晚期大肠癌的个体化治疗课件

0晚期大肠癌的个体化治疗1SUMMARYTargeted therapies have improved clinical outcome of mCRCNeed judicious use of these agents:when,howMany questions remainingHow to overcome the high cost Treatments need to be individualized:biomarkers and genetic signatures234Some Historical DataEGFR Targeted Therapies in CRCCetuximab&Panitumumab5BOND 1:Randomized Pivotal Trial in Metastatic Colorectal CancerRANDOMIZECetuximab+irinotecanCetuximab(initial dose,400 mg/m2 then weekly infusion 250 mg/m2)+irinotecan(same as prestudy therapy)(n=218)N=329Patients with mCRC who progressed during or within 3 mo after irinotecanEGFR+CRC Histamine receptor antagonist premedication given before at least the first cetuximab infusion.Cetuximab(initial dose,400 mg/m2 then weekly infusion 250 mg/m2)(n=111)Cunningham D,et al.N Engl J Med.2004;351:337-345.60510152025012345622.9%5.7 mo4.2 mo10.8%Objective Response RateMedian Duration of Response Cetuximab with irinotecan(n=218)Cetuximab as a single agent(n=111)Cetuximab Randomized Pivotal Trial:Response Rates P=0.007Cunningham D,et al.N Engl J Med.2004;351:337-345.7RANDOMIZEN=1298Patients with CRC who progressed on 5FU,Oxaliplatin,GFR+IrinotecanCetuximab+IrinotecanJonker et al.AACR 2007.Abstract 3556.EPIC:Cetuximab+Irinotecan vs Irinotecan as 2nd-line Therapy8EPIC Study Efficacy Data CetuximabCetuximab is active in 2 is active in 2ndnd line,irinotecan nave pts line,irinotecan nave pts Lack of overall survival:cross-over effect?Lack of overall survival:cross-over effect?9CRYSTAL:Phase III Trial of FOLFIRI+/-Cetuximab in First-line mCRCRANDOMIZEFOLFIRI+cetuximab(608)First-line mCRCFOLFIRI(609)Cutsem et aI,et al.ASCO 2007.4000.10CRYSTAL Efficacy DataCetuximab+FOLFIRI(N=608)Irinotecan(N=609)P ValuePFS8.98 0.036Response Rate(%)46.9%38.7%0.005 CetuximabCetuximab improves RR,PFS in 1st line,in improves RR,PFS in 1st line,in combination with FOLFIRIcombination with FOLFIRI11Phase III Study:Panitumumab vs Best Supportive CarePeeters M,et al.AACR 2006.Abstract CP-1.RANDOMIZEPanitumumab(6 mg/kg q2 wk)+BSC(n=231)N=463Patients third-line mCRCEGFR expression requiredOptional panitumumab crossover study(n=174)Best supportive care(n=232)PDPDStratification based on ECOG score,geographic region12Panitumumab Improves PFS over Best Supportive CarePFS longer with panitumumab vs BSC-HR,0.54(95%CI,0.44-0.66;P0.000000001)*P0.0001.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/a13Only a small portion of patients responded to EGFR targeted therapiesMajority of patients suffered the side effects and high cost without benefitsDilemmaWhat may help select these patients?14EGF/EGFR PathwayProliferationApoptosis ResistanceTranscriptionShcPI3KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1EGFR1516Phase III Study:Panitumumab vs Best Supportive Care17KRAS Mutation Predicts No Benefit from Panitumumab18CRYSTAL:Phase III Trial of FOLFIRI+/-Cetuximab in First-line mCRCRANDOMIZEFOLFIRI+cetuximab(608)First-line mCRCFOLFIRI(609)Cutsem et aI,et al.ASCO 2007.4000.19CRYSTAL:PFS in Patients With the KRAS Mutation00.20.40.60.81.004812MosPFS Estimate16Cetuximab+FOLFIRIFOLFIRIKRAS mutation(n=192)HR:1.07;P=.47261014Median PFS cetuximab+FOLIFIRI:7.6 mosMedian PFS FOLIFIRI:8.1 mos0.10.30.50.70.9Van Cutsem E,et al.ASCO 2008.Abstract 2.Reproduced with permission.20CRYSTAL:PFS in Patients With WT KRAS00.20.40.60.81.004812Mos18Cetuximab+FOLFIRIFOLFIRIWT KRAS(n=348):HR:0.68;P=.017261014Median PFS cetuximab+FOLIFIRI:9.9 mosMedian PFS FOLIFIRI:8.7 mos0.10.30.50.70.9161-yr PFS rate:43%Van Cutsem E,et al.ASCO 2008.Abstract 2.Reproduced with permission.1-yr PFS rate:25%PFS Estimate21 CRYSTAL:Initial and Retrospective ResultsITT PopulationK-ras Wild TypeK-ras MutationFOLFIRIFOLFIRIFOLFIRIWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX#of Patients 599 599 172 176 105 87Overall Response Rate 47%39%p=0.004 59%43%p=0.003 36%40%p=0.46Median 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=0.75222324KRAS Status and Efficacy of First-Line FOLFOX Cetuximab:OPUSGenomic DNA was isolated from archived tumor materialKRAS mutation status of codons 12/13 was determined using a sensitive,quantitative PCR-based assay Population with tissue available for KRAS analysis(n=233)was representative of overall ITT population(n=337)in terms of demographics and efficacy parametersKRAS mutations detected in 42%(99/233)of evaluable samplesBokemeyer C,et al.ASCO 2008.Abstract 4000.2526OPUS:Initial and