1、A new treatment paradigm for mCRCProfessor of Medicine Associate Director,Clinical Research USC Norris Comprehensive Cancer Center Los Angeles,CA Anti-EGFR antibodies in mCRC3rd line BOND:cetuximab irinotecan NCIC C0.17:cetuximab vs BSC Panitumumab vs BSC(KRAS wild-type)2nd line BOND:cetuximab irino
2、tecan EPIC:irinotecan cetuximab1st line(Randomized)Phase II studies(chemo+cetuximab)CRYSTAL:FOLFIRI cetuximab PACCE:chemo/bevacizumab panitumumab CAIRO2:capecitabine/oxaliplatin/bevacizumab cetuximab Other phase III studies in progressComparison of cetuximab and bevacizumabBleeding possible,wound-he
3、aling complicationsNo complicationsPerioperativeHypertension,thromboembolic eventsAcne-like skinrashSpecific side effect+?+RR with FOLFOX+RR with FOLFIRIFirst lineSecond/third lineRegistered?YesSingle-agent activityVEGF proteinEGF receptorAntibodyBevacizumabCetuximabCharacteristicPhase III CRYSTAL s
4、tudy:Study designStratification factors:Region ECOG performance statusPopulations:Randomized patients(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 o
5、n day 1,then 250 mg/m2 weekly)+irinotecan(180 mg/m2)+5-FU(400 mg/m2 bolus+2400 mg/m2 as 46-h continuous infusion)+LV(every 2 weeks)REGFR-expressing mCRC Van Cutsem E,et al.ASCO 2007(Abstract No.4000)Study endpoints Primary endpoint PFS time(as assessed by blinded independent review)Secondary endpoin
6、ts ORR(independently reviewed)DCR(CR+PR+SD)OS Quality of life(EORTC QLQ-C30)Safety Van Cutsem E,et al.ECCO 2007(Abstract No.3001)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
7、 rate:23%vs 34%FOLFIRI(n=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 OutcomeFOLFIRI(n=599)(%)ERBITUX+FOLFIRI(n=599)(%)CRPRSDPD0.338.446.7 9.0 0.546.437.4 8.8ORR95%CI38.734.842.846.942.951.0DCR 85.4 84.3 Van
8、 Cutsem E,et al.ECCO 2007(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
9、 analyses repeated on KRAS 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 populat
10、ion587 subjects analysed 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%)FOLFIRIERBITU
11、X+FOLFIRI Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)Patient demographics at baseline according to KRAS statusKRAS evaluable population,%KRAS wild-type(n=348)KRAS mutant(n=192)Age 65 years65.859.9Male57.857.8ECOG PS 0/196.697.9Prior adjuvant therapy21.612.5Involved disease sites 2 85.3
12、83.3Liver-limited disease 19.321.9 Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)ITT and KRAS evaluable population:ComparabilityITT population(n=1198)HR=0.85 Median PFS:ERBITUX+FOLFIRI 8.9 months vs FOLFIRI 8.0 monthsKRAS population(n=540)HR=0.82 Median PFS:ERBITUX+FOLFIRI 9.2 months vs F
13、OLFIRI 8.7 months 1.0PFS estimateTime(Months)0.50.40.30.20.10.60.70.80.90.0802461012141618200.51.00.40.30.20.10.60.70.90.0802461012141618200.8Time(Months)PFS estimateERBITUX+FOLFIRIFOLFIRI Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.abstract 2)First-line ERBITUX+FOLFIRI:Correlation of KRAS status
14、with efficacyFirst-line treatment:ERBITUX(6 weeks monotherapy),followed by ERBITUX+FOLFIRI(n=52)ERBITUXERBITUX+FOLFIRIOutcomeWild-typeMutantWild-typeMutantRR(CR+PR),%27.6055.231.6p=0.015p=0.144Median PFS,months9.45.6HR=2.12p=0.0475Tabernero J et al,ASCO GI 2008Relating KRAS status to efficacyPrimary
15、 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:8.7 months1-year PFS rate25%vs 43%Van Cutsem E,et al.J Clin Oncol 2008;26(Suppl.
