BRAF突变型晚期结直肠癌的治疗策略

北京大学肿瘤医院消化肿瘤内科王晰程BRAF突变型晚期结直肠癌的治疗策略晚期结直肠癌治疗的药物和方案

氟尿嘧啶类（5FUCape）奥沙利铂、伊立替康含奥沙利铂的方案FOLFOX±Bev/cetXELOX±BevFOLFOXIRI±Bev含伊立替康的方案CPT-11XELIRIFOLFIRI±Cet/Bev西妥昔单抗、帕尼单抗贝伐珠单抗、阿柏西普其它：瑞格菲尼细胞毒药物

分子靶向药物FIRE-3:RASWT生存分析

0.751.00.500.25122436486072TimeSinceStartofTreatment,Months171171Numberatrisk12812771683926209610.0ProbabilityofSurvivalEvents

n/N(%)Median,Months(95%CI)FOLFIRI+CET

91/171(53.2)33.124.5-39.4FOLFIRI+BEV110/171(64.3)25.622.7-28.6HR=0.70(95%CI,0.53-0.92)P(log-rank)=0.011Δ=7.5monthsStintzing,etal.ASCOGI.2014(abstr445).CALGB80405:RAS野生型亚组分析

SubgroupChemo+BEVNChemo+CETNResponserate%*BEVvs

Cetp-valuePFStimeHazardratio95%CIp-valueOStimeHazardratio95%CIp-valueRASevaluable†32434656.0vs.68.8p<0.0111.4vs.10.9‡1.10.9–1.3p=0.3430.3vs.30.8‡0.90.8–1.1p=0.49RASWT25627053.8vs.68.6p<0.0111.3vs.11.4‡1.10.9–1.3p=0.3131.2vs.32.0‡0.90.7–1.1p=0.40*406RASevaluableand319RASWTpatientswereevaluableforresponse†PatientswithKRAScodon12/13wild-typetumoursforwhichtumourDNAsampleswereevaluableforotherRASmutations;‡Median,monthsLenz,etal.ESMO2014.Abstract501O.OPUS:KRAS/BRAF状态与生存分析

Bokemeyer,etal.Annal

Onco2011.19.517.5CRYSTAL:KRAS/BRAF状态与生存

VanCustem

etal.JCO2011.16.72010.321.6SurvivalbenefitalsoindependentofVEGF(plasmaandtissue)andTSP-2

(0.45–1.10)

(0.15–0.70)

0.70

0.32

26.35

25.07

99

47

17.45

16.26

92

28

191

75p53overexpression

Positive

Negative

(0.30–0.95)

(0.32–1.42)

0.54

0.67

27.70

NR

76

35

21.72

16.36

63

31

139

66p53mutationstatus

Mutant

Wild-type

(0.37–1.20)

(0.34–0.82)

0.67

0.57

19.91

27.70

51

68

13.60

21.72

37

57

88

125KRASandBRAFmutationstatus

Mutant

Wild-type

(0.01–1.06)

(0.34–0.82)

0.11

0.53

15.93

26.35

7

120

7.95

17.45

3

97

10

217BRAFmutationstatus Mutant

Wild-type

(0.37–1.31)

(0.34–0.99)

0.69

0.58

19.91

27.70

44

85

13.6017.64

34

67

78

152KRASmutationstatus Mutant

Wild-type(0.39–0.85)0.5726.3514717.45120267Allsubjects

(95%CI)

HRMedian,months

nMedian,months

n

N

BiomarkerPlacebo+IFL 0.2 0.5 1 2 5HRBev+IFLJubb,etal.JCO2006

Ince,etal.JNCI2005Bev=bevacizumab

TSP-2=thrombospondin-2AVF2107g:KRAS/BRAF状态与生存

RAS/BRAF基因状态影响预后StintzingSetal.etal.ECC2013(AbstNoLBA17).RASwt

~50%KRASmt

(exon2)

~40%‘New’

RASmt

~10%*RAS/BRAF基因野生型患者充分接受细胞毒药物和靶向药物可以明显生存获益RAS/BRAF基因突变的患者预后不良晚期结直肠癌患者中：50~55%RAS突变

5~7%BRAF突变结直肠癌中的BRAF突变结直肠癌中，BRAF突变率约为5%-7%通过度活化MAPK通路导致肿瘤细胞增殖与KRAS突变相互排斥在老年、女性、右半结肠、MSI和病理类型分化差/粘液腺癌中突变比例高RasRaf*MEKERKProliferationSurvivalTieJetal.IJC2011TranBetal.Cancer2011BRAF基因突变的预后和转移方式Tranetal.(2011)CancerTieetal.(2014)Targ