Retrospective ResultsITT PopulationK-ras Wild TypeK-ras MutationFOLFOXFOLFOXFOLFOXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX#of Patients 169 168 61 73 52 47Overall Response Rate 46%36%p=0.006 61%37%p=0.01 33%49%p=0.11Median PFS 7.2 mos 7.2 mos Hazard Ratio:0.93 p=NSS 7.7 mos 7.2 mos Hazard Ratio:0.57 p=0.02 5.5 mos 8.6 mos Hazard Ratio:1.83 p=0.02272829303132CAIRO2 SummaryCetuximab+bevacizumab/capecitabine/oxaliplatin decreased PFS without affecting OSAlthough manageable,cetuximab+bevacizumab/chemotherapy increases skin toxicity and diarrhea adverse eventsTreatment discontinuation due to toxicity did not differ between arms-Negative interaction between anti-VEGF and anti-EGFR cannot be discountedPunt CJ,et al.J Clin Oncol.2008;26(May 20 suppl):abstr LBA4011.33Is KRAS independent from skin rash as a predictor for response?Can dose escalation overcome KRAS mutant-type?34KRAS and Efficacy of Irinotecan and Cetuximab in mCRC:EVERESTPatients with irinotecan-refractory metastatic cancerCetuximab 400 mg/m2 initial dose then 250 mg/m2/wk+Irinotecan 180 mg/m2 Q2WControl Standard Cetuximab regimen(250 mg/m2/wk)(n=23)Dose Escalation Cetuximab dose increasesof 50 mg/m2 Q2W up to maximum 500 mg/m2/wk(n=31)Nonrandomized Standard Cetuximab regimen(250 mg/m2/wk)SCREENINGDay 22Randomized:skin toxicity grade 0/1Not eligible for randomization:skin toxicity grade 2/3All patients continued to receive irinotecan Treatment until progression,unacceptable toxicity or withdrawal of consentSkin and tumor biopsy at baseline,Week 3,and at maximum cetuximab dose in dose-escalation armTejpar S,et al.ASCO 2008.Abstract 4001.35EVEREST:PFS(ITT Population)00.20.40.60.81.00200400600DaysPFS Estimate800P .0001KRAS mutantWT KRASKRAS mutation present83 days(95%CI:75.9-90.2)173 days(95%CI:141.3-204.7)Tejpar S,et al.ASCO 2008.Abstract 4001.Reproduced with permission.36EVEREST:PFS by Treatment Group and KRAS Status0.00.20.40.60.81.002004006008000.00.20.40.60.81.002004006008000.00.20.40.60.81.00200400600800DaysDaysDaysKRAS mutantWT KRASControlKRAS mutation presentP=.014KRAS mutantWT KRASDose EscalationKRAS mutation presentKRAS mutantWT KRASNonrandomizedKRAS mutation presentP .001P=.020Tejpar S,et al.ASCO 2008.Abstract 4001.Reproduced with permission.PFS EstimatePFS EstimatePFS Estimate37EVEREST SUMMARYDose escalation of cetuximab did increase response rateAmong patients without rash receiving,KRAS status still predicted response to cetuximabAmong patients receiving escalated dose of cetuximab(to rash),KRAS MT still did not respond-Higher dose did not overcome KRAS status-Skin rash and KRAS are independent predictors38SUMMARY of Kras DataKras status is a predictive marker for EGFR targeted therapy-Patients with wild-type Kras may benefit from EGFR targeted therapy-Patients with mutant Kras may NOT benefit from EGFR targeted therapyCetuximab may have detrimental effects in patients with mutant KrasWhenever considering to use EGFR targeted therapy,Kras status should be tested.39Questions Raised by KRAS DataWhat to do with current trials involving EGFR targeted-agents?What to do for patients with mutated KRAS?Any other predictive markers?Develop more reliable,affordable assays to test KRAS status40Ongoing Studies:CALGB/SWOG 80405Ongoing Studies:CALGB/SWOG 80405Cetuximab,Bevacizumab,and FOLFOX/FOLFIRICetuximab,Bevacizumab,and FOLFOX/FOLFIRIInvestigator/PatientChemotherapy ChoiceFOLFIRIorFOLFOX+Bevacizumab+Cetuximab+Bevacizumab+Cetuximab+Bevacizumab+Cetuximab+Bevacizumab+CetuximabRandomizationRandomizationAvailable at:http:/ctep.cancer.gov/resources/quarterly_news.pdf41Ongoing Study:iBET StudyFOLFIRI+CetuximabFOLFIRI+Cetuximab+Bevacizumab(5 mg/Kg)mCRC S/P FOLFOX/AvastinFOLFIRI+Cetuximab+Bevacizumab(10 mg/Kg)RANDOMIZE42What to Do for Patients with KRAS MT Tumor?Need novel agentsNeed trials specifically targeting this patient population43Other Markers?44EGFR Ligands(Epiregulin and Amphiregulin)EGFR Ligands(Epiregulin and Amphiregulin)Levels Correlate With Response to CetuximabLevels Correlate With Response to Cetuximab45Genetic Signatures to Predict Response?Gene expression profiles reflecting clinical response to neoadjuvant treatment in breast cancerUsing genetic signatures to choose treatments for individual CRC patients?46Now the“future”is here:Individualized therapy for mCRC47Individualized Therapy in TCM四四 诊诊 八八 纲纲 病情病情诊诊察察:望、望、问问、闻闻、切、切 病情分析病情分析:阴、阳、表、里、寒、阴、阳、表、里、寒、热热、虚、虚、实实 48THANK YOU!