晚期肠癌靶向治疗进展-徐瑞华教授.ppt

1、晚期肠癌靶向治疗进展,徐瑞华 MD p=0.048 mPFS ERBITUX + FOLFIRI: 8.9 months mPFS 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 investiga

2、te the impact of the KRAS mutation status of tumors on PFS 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

3、 12/13 determined using quantitative PCR-based assay,Van Cutsem 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 wit

4、h 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,FOLFIRI,ERBITUX + FOLFIRI,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2,Relating KRAS status to efficacyPrimary endpoint: PFS KRAS wild-type,Van

5、Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2,Relating KRAS status to efficacyPrimary 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 v

6、s mutant (n=105) 7.6 months,FOLFIRI HR=0.97 (p=0.87) Median PFS: Wild-type (n=176) 8.7 monthsvs 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 muta

7、nt,8,0,2,4,6,10,16,12,14,PFS estimate,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2,Relating KRAS status to efficacySecondary 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+ FOL

8、FIRI,Van Cutsem E, et al. J Clin 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

9、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 grade 3/4 adverse-event profile was similar in the KRAS wild-type and mutant populations,OPUS: Study

10、design,Primary endpoint Overall confirmed response rate (as assessed by independent review) Secondary endpoints PFS time OS time Rate of curative surgery for metastases Safety,ERBITUX + FOLFOX4a 400 mg/m2 initial IV infusion (day 1) then 250 mg/m2 weekly + oxaliplatin 85 mg/m2 + 5-FU/LV every 2 week

11、s,FOLFOX4a Oxaliplatin 85 mg/m2 + 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%) subject

12、s: KRAS evaluable population,134 (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

13、,p=0.16,Role of KRAS status in response rate,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000,37,61,49,33,Relating KRAS status to efficacySecondary 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 ERBI

14、TUX + FOLFOX: 7.7 monthsmPFS FOLFOX: 7.2 months,Progression-free survival estimate,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000,Relating KRAS status to efficacySecondary endpoint: PFS KRAS mutant,KRAS mutant HR=1.83; p=0.0192 mPFS ERBITUX + FOLFOX: 5.5 monthsmPFS FOLFOX: 8.6 months

15、,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,Progression-free survival estimate,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000,Relating KRAS status to efficacy:Progression-free survival,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,PFS estimate,Ti

16、me (months,0.5,1.0,0.4,0.3,0.2,0.1,0.0,0.6,0.7,0.8,0.9,8,0,2,4,6,10,12,Time (months,ERBITUX + FOLFOX HR=0.45; p=0.0009 mPFS Cet + FOLFOX wild-type (n=61): 7.7 monthsmPFS Cet + FOLFOX mutant (n=52): 5.5 months,FOLFOX HR=1.40; p=0.1655 mPFS FOLFOX wild-type (n=73): 7.2 monthsmPFS FOLFOX mutant (n=47):

17、 8.6 months,PFS estimate,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000,Most common grade 3/4 AEs,aThere 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

18、by 10% (46% vs 36%) 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 Onco

19、l 2008;26 (Abstract No. 4000,ERBITUX + CT in KRAS wild-type: Consistent results,Response rate (,59,37,0,10,20,30,40,50,60,70,CRYSTAL1 (n=348,OPUS2(n=134,43,61,FOLFIRI,FOLFOX,ERBITUX + FOLFIRI,ERBITUX + FOLF0X,CRYSTALKRAS wild-type: HR=0.68,p=0.017,32% risk reductionfor progression,OPUSKRAS wild-type

20、: HR=0.57,p=0.016,43% risk reductionfor progression,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,Time (months,PFS estimate,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,Time (months,PFS estimate,ERBITUX in pretreated mCRC,Evidence of correlation between KRAS wil

21、d-type and EGFR inhibitor efficacy in chemorefractory CRC: Response,NCIC CTG CO.17 Karapetis C, et al. WCGIC 2008 June 28 10:45 Session XVII,Role of KRAS mutations in predicting response, progression-free survival and overall survival in irinotecan-refractory patients treated with cetuximab plus iri

22、notecan for a metastatic colorectal cancer: Analysis of 281 individual data from published seriesAbstract 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

23、), Tejpar S (1)(1) Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven- Belgium; (2) Institut National de la Sant 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

24、 Pathology, Locarno- Switzerland; (5) Laboratory of Molecular Genetics Institute for Cancer Research and Treatment, University of Torino Medical School, Torino- Italy,Response to cetuximab-Irinotecan according to KRAS status (n=281,Di Fiore F, Van Cutsem E et al, WCGIC Barcelona, Ann Oncol, 2008 abs

25、tract O-018,Meta-analysis in chemorefractory CRC,6,Meta-analysis in chemorefractory CRC PFS according to KRAS status,Di Fiore F, Van Cutsem E et al, WCGIC Barcelona, Ann Oncol, 2008 abstract O-018,Meta-analysis in chemorefractory CRC OS according to KRAS status,Di Fiore F, Van Cutsem E et al, WCGIC

26、Barcelona, Ann Oncol, 2008 abstract O-018,Overall survival according to KRAS mutation and skin toxicity,Time (months,1.00,0.75,0.50,0.25,0.00,0,10,20,30,p=0.0008,15.6 months (95% CI: 10.922,10.7 months (95% CI: 8.316.3,5.6 months,95%CI: 2.810.6,Survival probability,2 good prognostic factors (wild-ty

