 2:Toxicities小小 结结 联合联合Bevacizumab与抗与抗EGFR抗体一线治疗晚期抗体一线治疗晚期CRC的临床研究结果中，未能显示协同的作用的临床研究结果中，未能显示协同的作用 联合联合Bevacizum
49、ab与抗与抗EGFR抗体的治疗毒性有抗体的治疗毒性有所增加所增加 如何进行多个靶点药物联合的临床试验提出了挑如何进行多个靶点药物联合的临床试验提出了挑战。战。理论理论 结果结果主要内容主要内容 以分子指标为指导的靶向治疗时代的来临以分子指标为指导的靶向治疗时代的来临 多个靶向药物联合的重新定位多个靶向药物联合的重新定位 靶向药物治疗的广泛研究靶向药物治疗的广泛研究Targeting Agents in CRC Bevacizumab VEGF Traps AZD2171 Sonafinib Sunitinib mTOR inhibitor Cell Cycle InhibitorsLeonar
50、d B.Saltz,et al.JCO,2007标准治疗失败后的转移性结直肠标准治疗失败后的转移性结直肠癌应用舒尼替尼治疗的癌应用舒尼替尼治疗的IIII期研究期研究舒尼替尼的最好临床有效率舒尼替尼的最好临床有效率 无贝伐单抗组无贝伐单抗组 贝伐单抗组贝伐单抗组 所有病例所有病例 （n=40）（n=42）（n=82）疗效疗效 病例数病例数%病例数病例数%病例数病例数%部分缓解部分缓解 0 0 1 2.4 1 1.2稳定稳定 14 35.0 10 23.8 24 29.3 稳定稳定22周周 11 27.5 2 48 13 15.9 有效性：舒尼替尼治疗后，病灶大小变化有效性：舒尼替尼治疗后，病灶大