16、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+FOLFIRIFOLFIRI0.00.10.20.30.40.50.60.70.80.91.0Progression-free survival estimate Van Cutsem E,et al.J Clin On
17、col 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 monthsvs mutant(n=87)8.1 months0.51.00.40.30.20.10.00.60.70.80.9802461016PFS estimate
18、Time(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 2)Relating KRAS status to efficacySecondary endpoint:Responsep=0.0025aFOLFIRIERB
19、ITUX+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 grade 3/4 adverse eventsKRAS wild-typeKRAS mutantAdverse events,%FOLFIRI(n=176)ERBITU
20、X+FOLFIRI(n=173)FOLFIRI(n=87)ERBITUX+FOLFIRI(n=105)Any Neutropenia50.616.578.025.455.223.072.421.9 Febrile neutropenia Diarrhea0.69.10.617.3012.63.813.3Vomiting2.84.66.92.9Fatigue4.52.32.39.5Acne-like rasha016.2017.1Infusion-related reactions01.703.8aThere was no grade 4 acne-like rash Van Cutsem E,
21、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 KRAS wild-type tumors:PFS(HR=0.68;p=0.017)Response rate 59%vs 43%(p=0.0025)The gra
22、de 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 time Rate of curative surgery for metastases SafetyERBITUX+FOLFOX4a400 mg/m2 initial
23、 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 2008;26(Suppl.abstract 4000)aTreatment until progression,symptomatic deterioration o
24、r unacceptable toxicityPhase II OPUS trial:KRAS analysisObjective To retrospectively investigate the impact of the KRAS mutation status of tumors on the response rate and PFS in the first-line treatment of mCRC with FOLFOX ERBITUX Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)KRAS evalu
25、able 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%)FOLFOXERBITUX+FOLFOX Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Patient demographics at baselineKRAS evaluable
26、 population,%KRAS wild-type(n=134)KRAS mutant(n=99)Age 65 years63.462.6Male 55.249.5ECOG PS 0/1 88.890.9Prior adjuvant therapy 18.717.2Involved disease sites 2 77.677.8Liver-limited disease 28.425.3 Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)KRAS wild-type:n=134(58%)KRAS mutant:n=99(
27、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-type0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsKRAS wild-type:HR=0.57;p=0.016 mPFS ERBITUX+FOLFOX:7.7 monthsm
28、PFS 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 KRAS mutantKRAS mutant HR=1.83;p=0.0192 mPFS ERBITUX+FOLFOX:5.5 monthsmPFS FOLFOX:8.6 monthsFOLFOXERBITUX+FOLF
29、OX0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsProgression-free survival estimate Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Relating KRAS status to efficacy:Progression-free survival0.51.00.40.30.20.10.00.60.70.80.9802461012PFS estimateTime(months)ERBITUX+FOLFOX wild-typeERBITUX+
30、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 mutant(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
31、monthsPFS estimate Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Most common grade 3/4 AEsKRAS wild-typeKRAS mutantAdverse event,%FOLFOX(n=73)ERBITUX+FOLFOX(n=61)FOLFOX(n=47)ERBITUX+FOLFOX(n=52)Any Neutropenia Febrile neutropenia 63.032.91.483.641.0078.744.74.367.325.00Diarrhea5.511.512
32、.85.8Peripheral sensory neuropathy8.24.92.13.8Acne-like rasha014.8011.5Infusion-related reactions01.407.7aThere was no grade 4 acne-like rash Bokemeyer C,et al.J Clin Oncol 2008;26(Suppl.abstract 4000)Conclusions:OPUS study The addition of ERBITUX to FOLFOX increased the response rate by 10%(46%vs 3
33、6%)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 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
34、+CT in KRAS wild-type:Consistent resultsResponse rate(%)5937010203040506070CRYSTAL1(n=348)OPUS2(n=134)4361FOLFIRIFOLFOXERBITUX+FOLFIRIERBITUX+FOLF0XCRYSTALKRAS wild-type:HR=0.68p=0.01732%risk reductionfor progressionOPUSKRAS wild-type:HR=0.57p=0.01643%risk reductionfor progression0.00.10.20.30.40.50
