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1、晚期肠癌靶向治疗进展,徐瑞华 MD & PhD 中山大学肿瘤医院内科 ,主要内容,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 靶向药物治疗的广泛研究,ERBITUX in first-line treatment of mCRC,Phase III CRYSTAL study: Study design,Stratification factors: Region ECOG performance status Populations: Randomized patients (n=1217) Safety population (n=1202) ITT populati
2、on (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 continuous infusion) + LV (ev
3、ery 2 weeks),R,EGFR-expressing mCRC,Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000),Primary 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%,PFS ITT: HR=0.85; p=0.048 mPFS ERBITUX + FOLFIRI: 8.9 months mPF
4、S FOLFIRI: 8.0 months,Independent assessment of response,Van Cutsem E, et al. ECCO 2007 (Abstract No. 3001),39%,47%,Response rate (%),p=0.0038a,aCochranMantelHaenszel test,KRAS analysis: Objective and methodology,To retrospectively investigate the impact of the KRAS mutation status of tumors on PFS
5、and RR in the first-line treatment of mCRC with FOLFIRI ERBITUX Efficacy 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 Cu
6、tsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2),KRAS evaluable population,587 subjects analysed for KRAS mutation status,540 (45%) subjects: KRAS evaluable population,348 (64.4%) KRAS wild-type,192 (35.6%) KRAS mutant,171 subjects with events (49.1%),Group A: 105 (54.7%),Group B: 87 (45.3%),
7、101 subjects with events (52.6%),1198 subjects (ITT),Group A: 172 (49.4%),Group B: 176 (50.6%),FOLFIRI,ERBITUX + FOLFIRI,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2),Relating KRAS status to efficacy Primary endpoint: PFS KRAS wild-type,Van Cutsem E, et al. J Clin Oncol 2008;26 (Supp
8、l. abstract 2),Relating KRAS status to efficacy Primary endpoint: PFS KRAS mutant,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2),Relating KRAS status to efficacy: PFS,ERBITUX + FOLFIRI HR=0.63 (p=0.007) Median PFS: Wild-type (n=172) 9.9 months vs mutant (n=105) 7.6 months,FOLFIRI HR=0
9、.97 (p=0.87) Median PFS: Wild-type (n=176) 8.7 months vs mutant (n=87) 8.1 months,0.5,1.0,0.4,0.3,0.2,0.1,0.0,0.6,0.7,0.8,0.9,8,0,2,4,6,10,16,PFS estimate,Time (months),12,14,0.5,1.0,0.4,0.3,0.2,0.1,0.0,0.6,0.7,0.8,0.9,Time (months),FOLFIRI wild-type,FOLFIRI mutant,8,0,2,4,6,10,16,12,14,PFS estimate
10、,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2),Relating KRAS status to efficacy Secondary endpoint: Response,p=0.0025a,FOLFIRI,ERBITUX + FOLFIRI,aCochran-Mantel-Haenszel (CMH) test,KRAS wild-type (n=348),KRAS mutant (n=192),p=0.46a,FOLFIRI,ERBITUX + FOLFIRI,Van Cutsem E, et al. J Cli
11、n Oncol 2008;26 (Suppl. abstract 2),Relating KRAS status to outcome: Most common grade 3/4 adverse events,aThere 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
12、 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 grade 3/4 adverse-event profile was similar in the KRAS wild-type and mutant populations,OPUS: Study design,Primary endpoint Over
13、all confirmed response rate (as assessed by independent review) Secondary endpoints PFS timeOS timeRate of curative surgery for metastasesSafety,ERBITUX + FOLFOX4a400 mg/m2 initial IV infusion (day 1) then 250 mg/m2 weekly + oxaliplatin 85 mg/m2 + 5-FU/LV every 2 weeks,FOLFOX4aOxaliplatin 85 mg/m2 +
14、 5-FU/LV every 2 weeks,EGFR-detectable mCRC,R,Stratification by: ECOG PS 0/1, 2,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000),aTreatment until progression, symptomatic deterioration or unacceptable toxicity,KRAS evaluable population,233 (69%) subjects: KRAS evaluable population,134
15、 (58%) KRAS wild-type,99 (42%) KRAS mutant,Group A: 52 (53%),Group B: 47 (47%),337 subjects (ITT),Group A: 61 (46%),Group B: 73 (54%),FOLFOX,ERBITUX + 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=0.011,p=0.16,Role of KR
16、AS status in response rate,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000),37,61,49,33,Relating KRAS status to efficacy Secondary endpoint: PFS KRAS wild-type,0.5,1.0,0.4,0.3,0.2,0.1,0.0,0.6,0.7,0.8,0.9,8,0,2,4,6,10,12,Months,KRAS wild-type: HR=0.57; p=0.016 mPFS ERBITUX + FOLFOX: 7.7 months mPFS FOLFOX: 7.2 months,