OncolBRAF抑制剂单独使用对结直肠癌疗效欠佳BRAF抑制剂在不同肿瘤的临床研究:PLX-4032inBRAFmutatedmelanoma

ChapmanetalNEJM201148%objectiveresponsePLX-4032inBRAFmutatedcolorectalcancer

KopetzetalASCO2010,Abstr353421patients1partialresponse(5%)and4minorresponsesReactivationofEGFRsignalinguponBRAFinhibitionSignalinginBRAFCRCCorcoranetal.CancerDiscov2012Prahalladetal.Nature2012PartialinhibitionofMAPKpathwaysignalingwithinhibitionofBRAFandEGFRUpdatedmodelRobustinhibitionofMAPKpathwaysignalingwithinhibitionofBRAF,MEK,EGFRMaximumTumorResponse

Barsaregroupedbybestunconfirmedresponse.*Indicatesmaximumreductionfrombaselineis0%.aDenotesthatsubjectreceivedprioranti-EGFRtherapy.bdenotesprogressivediseasesecondarytopresenceofnewlesion.cPatienthada30%reductionintargetlesionsbutwasdeemedtohavePDduetopresenceofonenewlesion.BendellJCetal.ASCO2014Abstract3515BRAF突变与MLH1过甲基化相关ParsonsMTetal(2012)JMedGenet2015ASCOLBA100.LBA100：MMR缺陷肿瘤中的PD-1阻断PD-1抑制剂(Pembrolizumab)：10mg/kgq2w主要终点：免疫相关20周PFS以及缓解率采用检测微卫星不稳定的标准PCR为基础的方法检测错配修复结直肠癌非结直肠癌队列A错配修复缺陷(n=25)队列B错配修复无缺陷(n=25)队列C错配修复缺陷(n=21)2015ASCOLBA100.肿瘤缓解MMR缺陷CRCMMR无缺陷CRCMMR缺陷非CRCN132510ORR62%0%60%DCR92%16%70%10080604020005101520时间(月)10080604020005101520时间(月)HR=0.103P<0.001HR=0.206P=0.02MMR缺陷MMR无缺陷MMR缺陷MMR无缺陷PFSOSPFS(%)OS(%)MMR缺陷MMR缺陷患者通过免疫治疗获益MasiGetal.(2010)LancetOncolBRAF突变生存从强烈治疗中获益GONO:PhaseIIStudyonFOLFOXIRI+BEVPFSOSLoupakisFetal.(2014)ASCOAbst3519BRAF突变生存从强烈治疗中获益SubgroupBiomarkerAnalysisinTRIBEStudyLoupakisFetal.(2014)ASCOAbst3519IntensiveTherapyonBRAFMutationSubgroupBiomarkerAnalysisinTRIBEStudy

LoupakisFetal.(2014)EJCIntensiveTherapyonBRAFMutationPhaseIIFOLFOXIRI+BEVinBRAFmuatant

mCRC中国结直肠癌改良FOLFOXIRI研究HeinemannV,etal.2014ASCOAbstract3600.王晰程，沈琳等（2016）解放军医学杂志CRC个体化治疗需多因素考虑CMS：ConcensusMolecularSubtypeDienstmann,etal.ASCO2014.Abstract3511CMS114%超突变,BRAF

mut,MSI,免疫通路活化/表达,右半结肠,诊断时年龄更大,女性CMS241%EGFR

扩增/过表达,CIN高表达,MSS,强WNT/MYC通路,左半结肠,TP53

mut,CMS38%KRAS

mut,CIN低表达,适度WNT/MYC通路活化,PIK3CA

mut,IGFBP2过表达CMS420%CIN/MSI异质性,间质/TGF-beta活化,诊断时年龄更轻,

NOTCH3/VEGFR2过表达复发后生存期短复发后生存期长复发后生存期一般复发后生存期一般总结BRAFV600E突变型患者生存期较野生型明显缩短。BRAF突变对单纯BRAF抑制剂效果欠佳，多靶点的阻断可能可以提高治疗效果。BRAF突变型对常规化疗不敏感，但可能从FOLFOXIRI+BEV强烈治疗中获益。BRAF/RAS突变型治疗方案选择：FOLFOXIRI+/-BEV？

新靶点药物(免疫治疗)？

大数据时代的结直肠癌分型……谢谢！谢谢！DudleyJetal.(2016)CCRGreystokeAetal.(2012)GastroenterolResPrctKRAS\BRAF突变率与肿瘤部位的相关性CRCSC–ResultsSummaryCMS113%Females,olderage,rightcolon,MSI,hypermutation,BRAF

mut,immuneactivationBetterRFS,intermediateOS,worseSaRCMS235%Leftcolon,epithelial,MSS,highCIN,TP53

mut,WNT/MYCpathwayactivationIntermediateRFS,betterOS,betterSaRCMS311%Epithelial,CIN/MSI,KRAS

mut,MYC

ampl,IGFBP2overexpressionIntermediateRFS,OSandSaRCMS420%Youngerage,stageIII/IV,mesenchymal,CIN/MSI,TGFβ/VEGFactivation,NOTCH3overexpression

