KRAS野生型转移性结直肠癌一线治疗探讨(王志强)

KRAS野生型的转移性结直肠癌一线治疗探讨中山大学肿瘤防治中心内科王志强概要病例介绍：KRAS野生型的转移性结直肠癌患者贝伐珠单抗和西妥昔单抗的临床研究数据KRAS野生型患者的最佳一线治疗是什么？正在进行的临床研究存在问题病例（一）患者男性，52岁2005-11-20行乙状结肠癌根治术，术后病理为腺癌Ⅱ级，分期：pT4N2M0IIIB期患者术后接受XELOX方案辅助化疗8程，此后定期随访病例（一）2009-5-7疾病进展，CT发现多发肝转移，1.2-6.0cm，无肝外转移。PS=1，实验室检查基本正常。KRAS野生型FiguremodifiedfromNordlinger,etal.AnnOncol2009转移性结直肠癌的一线治疗初始可切除根治性手术围手术期化疗+手术潜在可切除争取根治性手术化疗±靶向治疗不可切除延长生存提高生活质量化疗±靶向治疗患者评估治疗目标治疗策略转移性结直肠癌治疗策略病例一：结直肠癌仅有肝转移各种方法治疗结直肠癌肝转移的生存情况StanglRetal.Lancet1994;343:1405-10结直肠癌肝转移手术切除后的生存情况PaulBrousseHospital：710patients(Apr1988–Dec2003)Updatedfrom:AdamR,etal.AnnSurg2004;240:644–658可切除:n=535初始不可切除:n=20592%49%31%67%p0.000190%30%46%18%Time(years)20406080100012345678910Survival(%)0结直肠癌肝转移手术切除显著延长总生存期70%ofpopulationincludedPatientstatusMedianOS(mo)5-yearOSrate(%)Resected65.355.0Non-resected26.719.5HR0.35Time(months)012243648607220406080100OS(%)LandmarkNoliverresectionLiverresection0Errorbarsrepresent95%CIsKopetzS,etal.JClinOncol2009;27:3677–3683新辅助化疗的缓解率与转移灶的切除率密切相关未经选择的有不可切除转移的患者（II期及III期研究）(实线)(r=0.74;p0.001)经选择的仅有不可切除的肝转移的患者(r=0.96;p=0.002)未经选择的有不可切除转移的患者（III期研究）(虚线)(r=0.67;p=0.024)FolprechtG,etal.AnnOncol2005;16:1311–1319缓解率.9.8.7.6.5.4.3切除率.6.5.4.3.2.10.0一线治疗方案的选择1.FOLFOX/XELOX+贝伐珠单抗2.FOLFIRI/XELIRI+贝伐珠单抗3.FOLFOX+西妥昔单抗4.XELOX+西妥昔单抗5.FOLFIRI/XELIRI+西妥昔单抗6.FOLFOXILI贝伐单抗和西妥昔单抗的临床研究数据NO16966研究中，贝伐单抗并未提高化疗有效率Chemo+placeboChemo+bevFOLFOX+placeboFOLFOX+bevXELOX+placeboXELOX+bevInvestigatorreport49%47%50%47%48%46%p=0.90p=0.88p=0.91IndependentReviewCommitteedata38%38%36%38%39%37%p=0.99p=0.49p=0.48NO16966responseratesNO16966研究亚组分析表明，贝伐单抗并未显著提高肝转移瘤切除率6.34.9Patients(%)XELOX/FOLFOX4+bevacizumabn=699XELOX/FOLFOX4n=70120151050XELOX/FOLFOX4+bevacizumabXELOX/FOLFOX4Patients(%)20151050p=NS11.512.3p=NSR0resectionratesinLLDR0resectionratesinITTCassidyJ,etal.JClinOncol2008;26(Suppl.15):AbstractNo.4022010203040506070CRYSTALOPUSCOINResponserate(%)CTCT+ERBITUXp0.0001p=0.0027p=0.015405034575759KRAS野生型患者应用西妥昔单抗可提高化疗的有效率VanCutsemE,etal.ASCOGI2010(AbstractNo.281);BokemeyerC,etal.ASCOGI2010(AbstractNo.428);MaughanT,etal.ECCO-ESMO2009(AbstractNo.6LBA)靶向治疗联合化疗治疗后肝转移瘤切除率的比较VanCutsemE,etal.NEnglJMed2009BokemeyerC,etal.JClinOncol2009;27:663–671SaltzLBetal.JClinOncol2008FOLFOX+ERBITUXFOLFOXFOLFIRI+ERBITUXFOLFIRIFOLFOX/XELOX+bevacizumabFOLFOX/XELOXNO16966LLDCRYSTALLLDOPUSKRASwt02468101214p=NSPatients(%)9.84.19.84.512.311.6CELIM临床试验-设计Adjuvanttherapyfor6cycles(samescheduleaspre-operatively)RPatientswithtechnicallyunresectable/≥5livermetastaseswithoutextrahepaticdiseaseERBITUX+FOLFOX(n=54)8cycles(~4months)TechnicallyresectablePrimaryendpoint:Responserate4furthertreatmentcyclesRESECTIONERBITUX+FOLFIRI(n=54)TechnicallyunresectableFolprechtG,etal.LancetOncol2010;11:38–47CRYSTALWild-typenRR(%)RR:Livermetastases(%)FOLFIRI+ERBITUX1725977(n=35)FOLFIRI1764350(n=32)CELIM临床试验-有效率KRASKRASEGFREGFRwild-typemutantIHC+IHC–(n=67)(n=27)(n=77)(n=29)CR/PR70%41%60%69%95%CI58–81%22–61%48–71%49–85%OR3.42(1.35–8.66)p0.01OR0.67(0.27–1.66)p=0.38Responsesconfirmedby2ndCTscanaccordingtoRECISTorbyresectionFolprechtG,etal.LancetOncol2010;11:38–47FOLFOX6+FOLFIRI+AllERBITUXERBITUXPatients(n=53)(%)(n=53)(%)(n=106)(%)R0resections383034R1-resect/Resect+RFA285RFA968R0/R1resect./RFA494346CELIM临床试验的切除率FolprechtG,etal.LancetOncol2010;11:38–47三药方案的有效率和切除率010203040506070FOLFIRIFOLFOXIRIResponserateR0resectionrate(liver-limiteddisease)0510152025303540FOLFIRIFOLFOXIRIFalconeA,etal.JClinOncol2007;25:1670–1676Patients(%)Patients(%)GONOstudyp0.0001p=0.01734.060.012.036.0病例二：不可切除的转移性结直肠癌一线治疗方案的选择1.FOLFOX/XELOX+贝伐珠单抗2.FOLFIRI/XELIRI+贝伐珠单抗3.FOLFOX+西妥昔单抗4.XELOX+西妥昔单抗5.FOLFIRI/XELIRI+西妥昔单抗贝伐珠单抗在III期随机试验中的疗效治疗方案n中位PFS(月)中位OS(月)RR(%)FOLFOX/CAPOX±贝伐珠单抗11,4009.4vs8HR=0.8321.3vs19.8HR=0.8938vs38IFL±贝伐珠单抗281310.6vs6.2HR=0.5420.3vs15.6HR=0.6645vs355-FU/LV±贝伐珠单抗3(汇聚分析)2418.8vs5.6HR=0.6317.9vs14.6HR=0.7434vs24卡培他滨±贝伐珠单抗43138.7vs5.7HR=0.6318.9vs18.9HR=0.8856vs431.Saltz,etal.JCO2008;2.Hurwitz,etal.NEJM20043.Kabbinavar,etal.JCO2005;4.Tebbutt,etal.JCO2010NB:金色字体为具有显著统计学意义的结果OSHR(95%CI)一线0.79(0.69–0.96)Welch,etal.AnnOncol2009结论：当晚期结直肠患者接受一线以氟尿嘧啶为基础的化疗方案治疗时，联合贝伐珠单抗显著延长生存1.VanCutsem,etal.AnnOncol2009;2.Kozloff,etal.Oncologist2009贝伐珠单抗+FOLFIRI302520151050中位OS(月)总体n=1,914贝伐珠单抗+FOLFOX贝伐珠单抗+CAPOX22.722.923.722.925.924.423.023.6First-BEAT1BRiTE2n=1,953n=503n=279n=552n=1,093n=346n=94贝伐珠单抗：First-BEAT和BRiTEEGFR抑制剂在随机III期研究中的疗效（仅用于KRAS野生型患者）治疗方案中位PFS(月)中位OS(月)RR(%)CRYSTAL1(FOLFIRI±西妥昔单抗)9.9vs8.7HR=0.6823.5vs20.0HR=0.8059vs43COIN2(FOLFOX/XELOX±西妥昔单抗)8.6vs8.6HR=0.9617.0vs17.9HR=1.0464vs57PRIME3(FOLFOX±帕尼单抗)9.6vs8.0HR=0.8023.9vs19.7HR=0.8055vs481.VanCutsem,etal.NEJM2009;2.Grothey.JCO2010;3.Douillard,etal.JCO2010NB:金色字体为具有显著统计学意义的结果COIN研究：安全性分析西妥昔单抗可显著增加非血液性毒性和3或4级腹泻的发生率–FOLFOX,13%vs6%,p0.05–CAPOX,25%vs15%,p0.05在试验期间，对卡培他滨进行了减量（由1,000mg/m2减至850mg/m2bid）Adams,etal.BrJCancer2009COIN:治疗期间化疗剂量强度•治疗组之间化疗剂量降低幅度存在显著的不均衡1•FOLFOX组接受治疗的时间较XELOX组延长1个月左右(p0.001)21Adamsetal,BJC2009;100:251–258;2MaughanT,etal.(ASCO-GI2010AbstractNo.124)-25-20-15-10-50XELOXXELOX+cetuximabOxalreducedAnydelayCapecreducedcetuximabreducedChangeindos