晚期肠癌靶向治疗进展-徐瑞华教授

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,中 山 大 学 肿 瘤 医 院,Sun Yat-sen University Cancer Center,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 population (n=1198),FOLFIRI,Irinotecan,(180 mg/m,2,),+ 5-FU,(400 mg/m,2,bolus + 2400 mg/m,2,as 46-h continuous infusion),+ LV,(every 2 weeks),ERBITUX + FOLFIRI,ERBITUX,(IV 400 mg/m,2,on day 1,then 250 mg/m,2,weekly),+ irinotecan,(180 mg/m,2,),+ 5-FU,(400 mg/m,2,bolus + 2400 mg/m,2,as 46-h continuous infusion),+ LV,(every 2 weeks),R,EGFR-expressing,mCRC,Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000),1.0,0.8,0.9,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0,2,4,6,8,10,12,14,16,18,20,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%,FOLFIRI (n=599),ERBITUX + FOLFIRI (n=599),PFS ITT: HR=0.85;,p=0.048,mPFS ERBITUX + FOLFIRI: 8.9 months,mPFS FOLFIRI: 8.0 months,Independent assessment of response,Outcome,FOLFIRI(n=599)(%),ERBITUX+ FOLFIRI(n=599)(%),CR,PR,SD,PD,0.3,38.4,46.7,9.0,0.5,46.4,37.4,8.8,ORR,95% CI,38.7,34.842.8,46.9,42.951.0,DCR,85.4,84.3,Van Cutsem E, et al. ECCO 2007 (Abstract No. 3001),39%,47%,Response rate (%),p=0.0038,a,a,CochranMantelHaenszel 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 2021;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 2021;26 (Suppl. abstract 2),Relating KRAS status to efficacyPrimary endpoint: PFS KRAS wild-type,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,Months,Progression-free survival estimate,ERBITUX + FOLFIRI,FOLFIRI,KRAS wild-type (n=348) HR=0.68; p=0.017,mPFS ERBITUX + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months,1-year PFS rate,25% vs 43%,Van Cutsem E, et al. J Clin Oncol 2021;26 (Suppl. abstract 2),Relating KRAS status to efficacyPrimary endpoint: PFS KRAS mutant,KRAS mutant (n=192) HR=1.07; p=0.75,mPFS ERBITUX + FOLFIRI: 7.6 months mPFS FOLFIRI: 8.1 months,0,2,4,6,8,10,12,14,16,Months,ERBITUX + FOLFIRI,FOLFIRI,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Progression-free survival estimate,Van Cutsem E, et al. J Clin Oncol 2021;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 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),ERBITUX +FOLFIRI wild-type,ERBITUX +FOLFIRI mutant,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 2021;26 (Suppl. abstract 2),Relating KRAS status to efficacySecondary endpoint: Response,p=0.0025,a,FOLFIRI,ERBITUX+ FOLFIRI,a,Cochran-Mantel-Haenszel (CMH) test,KRAS wild-type (n=348),KRAS mutant (n=192),p=0.46,a,FOLFIRI,ERBITUX+ FOLFIRI,Van Cutsem E, et al. J Clin Oncol 2021;26 (Suppl. abstract 2),Relating KRAS status to outcome:Most common grade 3/4 adverse events,KRAS wild-type,KRAS mutant,Adverse events, %,FOLFIRI,(n=176),ERBITUX + FOLFIRI,(n=173),FOLFIRI,(n=87),ERBITUX + FOLFIRI,(n=105),Any,Neutropenia,50.6,16.5,78.0,25.4,55.2,23.0,72.4,21.9, Febrile neutropenia,Diarrhea,0.6,9.1,0.6,17.3,0,12.6,3.8,13.3,Vomiting,2.8,4.6,6.9,2.9,Fatigue,4.5,2.3,2.3,9.5,Acne-like rash,a,0,16.2,0,17.1,Infusion-related reactions,0,1.7,0,3.8,a,There was no grade 4 acne-like rash,Van Cutsem E, et al. J Clin Oncol 2021;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 + FOLFOX4,a,400 mg/m,2,initial IV infusion (day 1),then 250 mg/m,2,weekly,+ oxaliplatin 85 mg/,m,2,+ 5-FU/LV every 2 weeks,FOLFOX4,a,Oxaliplatin 85 mg/,m,2,+ 5-FU/LV every 2 weeks,EGFR-detectable,mCRC,R,Stratification by:,ECOG PS 0/1, 2,Bokemeyer C, et al. J Clin Oncol 2021;26 (Suppl. abstract 4000),a,Treatment until progression, symptomatic,deterioration or unacceptable