晚期大腸癌靶向治療新進(jìn)展課件

ASCO精選（2010)復(fù)旦大學(xué)附屬腫瘤醫(yī)院李進(jìn)..1晚期大腸癌靶向治療新進(jìn)展課件5/8/2024晚期大腸癌靶向治療新進(jìn)展MACRO:貝伐珠單抗維持治療一線治療晚期大腸癌2.COIN:西妥昔單抗聯(lián)合奧沙利鉑為基礎(chǔ)的化療治療晚期大腸癌..2晚期大腸癌靶向治療新進(jìn)展課件5/8/2024MACRO研究

XELOX

聯(lián)合貝伐珠單抗后繼續(xù)化療與貝伐珠單抗維持治療的隨機(jī)對照III期臨床研究J.TaberneroE.Aranda,A.Gomez,B.Massutí,J.Sastre,A.Abad,M.Valladares,F.Rivera,MaJ.Safont,E.Diaz-RubioOnbehalfoftheSpanishCooperativeGroupfortheTreatmentofDigestiveTumors(TTD)..3晚期大腸癌靶向治療新進(jìn)展課件5/8/2024方案設(shè)計：XELOX+A

對比

XELOX＋A

→

A

J.Tabernero,etal.ASCO2010(abstractno.3501)A組:

XELOX+BEVq3w直到PD(n=239)隨機(jī)入組既往未曾治療的轉(zhuǎn)移性結(jié)直腸癌Avastinq3w直到PDB組XELOX+Avastinq3wx6周期(n=241)主要終點(diǎn):PFS非劣效性次要終點(diǎn)：OS,ORR和安全性..4晚期大腸癌靶向治療新進(jìn)展課件5/8/2024研究目的通過貝伐珠的維持治療，降低化療毒性，同時保持同樣的治療效果。..5晚期大腸癌靶向治療新進(jìn)展課件5/8/2024確認(rèn)的有效率(RECIST)Patients%Xelox-Bev

(N=239)s/aBev

(N=241)46%49%Oddsratio(95%CI)=0.89(0.62-1.27)..6晚期大腸癌靶向治療新進(jìn)展課件5/8/2024療效分析療效A組(n=239)B組(n=241)p值HR/OR(95%CI)mPFS,月10.49.70.59HR:1.07(0.84-1.36)mOS,月23.421.70.63HR:1.07(0.81-1.32)ORR,%46490.51OR:0.89轉(zhuǎn)移灶切除,%108.30.51OR:1.23(0.66-2.32)J.Tabernero,etal.ASCO2010(abstractno.3501)..7晚期大腸癌靶向治療新進(jìn)展課件5/8/2024無進(jìn)展生存時間Follow-up 21.1(0-40)

20.4(0-38)median(range),months

Patientsatrisk..8晚期大腸癌靶向治療新進(jìn)展課件5/8/2024總生存時間PatientsatriskFollow-up 21.1(0-40)

20.4(0-38)median(range),months..9晚期大腸癌靶向治療新進(jìn)展課件5/8/2024MACRO

研究：安全性

不良事件,%A組(n=239)B組(n=241)?級腹瀉1113手足綜合癥126神經(jīng)毒性247J.Tabernero,etal.ASCO2010(abstractno.3501)..10晚期大腸癌靶向治療新進(jìn)展課件5/8/2024結(jié)論MACRO研究達(dá)到其主要研究終點(diǎn)。

mCRC一線治療中XELOX+貝伐珠誘導(dǎo)治療后繼以貝伐珠單藥維持治療，PFS不劣于XELOX＋貝伐珠持續(xù)治療。..11晚期大腸癌靶向治療新進(jìn)展課件5/8/2024COIN

研究西妥昔單抗聯(lián)合奧沙利鉑為基礎(chǔ)的化療治療晚期大腸癌MaughanTS,AdamsRA,SmithC,SeymourM,WilsonR,MeadeA,FisherD,MadiA,CheadleJ,KaplanRonbehalfoftheMRCCOINTrialInvestigatorsNCRIColorectalClinicalStudiesGroup..12晚期大腸癌靶向治療新進(jìn)展課件5/8/2024試驗設(shè)計XELOX

或FOLFOX隨機(jī)既往未曾治療的mCRC

(n=1630)XELOX

或FOLFOX+

西妥昔單抗66%XELOX;34%FOLFOX

入組1630位患者，1316位患者進(jìn)行KRAS檢測，729位KRAS野生型..13晚期大腸癌靶向治療新進(jìn)展課件5/8/2024COINquestion1

