陆舜-福州-晚期非小细胞肺癌整体治疗策略课件

晚期非小细胞肺癌整体治疗策略——美国临床肿瘤学协会(ASCO)临床实践指南更新解读上海市肺部肿瘤临床医学中心199720032009ASCOGuidelineNCCNGuidelineallianceof21oftheworldleadingcancercenter,isdedicatedtoimprovingthequalityandeffectivenessofcareprovidedtopatientswithcancer.ThroughtheleadershipandexpertiseofclinicalprofessionalsatNCCNMemberInstitutions,NCCNdevelopsresourcesthatpresentvaluableinformationtothenumerousstakeholdersinthehealthcaredeliverysystem.Asthearbiterofhigh-qualitycancercare,NCCNpromotestheimportanceofcontinuousqualityimprovementandrecognizesthesignificanceofcreatingclinicalpracticeguidelinesappropriateforusebypatients,clinicians,andotherhealthcaredecision-makers.TheprimarygoalofallNCCNinitiativesistoimprovethequality,effectiveness,andefficiencyofoncologypracticesopatientscanlivebetterlives.与NCCNGuideline相比，ASCOGuideline更有权威性背景介绍ASCO最初于1997年公布无法手术切除的NSCLC治疗的临床实践指南并于2003年进行了更新ASCO指南的更新是一个连续过程，自2003年以来，发表了大量与本指南相关的研究文献本次指南的更新基于2002年1月至2009年5月间所发表的文献主要基于OS改变有显著性统计学意义的前瞻性随机对照研究仅有PFS显著改善的研究结果仍需得到进一步验证毒性生活质量AzzoliCG,etal.JClinOncol2009;27(36):6251-66研究方法的更新情况文献评估结果至少与一个临床问题相关的190篇文献AzzoliCG,etal.JClinOncol2009;27(36):6251-66.入组文献的局限性体力状态评分较差患者的研究入组数目有限(ECOGPS>2或者KPS<70%)老年患者的研究入组数目有限(>65岁或者>70岁)三线及以上治疗缺乏III期研究数据AzzoliCG,etal.JClinOncol2009;27(36):6251-66.指南推荐更新--一线治疗哪些IV期患者应接受药物治疗？2003年指南推荐：对于IV期的NSCLC患者进行药物治疗可延长生存期。药物治疗适用于ECOG/ZubrodPS0-1以及PS2的患者，并应在PS评分较好的时期开始治疗2009年指南推荐A1：ECOGPS0-1以及PS2的患者AzzoliCG,etal.JClinOncol2009;27(36):6251-66.化疗在晚期NSCLC治疗地位的确立汇聚16项随机对照研究，2714例NSCLC患者的荟萃分析显示：化疗有显著生存获益，HR=0.77，p≤0.0001

；MST增加1.5个月；1年生存率提高9%NSCLCMeta-AnalysesCollaborativeGroup.JClinOncol.2008;26(28):4617-25OS对于PS0-1的患者应选择两药联合化疗汇聚65项随机对照研究，13601例NSCLC患者的荟萃分析显示：两药联合化疗的疗效优于单药化疗或三药化疗DelbaldoC.etal.,JAMA2004;292:470-484两药/三药联合化疗vs.单药化疗非铂类两药联合化疗健择®+紫杉醇用于NSCLC治疗的研究研究设计：健择

®1000mg/m2d1,8+紫杉醇200mg/m2d1q3weeks紫杉醇200mg/m2d1q3wks+卡铂AUC6d1q3weeksRANDOMIZEKosmidis,ASCO2000Abstract#1908非铂类两药联合化疗健择®+紫杉醇用于NSCLC治疗的研究研究结果：¾级毒性(>5%)健择®+紫杉醇紫杉醇+卡铂中性粒细胞减少10.5%9.6%神经毒性5.4%6.2%Kosmidis,ASCO2000Abstract#1908指南推荐更新--一线治疗IV期PS2患者的最佳治疗方案是什么？2003年指南推荐：对于老年患者或ECOG/ZubrodPS2的患者，证据支持单药治疗2009年指南推荐A3：现有证据支持PS2的患者应接受单药治疗尚无充分证据推荐PS2的患者应/不应接受两药联合化疗AzzoliCG,etal.JClinOncol2009;27(36):6251-66.GridelliC,etal.AnnOncol.2004;15(3):419-26.单药治疗指南推荐更新--一线治疗IV期老年患者的最佳治疗方案是什么？2003年指南推荐：对于老年患者或ECOG/ZubrodPS2的患者，证据支持单药治疗2009年指南推荐A4：没有证据支持仅根据年龄来选择某特定一线单药或联合化疗AzzoliCG,etal.JClinOncol2009;27(36):6251-66.单药治疗WJTOG9904研究证实，多西他赛用于老年晚期NSCLC患者的mPFS优于诺维本(5.5mvs.3.1m)，mOS无差别(14.3mvs.9.9m)KudohS,etal.JClinOncol2006;24(22):3657-63.P<0.001P=0.138联合化疗GridelliC,etal.JClinOncol.2005;23(13):3125-37.指南推荐更新--一线治疗IV期患者的一线治疗，顺铂比卡铂更有效吗？2003年指南推荐：