toxicity,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 2021;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 2021;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 ERBITUX + FOLFOX: 7.7 monthsmPFS FOLFOX: 7.2 months,Progression-free survival estimate,FOLFOX,ERBITUX + FOLFOX,Bokemeyer C, et al. J Clin Oncol 2021;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,FOLFOX,ERBITUX + FOLFOX,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 2021;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),ERBITUX +FOLFOX wild-type,ERBITUX +FOLFOX mutant,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),FOLFOX wild-type,FOLFOX mutant,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): 8.6 months,PFS estimate,Bokemeyer C, et al. J Clin Oncol 2021;26 (Suppl. abstract 4000),Most common grade 3/4 AEs,KRAS wild-type,KRAS mutant,Adverse event, %,FOLFOX(n=73),ERBITUX+ FOLFOX(n=61),FOLFOX(n=47),ERBITUX+ FOLFOX(n=52),Any,Neutropenia, Febrile neutropenia,63.0,32.9,1.4,83.6,41.0,0,78.7,44.7,4.3,67.3,25.0,0,Diarrhea,5.5,11.5,12.8,5.8,Peripheral sensory neuropathy,8.2,4.9,2.1,3.8,Acne-like rash,a,0,14.8,0,11.5,Infusion-related reactions,0,1.4,0,7.7,a,There was no grade 4 acne-like rash,Bokemeyer C, et al. J Clin Oncol 2021;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 2021;26 (Abstract No. 2); 2. Bokemeyer C, et al. J Clin Oncol 2021;26 (Abstract No. 4000),ERBITUX + CT in KRAS wild-type: Consistent results,Response rate (%),59,37,0,10,20,30,40,50,60,70,CRYSTAL,1,(n=348),OPUS,2,(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: 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 wild-type and EGFR inhibitor efficacy in chemorefractory CRC: Response,Reference,Treatment,No. of patients (wild-type: mutant),Objective response,n (%),Wild-type,Mutant,Livre A, et al. (J Clin Oncol 2008),ERBITUX CT,114 (78:36),34 (44),0 (0),Benvenuti S, et al. (Cancer Res 2007),Panitumumab or ERBITUX or ERBITUX + CT,48 (32:16),10 (31),1 (6),DeRoock W, VanCutsem E, Tejpar S et al. (Ann Onc 2008),ERBITUX or ERBITUX + irinotecan,113 (67:46),27 (41),0 (0),Finocchiaro G et al. (ASCO Proceedings 2007),ERBITUX CT,81 (49:32),13 (26),2 (6),Di Fiore F et al.(Br J Cancer 2007),ERBITUX + CT,59 (43:16),12 (28),0 (0),Khambata-Ford S et al. (J Clin Oncol 2007),ERBITUX,80 (50:30),5 (10),0 (0),Amado R, Van Cutsem E et al. (J Clin Oncol 2008),Panitumumab,208 (124:84),21 (17),0 (0),NCIC CTG CO.17 Karapetis C, et al. WCGIC 2021 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 seriesAbstract O-018 World Congress GI Cancer Barcelona 2021Di 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,n,KRAS mutation (n),KRAS WT (n),Complete response (CR),3,0 (0),3 (1.6),Partial response (PR),74,0 (0),74 (40.6),Stable disease (SD),107,41 (41.4),66 (36.3),Progressive disease (PD),97,58 (58.6),39 (21.5),Response to cetuximab-Irinotecan according to,KRAS,status (n=281),Di Fiore F, Van Cutsem E et al, WCGIC Barcelona, Ann Oncol, 2021 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, 2021 abstract O-018,Meta,-,analysis in chemorefractory CRC,OS according to,KRAS,status,Di Fiore F, Van Cutsem E et al, WCGIC Barcelona, Ann Oncol, 2021 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 2021,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,R,ANDOMI ZE,1:1,ERBITUX + BSC,BSC alone,Failed or intolerant to all recommended therapies,Jonker D, et al. N Engl J Med 2021,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,Study arm,MS,95% CI,ERBITUX + BSC,6.1 months,5.4, 6.7,BSC alone,4.6 months,4.2, 