27、pe and grade 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 2008,NCIC CO.17: randomized phase III trial,EGFR testing by IHC,Disease progression or Unacceptable toxicity,S

28、tratification: Center ECOG PS (0 or 1 vs 2,REGISTER,RANDOMI ZE,1:1,ERBITUX + BSC,BSC alone,Failed or intolerant to all recommended therapies,Jonker D, et al. N Engl J Med 2008,ERBITUX + BSC,CENSORED,BSC,CENSORED,Subjects at risk,ERBITUX+BSC,287,217,136,78,37,14,4,0,0,0,BSC,285,197,85,44,26,12,8,2,1,

29、0,Proportion alive,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Months,0,3,6,9,12,15,18,21,24,27,HR 0.77 (95% CI: 0.64, 0.92) Stratified log-rank p=0.0046,Jonker D, et al. N Engl J Med 2008,NCIC CTG CO.17: Overall Survival,ERBITUX + BSC,CENSORED,BSC,CENSORED,Proportion progression-free,0,0.1,0.2,0.3,0.

30、4,0.5,0.6,0.7,0.8,0.9,1.0,Months,0,3,6,9,12,15,HR 0.68 (95% CI: 0.570.80) Stratified log-rank p0.0001,Jonker D, et al. N Engl J Med 2008,NCIC CTG CO.17: Progression Free Survival,NCIC CTG CO.17 K-Ras Analysis,Genomic DNA extracted from FFPET slides or sections Assessed by bidirectional sequencing fo

31、r codon 12/13 mutations No difference between K-ras mutated and WT patients re: demographics, previous treatment or other variables,N=572 randomized: ITT subset,N=394: K-ras assessed subset (69,N=164 (42%) mutant,N=230 (58%) wild-type,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: PFS in t

32、he Mutant K-ras Subgroup,HR 0.99 95% CI (0.73,1.35) Log rank p-value: 0.96,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: PFS in the K-ras Wild-Type Patients,HR 0.40 95% CI (0.30,0.54) Log rank p-value: 0.0001,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: Overall survival in K-r

33、as Mutant patients,HR 0.98 95% CI (0.70,1.37) Log rank p-value: 0.89,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: Overall survival in K-ras Wild-Type patients,HR 0.55 95% CI (0.41,0.74) Log rank p-value: 0.0001,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: Overall Survival by

34、K-ras Status in BSC ARM,HR 1.01 95% CI (0.74,1.37) Log rank p-value: 0.97,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: Overall Survival by K-ras Status in BSC ARM,HR 1.01 95% CI (0.74,1.37) Log rank p-value: 0.97,NO PROGNOSTIC IMPACT OF K-ras STATUS,Karapetis C et al, WCGIC Barcelona, 20

35、08,Conclusions: pretreated mCRC,In pretreated patients with mCRC, ERBITUX shows significantly increased survival benefit as well as a PFS benefit in patients with KRAS wild type tumors Erbitux in combination with irinotecan is more active than Erbitux monotherapy in irinotecan refractory patients. T

36、he benefit is statistically significant, but also clinical relevant,Cross trial comparison,0,0.2,0.4,0.6,0.8,1,0,2,4,6,8,10,12,14,16,18,Time from Randomisation (Months,Proportion Alive,BSC in NCIC CO17,Erbitux in NCIC CO 17,ERBITUX with wild type in NCIC CO 17,Erbitux+Iri in Bond,ERBITUX +Iri with w

37、ild type in pretreated patients,4.5m,6.1m,8.6m,9.5m,10m,Conclusions,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 therapy to treatment of mCRC ERBITUX in combination with a standard first-

38、line treatment for patients with mCRC is an important new option in patients with KRAS wild-type tumors,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,Interim results from PACCE irinotecan + bevacizumab panitumumab for first-line treatment of mCRC study design,Hecht J, et al. Abstract 279,SCREE N

39、ING,RANDOMIZE,Ox-based CT(e.g. FOLFOX)N=800 inv choice,In-based CT(e.g. FOLFIRI)N=200inv choice,Panitumumab6mg/kg Q2WOx-CTBevacizumab,Panitumumab6 mg/kg Q2WIri-CTBevacizumab,Ox-CTBevacizumab,Iri-CTBevacizumab,1:1,1:1,Interim results from PACCE irinotecan + bevacizumab +/- panitumumab for first-line

40、treatment of mCRC median PFS (central review,Hecht J, et al. Abstract 279,100 80 60 40 20 0,PFS (,0510152025,Time (days,Panitumumab + Bevacizumab/Iri-CT Bevacizumab/Iri-CT,HR = 1.2 (95% CI: 0.801.82)* *Descriptive only,BACK,Interim results from PACCE irinotecan + bevacizumab panitumumab for first-li

41、ne treatment of mCRC response by KRAS status,Hecht J, et al. Abstract 279,BACK,0510152025,Interim results from PACCE oxaliplatin + bevacizumab +/- panitumumab for first-line treatment of mCRC PFS (central review,Hecht JR, et al. Abstract 273,100 80 60 40 20 0,HR=1.27 (95% CI: 1.051.53)*Descriptive o

42、nly,Time (months,PFS (,BACK,Surviving (,Interim results from PACCE oxaliplatin + bevacizumab +/- panitumumab for first-line treatment of mCRC OS (central review,Hecht JR, et al. Abstract 273,06121824,100 80 60 40 20 0,Time (months,HR=1.43 (95% CI: 1.111.83)*Descriptive only. Statistical significance is limit