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1、,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 2008,SUMMARY,Targeted therapies have improved clinical outcome of mCRC Need judicious use of these agents: when, how Many questions remaining How t
2、o overcome the high cost Treatments need to be individualized: biomarkers and genetic signatures,Story for GI at ASCO 2008,1st biomarker for individualized therapy for colorectal cancer: KRAS status predicts responsiveness (or lack of responsiveness) to EGFR targeted therapies,Advances in the Treatm
3、ent 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 Data EGFR Targeted Therapies in CRC Cetuximab & Pan
4、itumumab,BOND 1: Randomized Pivotal Trial in Metastatic Colorectal Cancer,RANDOMIZE,Cetuximab + irinotecan Cetuximab (initial dose, 400 mg/m2 then weekly infusion 250 mg/m2) + irinotecan (same as prestudy therapy) (n=218),N=329 Patients with mCRC who progressed during or within 3 mo after irinotecan
5、 EGFR+ 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.,0,5,10,15,20,25,0,1,2,3,4,5,6,22.9%,5.7 mo,4.2 mo,10.8%,Objective
6、 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
7、+,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 2nd line, irinotecan nave pts,Lack of overall survival: cross-over effect?,CRYSTAL: Phase III Trial of FOLFIRI +/
8、- 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 improves RR, PFS in 1st line, in combination with FOLFIRI,Phase III Study: Panitumumab vs Best Supportive Care,Peeters M, et al. AACR
9、 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 S
10、upportive Care,PFS 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.,Only a small portion of patients responded to EGFR targeted therapies Majority of patients suffered the side effects and high cost without benefits,Dilem
11、ma,What may help select these patients?,EGF/EGFR Pathway,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,RAN
12、DOMIZE,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
13、 + 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 2008. 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
14、 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 2008. Abstract 2. Reproduced with permission.,1-yr PFS rate: 25%,PFS Estimate,CRYSTAL: Initial and Retrospective Results,KRAS Status and Efficacy of First-Line FOLFOX C
15、etuximab: OPUS,Genomic DNA was isolated from archived tumor material KRAS 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 dem
16、ographics and efficacy parameters KRAS mutations detected in 42% (99/233) of evaluable samples,Bokemeyer C, et al. ASCO 2008. Abstract 4000.,OPUS: Initial and Retrospective Results,CAIRO2 Summary,Cetuximab + bevacizumab/capecitabine/oxaliplatin decreased PFS without affecting OS Although manageable,
17、 cetuximab + bevacizumab/ chemotherapy increases skin toxicity and diarrhea adverse events Treatment discontinuation due to toxicity did not differ between arms Negative interaction between anti-VEGF and anti-EGFR cannot be discounted,Punt CJ, et al. J Clin Oncol. 2008;26(May 20 suppl):abstr LBA4011
18、.,Is KRAS independent from skin rash as a predictor for response? Can dose escalation overcome KRAS mutant-type?,KRAS and Efficacy of Irinotecan and Cetuximab in mCRC: EVEREST,Patients with irinotecan-refractory metastatic cancer,Cetuximab 400 mg/m2 initial dose then 250 mg/m2/wk + Irinotecan 180 mg
19、/m2 Q2W,Control Standard Cetuximab regimen (250 mg/m2/wk) (n = 23),Dose Escalation Cetuximab dose increases of 50 mg/m2 Q2W up to maximum 500 mg/m2/wk (n = 31),Nonrandomized Standard Cetuximab regimen (250 mg/m2/wk),SCREENING,Day 22,Randomized: skin toxicity grade 0/1,Not eligible for randomization:
20、 skin toxicity grade 2/3,All patients continued to receive irinotecan Treatment until progression, unacceptable toxicity or withdrawal of consent Skin and tumor biopsy at baseline, Week 3, and at maximum cetuximab dose in dose-escalation arm,Tejpar S, et al. ASCO 2008. Abstract 4001.,EVEREST: PFS (I
21、TT Population),0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,Days,PFS Estimate,800,P .0001,KRAS mutant,WT KRAS,KRAS mutation present,83 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.,EVEREST: PFS by Treatment Group and KRAS Status
22、,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,0.0,0.2,0.4,0.6,0.8,1.0,0,200,400,600,800,Days,Days,Days,KRAS mutant,WT KRAS,Control,KRAS mutation present,P = .014,KRAS mutant,WT KRAS,Dose Escalation,KRAS mutation present,KRAS mutant,WT KRAS,Nonrandomized,KRAS mu
23、tation present,P .001,P = .020,Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.,PFS Estimate,PFS Estimate,PFS Estimate,EVEREST SUMMARY,Dose escalation of cetuximab did increase response rate Among patients without rash receiving, KRAS status still predicted response to cetuxima
24、b Among 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 predictors,SUMMARY of Kras Data,Kras status is a predictive marker for EGFR targeted therapy Patients with wild-type Kras may be
25、nefit from EGFR targeted therapy Patients with mutant Kras may NOT benefit from EGFR targeted therapy Cetuximab may have detrimental effects in patients with mutant Kras Whenever considering to use EGFR targeted therapy, Kras status should be tested.,Questions Raised by KRAS Data,What to do with cur
26、rent 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 status,Ongoing Studies: CALGB/SWOG 80405 Cetuximab, Bevacizumab, and FOLFOX/FOLFIRI,Investigator/Patient Chemotherapy Choice,FOLF
27、IRI or FOLFOX,+ Bevacizumab,+ Cetuximab,+ Bevacizumab + Cetuximab,+ Bevacizumab,+ Cetuximab,+ Bevacizumab + Cetuximab,Randomization,Randomization,Available at: http:/ctep.cancer.gov/resources/quarterly_news.pdf,Ongoing Study: iBET Study,FOLFIRI + Cetuximab,FOLFIRI +Cetuximab +Bevacizumab (5 mg/Kg),m
28、CRC S/P FOLFOX/Avastin,FOLFIRI +Cetuximab +Bevacizumab (10 mg/Kg),RANDOMIZE,What to Do for Patients with KRAS MT Tumor?,Need novel agents Need trials specifically targeting this patient population,Other Markers?,EGFR Ligands (Epiregulin and Amphiregulin) Levels Correlate With Response to Cetuximab,G
29、enetic Signatures to Predict Response?,Gene expression profiles reflecting clinical response to neoadjuvant treatment in breast cancer,Using genetic signatures to choose treatments for individual CRC patients?,Now the “future” is here: Individualized therapy for mCRC,Individualized Therapy in TCM,四 诊 八 纲,病情诊察: 望、问、闻、切,病情分析: 阴、阳、表、里、寒、热、虚、实,THANK YOU!,