4.9,Jonker D, et al. N Engl J Med 2021,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,Study arm,Med PFS,95% CI,ERBITUX + BSC,1.9 months,1.8, 2.1,BSC alone,1.8 months,1.8, 1.9,Jonker D, et al. N Engl J Med 2021,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, 2021,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,Study arm,Med PFS (months),95% CI,Cetuximab + BSC,1.8,1.7 1.8,BSC alone,1.8,1.7 1.8,Karapetis C et al, WCGIC Barcelona, 2021,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,Study arm,Med PFS (months),95% CI,Cetuximab + BSC,3.8,3.1 5.1,BSC alone,1.9,1.8 2.0,Karapetis C et al, WCGIC Barcelona, 2021,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,Study arm,MS (months),95% CI,Cetuximab + BSC,4.5,3.8 5.6,BSC alone,4.6,3.6 5.5,Karapetis C et al, WCGIC Barcelona, 2021,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:,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-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,NING,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 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,*PFS events (%),Median (95% CI months,54 (47),10.1 (8.213.1),43 (37),11.1 (9.013.2),HR = 1.2 (95% CI: 0.801.82)*,*Descriptive only,BACK,Interim results from PACCE irinotecan + bevacizumab,panitumumab for first-line treatment of mCRC response by,KRAS,status,Hecht J, et al. Abstract 279,N,Pmab+Bev/iri-CTn/N (%),Bev/iri-CTn/N (%),Odds ratio,(95% CI),Wild-type,KRAS,115,31/57 (54),27/58 (47),1.42 (0.633.21),Mutant K,RAS,85,14/46 (30),15/39 (38),0.59 (0.231.55),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,PFSevents (%),Median(95% CI) months,pmab+bev/Ox-CT,59,9.6 (8.810.9),bev/Ox-CT,52,11.1 (10.311.9),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 273,06121824,100,80,60,40,20,0,Time (months),Deathevents n(%),Median(95% CI), months,pmab+bev/Ox-CT,143 (35),19.4 (18.420.8,bev/Ox-CT,108 (26),NE,HR=1.43 (95% CI: 1.111.83)*Descriptive only. Statistical significance is limited by the lackof a prespecified significance boundary,Interim results from PACCE oxaliplatin + bevacizumab +/- panitumumab for first-line treatment of mCRC OS by age,Hecht JR, et al. Abstract 273,100,80,60,40,20,0,06121824,Time (months),Age 80 years,100,80,60,40,20,0,06121824,Time (months),Age 80 years,bev/Ox-CT,pmab+bev/Ox-CT,Surviving (%),Surviving (%),BACK,Interim results from PACCE oxaliplatin + bevacizumab +/- panitumumab for first-line treatment of mCRC response rates (central review),Hecht JR, et al. Abstract 273,Tumour response, n (%),Pmab + bev/OX-CT,(N = 413),Bev/OX-CT(N=410),Best ORR,187 (45),189 (46),Complete response,0 (0),2 (1),Partial response,187 (45),189 (46),Stable disease,121 (29),138 (34),Progressive disease,b,28 (7),17 (4),Not done or unevaluable,c,78 (19),64 (16),BACK,Metastatic CRC Trial: CAIRO 2,750,Previously untreated patients,PFS +3 months,Arm B,：,XELOX + Bevacizumab,+ Cetuximab,Arm A:,XELOX + Bevacizumab,RANDOMI,SAT,ION,CAIRO 2,: Results,Arm A: Chemo + Bev,Arm B: Chemo + Bev + C225,CAIRO 2,: TTP,CAIRO 2,: Overall Survival,CAIRO 2,: Toxicities,小 结,联合,Bevacizumab,与抗,EGFR,抗体一线治疗晚期,CRC,的临床研究结果中，未能显示协同的作用,联合,Bevacizumab,与抗,EGFR,抗体的治疗毒性有所增加,如何进行多个靶点药物联合的临床试验提出了挑战。,理论 结果,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,Targeting Agents in CRC,Bevacizumab,VEGF Traps,AZD2171,Sonafinib,Sunitinib,mTOR inhibitor,Cell Cycle Inhibitors,Leonard B. Saltz,et al.,JCO,2007,标准治疗失败后的转移性结直肠癌应用舒尼替尼治疗的,II,期研究,舒尼替尼的最好临床有效率,无贝伐单抗组 贝伐单抗组 所有病例,n=40 n=42 n=82,疗效 病例数 % 病例数 % 病例数 %,局部缓解 0 0 1 2.4 1 1.2,稳定 14 35