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Click to editMaster title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Individualized Treatments for,Advanced Colorectal Cancer:,The KRAS Story,David Z.Chang,MD,PhD,UT MD Anderson Cancer Center,张 宗 圣,CSCO Annual Meeting 2021,SUMMARY,Targeted therapies have improved clinical outcome of mCRC,Need judicious use of these agents:when,how,Many questions remaining,How to overcome the high cost,Treatments n,eed to be individualized:biomarkers and genetic signatures,Story for GI at ASCO 2021,1,st,biomarker for,individualized therapy for colorectal cancer:,KRAS status predicts responsiveness(or lack of responsiveness)to EGFR targeted therapies,Advances in the Treatment of Colorectal Cancer,1980,1985,1990,1995,2000,2005,Capecitabine,Oxaliplatin,Cetuximab,Bevacizumab,Irinotecan,5-FU,Panitumumab,Median Survival,BSC:4-6 months,5FU:10-14 months,5FU/OX/Iri:20 months,+targeted therapy:30 months?,Some Historical DataEGFR Targeted Therapies in CRCCetuximab&Panitumumab,BOND 1:Randomized Pivotal Trial in Metastatic Colorectal Cancer,RANDOMIZE,Cetuximab+irinotecan,Cetuximab(initial dose,400 mg/m,2,then weekly infusion 250 mg/m,2,)+,irinotecan(same as prestudy therapy),(n=218),N=329,Patients with mCRC who progressed during or within 3 mo after irinotecan,EGFR+CRC,Histamine receptor antagonist premedication given before at least the first cetuximab infusion,.,Cetuximab,(initial dose,400 mg/m,2,then weekly infusion 250 mg/m,2,),(n=111),Cunningham D,et al.,N Engl J Med,.2004;351:337-345.,0,5,10,15,20,25,0,1,2,3,4,5,6,22.9%,5.7 mo,4.2 mo,10.8%,Objective Response Rate,Median Duration of Response,Cetuximab with irinotecan(n=218),Cetuximab as a single agent(n=111),Cetuximab Randomized Pivotal Trial:Response Rates,P,=0.007,Cunningham D,et al.,N Engl J Med,.2004;351:337-345.,RANDOMIZE,N=1298,Patients with CRC who progressed on 5FU,Oxaliplatin,GFR+,Irinotecan,Cetuximab+Irinotecan,Jonker et al.AACR 2007.Abstract 3556.,EPIC:Cetuximab+Irinotecan vs Irinotecan as,2nd-line,Therapy,EPIC Study Efficacy Data,Cetuximab,is active in 2,nd,line,irinotecan nave pts,Lack of overall survival:cross-over effect?,CRYSTAL:Phase III Trial of FOLFIRI+/-Cetuximab in First-line mCRC,RANDOMIZE,FOLFIRI+cetuximab,(608),First-line,mCRC,FOLFIRI,(609),Cutsem et aI,et al.ASCO 2007.4000.,CRYSTAL Efficacy Data,Cetuximab,+FOLFIRI,(N=608),Irinotecan,(N=609),P Value,PFS,8.9,8,0.036,Response Rate(%),46.9%,38.7%,0.005,Cetuximab,improves RR,PFS in 1st line,in combination with FOLFIRI,Phase III Study:Panitumumab vs Best Supportive Care,Peeters M,et al.AACR 2006.Abstract CP-1.,RANDOMIZE,Panitumumab,(6 mg/kg q2 wk)+BSC(n=231),N=463,Patients third-line mCRC,EGFR expression required,Optional panitumumab crossover study,(n=174),Best supportive care,(n=232),PD,PD,Stratification based on ECOG score,geographic region,Panitumumab Improves PFS over Best Supportive Care,PFS longer with panitumumab vs BSC,HR,0.54(95%CI,0.44-0.66;,P,0.000000001),*P,0.0001.,Peeters M,et al.AACR 2006.Abstract CP-1.,Panitumumab,(n=231),BSC,(n=232),PR,n(%),19(8)*,0(0),SD,n(%),64(28),24(10),Median duration response,wk(range),17(4+-40+),n/a,Only a small portion of patients responded to EGFR targeted therapiesMajority of patients suffered the side effects and high cost without benefits,Dilemma,What may help select these patients?,EGF/EGFR Pathway,Proliferation,Apoptosis Resistance,Transcription,Shc,PI3K,Raf,MEKK-1,MEK,MKK-7,JNK,ERK,Ras,mTOR,Grb2,AKT,Sos-1,EGFR,Phase III Study:Panitumumab vs Best Supportive Care,KRAS Mutation Predicts No Benefit from Panitumumab,CRYSTAL:Phase III Trial of FOLFIRI+/-Cetuximab in First-line mCRC,RANDOMIZE,FOLFIRI+cetuximab,(608),First-line,mCRC,FOLFIRI,(609),Cutsem et aI,et al.ASCO 2007.4000.,CRYSTAL:PFS in Patients With the,KRAS,Mutation,0,0.2,0.4,0.6,0.8,1.0,0,4,8,12,Mos,PFS Estimate,16,Cetuximab+FOLFIRI,FOLFIRI,KRAS,mutation(n=192)HR:1.07;,P,=.47,2,6,10,14,Median PFS cetuximab+FOLIFIRI:7.6 mos,Median PFS FOLIFIRI:8.1 mos,0.1,0.3,0.5,0.7,0.9,Van Cutsem E,et al.ASCO 2021.Abstract 2.Reproduced with permission.,CRYSTAL:PFS in Patients With WT,KRAS,0,0.2,0.4,0.6,0.8,1.0,0,4,8,12,Mos,18,Cetuximab+FOLFIRI,FOLFIRI,WT,KRAS,(n=348):HR:0.68;,P,=.017,2,6,10,14,Median PFS cetuximab+FOLIFIRI:9.9 mos,Median PFS FOLIFIRI:8.7 mos,0.1,0.3,0.5,0.7,0.9,16,1-yr PFS rate:43%,Van Cutsem E,et al.ASCO 2021.Abstract 2.Reproduced with permission.,1-yr PFS rate:25%,PFS Estimate,CRYSTAL:Initial and Retrospective Results,ITT Population,K-ras Wild Type,K-ras Mutation,FOLFIRI,FOLFIRI,FOLFIRI,With ERBITUX No ERBITUX,With ERBITUX No ERBITUX,With ERBITUX No ERBITUX,#of Patients,599 599,172 176,105 87,Overall Response Rate,47%39%,p=0.004,59%43%,p=0.003,36%40%,p=0.46,Median PFS,8.9 mos 8.0 mos,Hazard Ratio:0.85 p=0.05,9.9 mos 8.7 mos,Hazard Ratio:0.68 p=0.02,7.6 mos 8.1 mos,Hazard Ratio:1.07 p=0.75,KRAS,Status and Efficacy of First-Line FOLFOX,Cetuximab:OPUS,Genomic DNA was isolated from archived tumor material,KRAS,mutation status of codons 12/13 was determined using a s
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