没有明确推荐2009年指南推荐A5：选择顺铂或卡铂都是可以接受的顺铂与卡铂可分别联合第三代化疗药物(多西他赛、吉西它滨、伊立替康、紫杉醇、培美曲赛和长春瑞滨)相比卡铂，顺铂联合第三代化疗药物的缓解率更高，能延长生存期卡铂引起恶心、肾毒性和神经毒性的风险低于顺铂，但更容易发生血小板减少AzzoliCG,etal.JClinOncol2009;27(36):6251-66.顺铂与卡铂的疗效比较对汇聚8项随机对照研究，2948例NSCLC患者的荟萃分析的亚组分析(联合第三代化疗药的方案)显示：与卡铂相比，含顺铂联合化疗可使生存期延长11%(HR=1.106，P=0.039)对汇聚9项随机对照研究，2968例NSCLC患者的荟萃分析的亚组分析显示：卡铂联合三代化疗药可引起死亡风险显著增加(HR=1.11)；对非鳞癌患者，含卡铂方案引起死亡风险显著增加(HR=1.12)HottaK.etal.,JClinOncol2004;22(19):3852-9ArdizzoniA,etal.,JNatlCancerInst.2007;99(11):847-57铂类联合三代化疗药物治疗晚期NSCLC以铂类为基础的三代化疗药仍是晚期NSCLC一线治疗基石StudyDrugs#Pts%,St.IV%,ORRMST%,1-YSKelly,2001SWOG9503Vnr/CisTax225/Cb20220888892825883336Schiller,2002ECOG1594Tax135/CisGem/CisTxt/CisTax225/Cb2922882932908986868621.32117.315.38.18.17.48.331363135Scagliotti,2002ILCPVnr/CisGem/CisTax225/Cb2012052018181823030329.59.89.9373743Belani,2002TAX326Vnr/CisTxt/CisTxT/Cb40440840267676725322410.111.39.4414638铂类联合三代化疗药物治疗晚期NSCLCJMDB:一线对照健择®/顺铂治疗晚期NSCLC的III期研究ScagliottiGV,etal.JClinOncol.2008;26(21):3543-51迄今样本最大且唯一入组>1600例晚期NSCLC一线治疗的前瞻性、随机、双盲、全球多中心的III期研究铂类联合三代化疗药物治疗晚期NSCLCJMDB研究研究设计随机、III期、非劣效性设计试验IIIB/IV期NSCLC一线治疗每3周方案，最多6个周期特定的组织学亚组分析随机因素ECOGPS分期脑转移史性别病理学类型组织学Vs.细胞学随机分组力比泰®

(n=862)500mg/m2

IV每3周+顺铂75mg/m2D1健择®

(n=863)

1250mg/m2D1,D8

+顺铂75mg/m2

第1天ScagliottiGV,etal.JClinOncol.2008;26(21):3543-51铂类联合三代化疗药物治疗晚期NSCLC

JMDB研究总生存时间：力比泰®/顺铂OS与健择®/顺铂相似ScagliottiGV,etal.JClinOncol.2008;26(21):3543-51铂类联合三代化疗药物治疗晚期NSCLCJMDB研究力比泰®顺铂的安全性更好3/4度毒性

力比泰®

+顺铂(N=839)健择®+顺铂

(N=830)P值中性粒细胞减少15.1%26.7%<0.001贫血5.6%9.9%0.001血小板减少4.1%12.7%<0.001白细胞减少4.8%7.6%0.019ScagliottiGV,etal.JClinOncol.2008;26(21):3543-51EntireStudyPopulationEastAsianSubgroupCPArm,n=862CGArm,n=863CPArm,n=67CGArm,n=59Progression-freesurvivalAllpatients,n8628636769Censored,n(%)60(7.0)68(7.9)7(10.4)7(11.9)MedianOStime,mo4.85.15.65.5AdjustedHR(CPvs.CG),(95%CI)1.04(0.95–1.15)0.78(0.53–1.15)Non-Squamouspatients,n6186344746MedianPFStime,mo5.35.06.45.6AdjustedHR(CPvs.CG),(95%CI)0.95(0.84–1.06)0.61(0.39–0.96)Squamouspatients,n2442292013MedianPFStime,mo4.45.54.25.3AdjustedHR(CPvs.CG),(95%CI)1.36(1.12–1.65)2.03(0.70–5.85)SummaryofProgression-freesurvivalforAllofthePatientsandtheEastAsianSubgroup*Chih-HsinYang,etalJThoracOncol.2010;5

