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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),FOLFIRI Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-h continuous infusion) + LV (every 2 weeks),ERBITUX + FOLFIRI ERBITUX (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 (
3、every 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 m
4、PFS 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 PF
5、S 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
6、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 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 (Su
8、ppl. 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
9、=0.97 (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 estima
10、te,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 C
11、lin 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
12、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 design,Primary endpoint Ov
13、erall 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 weeks,FOLFOX4a Oxaliplatin 85
14、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%) subjects: KRAS evaluable populat
15、ion,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,p=0.16,Rol
16、e 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 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 + FOL
17、FOX: 7.7 months mPFS FOLFOX: 7.2 months,Progression-free survival estimate,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000),Relating KRAS status to efficacy Secondary endpoint: PFS KRAS mutant,KRAS mutant HR=1.83; p=0.0192 mPFS ERBITUX + FOLFOX: 5.5 months mPFS FOLFOX: 8.6 months,0.5,
18、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,Time
19、(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 months mPFS Cet + FOLFOX mutant (n=52): 5.5 months,FOLFOX HR=1.40; p=0.1655 mPFS FOLFOX wild-type (n=73): 7.2 months mPFS FOLFOX mutant (n=47)
20、: 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 ra
21、te 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
22、Oncol 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 reduction for progression,OPUSKRA
23、S wild-type: HR=0.57,p=0.016,43% risk reduction for 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 be
24、tween KRAS wild-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 cetu
25、ximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from published series Abstract O-018 World Congress GI Cancer Barcelona 2008 Di 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
26、), Bardelli A (5), 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;
27、 (4) Institute Of 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, A
28、nn Oncol, 2008 abstract 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 Cuts
29、em E et al, WCGIC 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 prog
30、nostic factors (wild-type 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
31、or Unacceptable toxicity,Stratification: 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
32、,285,197,85,44,26,12,8,2,1,0,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 progre
33、ssion-free,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,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
34、bidirectional sequencing for 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,
35、2008,NCIC CTG C0.17: PFS in the 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 C
36、0.17: Overall survival in K-ras 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 CT
37、G 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,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
38、 C et al, WCGIC Barcelona, 2008,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 irin
39、otecan refractory patients. The 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+I
40、ri in Bond,ERBITUX +Iri with wild 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 comb
41、ination with a standard first-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
42、J, et al. Abstract 279,S C R E E N I N G,R A N D O M I Z E,Ox-based CT (e.g. FOLFOX) N=800 inv choice,In-based CT (e.g. FOLFIRI) N=200 inv choice,Panitumumab 6mg/kg Q2W Ox-CT Bevacizumab,Panitumumab 6 mg/kg Q2W Iri-CT Bevacizumab,Ox-CT Bevacizumab,Iri-CT Bevacizumab,1:1,1:1,Interim results from PACC
43、E irinotecan + bevacizumab +/- panitumumab for first-line treatment of mCRC median PFS (central review),Hecht J, et al. Abstract 279,100 80 60 40 20 0,PFS (%),0 5 10 15 20 25,Time (days),Panitumumab + Bevacizumab/Iri-CT Bevacizumab/Iri-CT,HR = 1.2 (95% CI: 0.801.82)* *Descriptive only,BACK,Interim r
44、esults from PACCE irinotecan + bevacizumab panitumumab for first-line treatment of mCRC response by KRAS status,Hecht J, et al. Abstract 279,BACK,0 5 10 15 20 25,Interim results from PACCE oxaliplatin + bevacizumab +/- panitumumab for first-line treatment of mCRC PFS (central review),Hecht JR, et al
45、. Abstract 273,100 80 60 40 20 0,HR=1.27 (95% CI: 1.051.53)* *Descriptive only,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 273,0 6 12 18 24,100 80 60 40 20 0,Time (months),HR=1.43 (95% CI: 1.111.83)* *Descriptive only. Statistical significance is limited by the lack of a prespecified significance boundary,Interim results from PACCE oxaliplatin + bevacizumab +/- panitumumab for first-line treatment of mCRC OS b