主要終點(diǎn)：總生存時間KRAS：12,13和61位點(diǎn)無突變的患者次要終點(diǎn)KRAS突變以及其他所有患者的總生存無進(jìn)展生存有效率生活質(zhì)量健康經(jīng)濟(jì)評估目的：西妥昔聯(lián)合奧沙利鉑為基礎(chǔ)的化療能否改善總生存？..14晚期大腸癌靶向治療新進(jìn)展課件5/8/2024ArmAArmBDiff.MedianOS:mo17.917.0-0.922-yearsurvivalrates36.1%34.4%-1.66%ArmAArmBDiff.MedianPFS:mo8.68.6+0.072-yearsurvivalrates8.83%9.55%+0.72%KRAS野生型患者的OS(最初分析)和PFS0.000.250.500.751.00Survival3623062381498042173

B3673162501548344191ANpatientsatrisk:06121824303642Time(months)ArmA(OxFp)ArmB(OxFp+cetux)HRpointestimate=1.03895%CI=(0.90,1.20)Χ2=0.18;p=0.68總生存無進(jìn)展生存3612491034222960367245924118116106121824303642Time(months)HRpointestimate=0.95995%CI=(0.84,1.09)Χ2=0.27;p=0.60ArmA(OxFp)ArmB(OxFp+cetux)..15晚期大腸癌靶向治療新進(jìn)展課件5/8/2024無疾病進(jìn)展:KRAS,NRAS,BRAF突變3662005921842034020461247210Time(months)ArmAArmBDiff.MedianPFS:mo8.89.2+0.432-yearPFSrates10.2%10.8%+0.55%ArmAArmBDiff.MedianPFS:mo6.66.3-0.332-yearPFSrates3.45%3.19%-0.26%野生型突變型0.000.250.500.751.00Survival292220943719850ArmB2892007535181161ArmANoatrisk06121824303642Time(months)ArmA(OxFp)ArmB(OxFp+cetux)HR=0.92295%CI=(0.80,1.07)97%CI=(0.78,1.09)p=0.3606121824303642ArmA(OxFp)ArmB(OxFp+cetux)HR=1.07995%CI=(0.95,1.23)97%CI=(0.93,1.25)p=0.33..16晚期大腸癌靶向治療新進(jìn)展課件5/8/2024有效率AllptsKRASwtKRASmutArmAArmBArmAArmBArmAArmBNrandomised815815367362268297OverallResponseRateat12weeks45%49%50%59%41%40%Oddsratio(BvsA)OR=1.17P=0.124OR=1.44P=0.015OR=0.97P=0.877BestOverallResponse51%53%57%64%46%43%Oddsratio(BvsA)OR=1.08P=0.428OR=1.35P=0.049OR=0.88P=0.449..17晚期大腸癌靶向治療新進(jìn)展課件5/8/20240.88(0.72,1.08)1.05(0.75,1.46)428153<10,000/l≥10,000/l所有患者性別年齡轉(zhuǎn)移病灶治療方案亞組男女<=65歲>65歲0/12+XeloxOxMdG581408173338243230351391190數(shù)量0.92(0.78,1.10)0.87(0.71,1.07)1.02(0.74,1.41)1.00(0.80,1.26)0.81(0.62,1.06)0.73(0.55,0.97)1.07(0.86,1.33)1.02(0.82,1.26)0.72(0.53,0.98)HR(95%CI)西妥昔有益西妥昔無益10.250.524交互p-值P=0.381P=0.222P=0.036P=0.103預(yù)設(shè)的亞組分析（野生型患者的PFS）WBCP=0.411..18晚期大腸癌靶向治療新進(jìn)展課件5/8/2024無疾病進(jìn)展：不同氟尿嘧啶

(OxMdG比XELOX)HRp=0.07KRAS野生型患者0.000.250.500.751.00生存估計0612182430364248XELOXXELOX+西妥昔XELOX(n=485)0612182430364248OxMdGOxMdG+西妥昔OxMdG(n=244)時間(月)HR=1.06HR=0.77時間(月)0.000.250.500.751.00..19晚期大腸癌靶向治療新進(jìn)展課件5/8/2024消化道毒性的增加導(dǎo)致了

卡培他濱的減量

因為消化道的毒性，B組的卡培他濱劑量從1000降低到850mg/m2

。Xelox:OxMdG所有患者報告的三級以上的腹瀉P-值vsOxMdG,B組B比AP=0.00520%11%P=0.030P<0.00126%15%所有患者P=0.002P<0.00130%17%減量前P=0.41P=0.2516%12%減量后279536534A組B組nn281153381..20晚期大腸癌靶向治療新進(jìn)展課件5/8/2024滴注5-FU卡培他濱Hazardratio(95%CI)1.00.50.751.25CRYSTAL(n=666)OPUS(n=179)COINOxMdG(n=244)0.70(0.56–0.87)0.57(0.38–0.86)0.77(0.59–1.01)COINXELOX(n=485)1.06(0.88–1.28)

Cetuximab有益BenefitunderCTalone

KRAS基因野生型患者PFS: