转移性结肠癌的一种新的治疗模式

A new treatment paradigm for mCRC,Heinz-Josef Lenz Professor of Medicine Associate Director, Clinical Research USC Norris Comprehensive Cancer Center Los Angeles, CA,Anti-EGFR antibodies in mCRC,Comparison of cetuximab and bevacizumab,Bleeding possible, wound-healing complications,No complications,Perioperative,Hypertension, thromboembolic events,Acne-like skin rash,Specific side effect,+?,+,RR with FOLFOX,+,+,RR with FOLFIRI,First line,Second/third line,Registered,?,Yes,Single-agent activity,VEGF protein,EGF receptor,Antibody,Bevacizumab,Cetuximab,Characteristic,Phase III CRYSTAL study: Study design,Stratification factors: Region ECOG performance status Populations: Randomized patients (n=1217) Safety population (n=1202) ITT population (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 (every 2 weeks),R,EGFR-expressing mCRC,Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000),Study endpoints,Primary endpoint PFS time (as assessed by blinded independent review) Secondary endpoints ORR (independently reviewed) DCR (CR+PR+SD) OS Quality of life (EORTC QLQ-C30) Safety,Van Cutsem E, et al. ECCO 2007 (Abstract No. 3001),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 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 investigate 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 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 with 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),Patient demographics at baseline according to KRAS status,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2),ITT and KRAS evaluable population: Comparability,ITT population (n=1198) HR=0.85 Median PFS: ERBITUX + FOLFIRI 8.9 months vs FOLFIRI 8.0 months,KRAS population (n=540) HR=0.82 Median PFS: ERBITUX + FOLFIRI 9.2 months vs FOLFIRI 8.7 months,1.0,PFS estimate,Time (Months),0.5,0.4,0.3,0.2,0.1,0.6,0.7,0.8,0.9,0.0,8,0,2,4,6,10,12,14,16,18,20,0.5,1.0,0.4,0.3,0.2,0.1,0.6,0.7,0.9,0.0,8,0,2,4,6,10,12,14,16,18,20,0.8,Time (Months),PFS estimate,ERBITUX + FOLFIRI,FOLFIRI,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. abstract 2),First-line ERBITUX + FOLFIRI: Correlation of KRAS status with efficacy,First-line treatment: ERBITUX (6 weeks monotherapy), followed by ERBITUX + FOLFIRI (n=52),Tabernero J et al, ASCO GI 2008,Relating KRAS status to efficacy Primary endpoint: PFS KRAS wild-type,Van Cutsem E, et al. J Clin Oncol 2008;26 (Suppl. 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=0.97 (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,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 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 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 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 weeks,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,Phase II OPUS trial: KRAS analysis,Objective To retrospectively investigate the impact of the KRAS mutation status of tumors on the response rate and PFS in the first-line treatment of mCRC with FOLFOX ERBITUX,Bokemeyer C, et al. J Clin Oncol 2008;26 (Suppl. abstract 4000),KRAS evaluable population,233 (69%) subjects: 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),Patient demographics at baseline,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 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 + FOLFOX: 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,0.5,1.0,0.4,0.3,0.2,0.1,0.0,0.6,0.7,0.8,0.9,8,0,2,4,6,10,12,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 (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): 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 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 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,OPUSKRAS 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 between 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 cetuximab 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), 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; (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, Ann Oncol, 2008 abstract O-018,Metaanalysis in chemorefractory CRC,6,Metaanalysis in chemorefractory CRC,PFS according to KRAS status,Di Fiore F, Van Cutsem E et al, WCGIC Barcelona, Ann Oncol, 2008 abstract O-018,OS according to KRAS status,Metaanalysis in chemorefractory CRC,Di Fiore F, Van Cutsem 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 prognostic 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 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,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 progression-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 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, 2008,Comparison of ITT and K-ras assessed subsets,*between mutated and wild-type K-RAS groups from chi-square test for categorical variables and t-test for continuous variables.,Karapetis C et al, WCGIC Barcelona, 2008,NCIC CTG C0.17: Primary endpoint overall survival,Total study population (ITT analysis),K-ras assessed subset,Karapetis C et al, WCGIC Barcelona, 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 C0.17: 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 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,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, 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 irinot