35、.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-type and EGFR inhibitor efficacy in chemorefractory CRC:ResponseReference Treatment No.of patients(wild-type:muta
36、nt)Objective response,n(%)Wild-typeMutantLivre A,et al.(J Clin Oncol 2008)ERBITUX CT114(78:36)34(44)0(0)Benvenuti S,et al.(Cancer Res 2007)Panitumumab or ERBITUX or ERBITUX+CT48(32:16)10(31)1(6)DeRoock W,VanCutsem E,Tejpar S et al.(Ann Onc 2008)ERBITUX or ERBITUX+irinotecan113(67:46)27(41)0(0)Finocc
37、hiaro G et al.(ASCO Proceedings 2007)ERBITUX CT81(49:32)13(26)2(6)Di Fiore F et al.(Br J Cancer 2007)ERBITUX+CT59(43:16)12(28)0(0)Khambata-Ford S et al.(J Clin Oncol 2007)ERBITUX80(50:30)5(10)0(0)Amado R,Van Cutsem E et al.(J Clin Oncol 2008)Panitumumab208(124:84)21(17)0(0)NCIC CTG CO.17 Karapetis C
38、,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 cetuximab plus irinotecan for a metastatic colorectal cancer:Analysis of 281 individual data from published seriesAb
39、stract 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),Tejpar S(1)(1)Digestive Oncology Unit,University Hospital Gasthuisberg,Leuven-Belgium;(2)Institut National de la S
40、ant 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-Switzerland;(5)Laboratory of Molecular Genetics Institute for Cancer Research and Treatment,University of Torino Me
41、dical 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)9758(58.6)39(21.5)Response to cetuximab-Irinotecan according to KRAS status(n=281)Di Fiore F,Van Cutsem E et al,WC
42、GIC Barcelona,Ann Oncol,2008 abstract O-018Metaanalysis in chemorefractory CRC6Metaanalysis in chemorefractory CRCPFS according to KRAS statusDi Fiore F,Van Cutsem E et al,WCGIC Barcelona,Ann Oncol,2008 abstract O-018OS according to KRAS statusMetaanalysis in chemorefractory CRCDi Fiore F,Van Cutsem
43、 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:10.922)10.7 months(95%CI:8.316.3)5.6 months(95%CI:2.810.6)Survival probability2 good prognostic factors(wild-type and gr
44、ade 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 CO.17:randomized phase III trialEGFR testing by IHC Disease progression orUnacceptable toxicityStratification:Cent
45、er 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 at riskERBITUX+BSC 2872171367837144000BSC285197854426128210Proportion alive00.10.20.30.40.50.60.70.80.91.0Months0369
46、121518212427 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:Overall SurvivalERBITUX+BSCCENSOREDBSCCENSOREDProportion progression-free00.10.20.30.40.50.60.70.80.91.0Months03691215
47、 HR 0.68(95%CI:0.570.80)Stratified log-rank p10mResection rate of metastases and tumor responseResponse rate,9,8,7,6,5,4,3Resection rate,6,5,4,3,2,10,0Studies including all patients with mCRC(solid line)(r=0.74;p0.001)Studies including selected patients(liver metastases only,no extrahepatic disease)
48、(r=0.96;p=0.002)Phase III studies including all patients with mCRC(dashed line)(r=0.67;p=0.024)Folprecht,et al.Ann Oncol 2005;16:1311131954%Survival after primary or secondary resection of liver metastasesProportion SurvivingSurvival Time(years)98765432101.9.8.7.6.5.4.3.2.1029%34%50%34%27%Resectable
49、(n=425)Initially non resectable(n=95)Bismuth et al,1996CRYSTAL Trial:Surgery with Curative Intent*CMH testn=599/groupn=599/groupn=134/n=122p=0.0034*odds ratio 3.0 95%CI:1.4-6.5 FOLFIRI alone ERBITUX+FOLFIRINo residual tumor in patients with liver metastasesITT populationLiver-limited disease populat
50、ionVan Cutsem et al,ASCO 2007 OncoSurgical strategies in liver metastasesfrom palliative to curativePalliativeCurativeSurvivalTimeConclusions KRAS is the first molecular marker used to select a targeted therapy in combination with a standard chemotherapy regimen ERBITUX brings a new era of tailored