WorseRFS,worseOSIntermediateSaRUnclassified

21%Mixedsubtypewithvariableepithelial-mesenchymalactivation?IntermediateRFS,OSandSaRCRCSC–Results

Relapse-freeSurvivalOveralllogrankp=0.00342*CMS4vs.CMS1

HR=1.8(1.1–2.9) p=0.023*CMS4vs.CMS2

HR=1.7(1.3–2.2) p=0.00024**Adjustedforstage,adjuvantchemotherapy,MSI,BRAF

mut,andstratifiedbydataset.Natrisk22521825148912231007840621CRCSC–Results

SurvivalafterrelapseOveralllogrankp=0.00105*CMS1vs.CMS2

HR=2.8(1.6–5.2) p=0.0006*CMS4vs.CMS2

HR=1.6(1.1–2.3) p=0.03*Natrisk420269173105 56 16 0*Adjustedforstage,MSI,BRAF

mut,andstratifiedbydataset.CatalanoV,

LoupakisF,

GrazianoF,etal.BrJ

Cancer.

2009Mar24;100(6):881-7.粘液腺癌对比非粘液腺癌一线治疗疗效差MSIandBRAFStatusonOSLochheadPetal(2013)JNCIMSI-H/BRAF-WTMSS/BRAF-mutantTieJetal.Targ

Oncol

2014FIRE3研究：

不同原发肿瘤部位患者的PFS及OSFOLFIRI+西妥昔单抗(A组)FOLFIRI+贝伐珠单抗(B组)PFS时间(月)左侧(n=127)中位PFS=10.5个月右侧(n=39)中位PFS=8.8个月P=0.065HR=0.69(0.47-1.03)OS时间(月)左侧(n=127)中位OS=28.0个月右侧(n=39)中位OS=22.7个月P=0.034HR=0.63(0.41-0.97)1.000.750.500.250.001224364860721.000.750.500.250.00122436486072PFS时间(月)左侧(n=137)中位PFS=10.8个月右侧(n=30)中位PFS=6.9个月P<0.0001HR=0.35(0.23-0.53)OS时间(月)左侧(n=137)中位OS=38.7个月右侧(n=30)中位OS=16.1个月P<0.0001HR=0.26(0.16-0.42)1.000.750.500.250.001224364860721.000.750.500.250.00122436486072HeinemannV,etal.2014ASCOAbstract3600.西妥昔单抗、贝伐单抗一线治疗，KRAS野生型的左半结肠患者OS明显优于右半结肠患者KRASWTKRASMUT:codons12,13TreatmentFOLFOX(N=331)Panitumumab+FOLFOX(N=325)FOLFOX(N=219)Panitumumab+FOLFOX(N=221)PFS,mosHR(95%CI)Pvalue8.6100.80(0.67-0.95)0.019.27.41.27(1.04-1.55)0.02OS,mosHR(95%CI)Pvalue19.723.90.88(0.73-1.06)0.1719.215.51.17(0.95-1.45)0.15ORR,*%(95%CI)48(42-53)57

(51-63)41(34-48)40(33-47)Oddsratio(95%CI)1.47(1.07-2.04)P=0.020.98(0.65-1.47)P=0.92DouillardJY,etal.PresentedatASCO2011(abstr3510).SienaS,etal.PresentedatASCOGI.2011(abstr3510).PRIME研究：疗效(ByKRASStatus)RASWTaRASMUTbTreatmentFOLFOX(N=253)Panitumumab+FOLFOX(N=259)FOLFOX(N=276)Panitumumab+FOLFOX(N=272)PFS,mosHR(95%CI)Pvalue7.910.10.72(0.58–0.90)<0.018.77.31.31(1.07–1.60)0.01OS,mosHR(95%CI)Pvalue20.226.00.78(0.62–0.99)0.0419.215.61.25(1.02–1.55)0.04aWTinKRASandNRASexons2,3,and4.b.MUTinanyKRASorNRASexon2,3,or4PRIME研究：疗效(ByKRASStatus)17%ofpatientswithnon-mutatedKRASexon2hadotherRASmutations52%ofallpatientshadsomeRASmutationNEnglJMed2013;369:1023-34KRAS\BRAF状态

与总生存的相关性RothAD,etal(2010)JClinicalOncologyII期和III期结直肠癌术后BRBRAFKRASBRAF抑制剂(dabrafenib)联合MEK抑制剂(trametinib)

治疗36例BRAF突变的CRC患者MaximumPercentReduction

FromBaselineMeasurementUnconfirmedresponses(CR+PR): 4(11%)

2confirmedresponses(1CRand1PR)Unconfirmedminorresponses: 8(22%)CorcoranetalASCO2013Be