EntireStudyPopulationEastAsianSubgroupCPArm,n=862CGArm,n=863CPArm,n=67CGArm,n=59OverallsurvivalAllpatients,n8628636769Censored,n(%)239(27.7)216(25.0)28(41.8)28(47.5)MedianOStime,mo10.310.317.116.5AdjustedHR(CPvs.CG),(95%CI)0.94(0.84–1.05)0.84(0.51–1.36)Non-Squamouspatients,n6186344746MedianOStime,mo11.010.121.217.7AdjustedHR(CPvs.CG),(95%CI)0.84(0.74–0.96)0.70(0.39–1.24)Squamouspatients,n2442292013MedianOStime,mo9.410.813.410.8AdjustedHR(CPvs.CG),(95%CI)1.23(1.00–1.51)1.18(0.42–3.35)SummaryofMedianSurvivalTimesforAllofthePatientsandtheEastAsianSubgroup*Chih-HsinYang,etalJThoracOncol.2010;5:)SurvivaltimeinallpatientsfromTaiwan/Korea*Chih-HsinYang,etalJThoracOncol.2010;5:)Survivaltimeinallnon-squamouspatientsfromTaiwan/Korea(Months)*Chih-HsinYang,etalJThoracOncol.2010;5:)SurvivaltimeinallsquamouspatientsfromTaiwan/Korea(Months)*Chih-HsinYang,etalJThoracOncol.2010;5:)ConclusionsTheNSCLChistologyeffectontreatmentoutcomesforpemetrexedtreatedpatientsseenintheentirestudypopulationwasalsoapparentintheEAsubgroupThepotentialprognosticinfluenceofrace,histologysubtype,andsmokingstatusshouldbeassessedinfutureNSCLCstudies*Chih-HsinYang,etalJThoracOncol.2010;5指南推荐更新--一线治疗一线治疗的最佳持续时间是多久？2003年指南推荐：对于IV期NSCLC患者，4个周期治疗后未缓解应停药，最长治疗时间不应超过6个周期2009年指南推荐A6：4周期细胞毒药物化疗后出现疾病进展或未缓解时，应停药不应给予患者超过6周期的细胞毒药物双药化疗方案一线治疗后稳定或缓解的患者，不推荐继续化疗直至进展或在疾病进展前给予不同的化疗**注：本指南完稿印刷时，美国FDA于2009年7月批准了力比泰®维持治疗晚期NSCLC，全文也于2009年9月发表于Lancet，该数据尚未列入本指南的文献评估中。有关维持治疗的推荐会根据近期发表的数据进行更新AzzoliCG,etal.JClinOncol2009;27(36):6251-66.一线治疗持续的时间中位周期数(范围)mST，月(范围)Socinskietal,ArmA(standard)4(0–6)6.6(5.4–9.0)Socinskietal,ArmB(extended)4(0–19)8.5(6.3–10.3)vonPlessenCetal,ArmA(3cycles)2.77vonPlessenCetal,ArmB(6cycles)4.58Parketal,ArmA(2+4cycles)6(2–6)14.9(13.0–16.8)Parketal,ArmB(2+2cycles)4(2–4)15.9(12.4–19.4)SocinskiMA,etal.JClinOncol2002;20(5):1335–1343.

vonPlessenCetal.BrJCancer2006;95(8):966-73.ParkJO,etal.JClinOncol2007;25(33):5233–5239.一线两药化疗直到4-6个周期后，将导致毒性累积，但没有确切的疗效优势JMEN研究研究设计：多中心、双盲、安慰剂对照Ⅲ期临床研究ⅢB/Ⅳ期NSCLC患者ECOGPS0-1既往接受4周期含铂诱导化疗未进展2:1比例随机化力比泰®500mg/m2(d1,q21d)

+BSC*N=441安慰剂(d1,q21d)+BSCN=222*BSC:所有患者均接受VB12、叶酸和地塞米松CiuleanuTetal.,Lancet2009;

374(9699):1432-40

JMEN研究研究结果：力比泰®维持治疗可显著延长ITT人群的OSCiuleanuTetal.,Lancet2009;

374(9699):1432-40

JMEN研究研究结果：力比泰®维持治疗对非鳞癌患者的OS改善更显著CiuleanuTetal.,Lancet2009;

374(9699):1432-40

毒性反应

¾级

AEs(%)力比泰®n=441安慰剂n=222中性粒细胞减少‡30贫血31白细胞减少21乏力‡51食欲不振20感染10腹泻10恶心11呕吐<10感觉神经病变10粘膜炎/口腔炎10‡P<0.05forgrade3/4ratesofneutropeniaandfatigueJMEN研究CiuleanuTetal.,Lancet2009;

374(9699):1432-40

JMEN研究研究结论：这是第一项证明维持治疗可显著延长NSCLC患者OS的随机、双盲、安慰剂对照研究，也证明了力比泰®维持治疗的疗效再次证明：非鳞癌组织类型可作为力比泰®治疗NSCLC疗效的预测指标力比泰®在维持治疗应用中具有良好的安全性和耐受性CiuleanuTetal.,Lancet2009;

374(9699):1432-40

SATURNstudydesign

Stratificationfactors:EGFRIHC(positivevsnegativevsindeterminate)Stage(IIIBvsIV)ECOGPS(0vs1)CTregimen(cis/gemvscarbo/docvsothers)Smokinghistory(currentvsformervsnever)Region1:1ChemonaïveadvancedNSCLCn=1,949Non-PDn=8894cyclesof

1st-lineplatinum-baseddoublet*PlaceboPDErlotinib150mg/dayPDMandatorytumoursampling*Cisplatin/paclitaxel;cisplatin/gemcitabine;cisplatin/docetaxelcisplatin/vinorelbine;carboplatin/gemcitabine;carboplatin/docetaxelcarboplatin/paclitaxelEGFR=epidermalgrowthfactorreceptor;IHC=immunohistochemistryCo-primaryendpoints:PFSinallpatientsPFSinpatientswithEGFRIHC+tumoursSecondaryendpoints:Overallsurvival(OS)inallpatientsandthosewithEGFRIHC+tumours,OSandPFSinEGFRIHC–tumours;biomarkeranalyses;safety;timetosymptomprogression;qualityoflife(QoL)F.Cappuzzo.etal,JClinOncol27:7s,2009(suppl;abstr8001)Erlotinib

(n=60)Placebo

(n=65)Medianage,years(range)55(33–73)54(30–77)Male/female(%)67/3365/35StageIIIB/IV(%)18/8223/77ECOGPS0/1(%)17/8328/72Current/former/neversmoker(%)35/25/4043/18/38Adenocarcinoma/squamous/other(%)65/10/2546/34/20Responsetopriorchemotherapy,CR/PR/SD/PD(%)0/42/57/20/45/52/3EfficacyandsafetyoferlotinibinAsianpatientswithadvancednon-small-celllungcancerBaselinecharacteristicsintheAsianpopulationBestresponseinAsianpopulation14%ofpatientsintheerlotinibarmhadanupgradeofresponsefromSDtoPRinthemaintenancephase,versus0%intheplaceboarmPatients(%)6050403020100ErlotinibPlaceboPFSinAsianpopulation1.00.80.60.40.20Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 Time(weeks) 63 62 39 28 23 17 13 10 5 4 4 3 2 2 2 2 2 2 1 1 1 1 1 0 0 0 0 59 59 37 31 28 23 19 17 15 15 14 13 13 10 8 6 4 3 2 0 0 0 0 0 0 0 0natriskPlaceboErlotinib11.417.9PlaceboErlotinibHR=0.57(0.37–0.86)Log-rankp=0.0067OSinAsianpopulation1.00.80.60.40.20SurvivalTime(months) 0 3 6 9 12 15 18 21 24 27 30 33 36 65 61 53 46 42 33 21 16 11 10 6 0 0 60 57 50 45 37 35 26 19 16 10 3 1 0natriskPlaceboErlotinib15.220.8HR=0.67(0.42–1.07)Log-rankp=0.0931PlaceboErlotinibSummaryofAsiansafetydataOnlytwopatientshadtreatment-relatedinterstitiallungdisease(ILD);bothwereintheerlotinibarm,onewasgrade≥3Erlotinib

(n=59)Placebo

(n=63)WithdrawalduetoanyAE(%)30Dosemodification/interruptionduetoanyAE(%)245AEsoccurringin≥10%ofpatientsRash(%)7613Grade390Grade400Diarrhoea(%)293Grade330Grade400化疗药物作为维持治疗的荟萃分析研究发表时间入组人数患者的中位年龄男性(%)随机前的化疗方案随机前的化疗周期数随机后化疗方案维持治疗组患者的化疗周期标准治疗组的化疗周期评分Buccheri[14]1989746291氨甲喋呤,阿霉素,环磷酰胺,环己亚硝脲2-3氨甲喋呤,阿霉素,环磷酰胺,环己亚硝脲维持到疾病进展2-3B1Tourani[15]199023NRNR顺铂+长春地辛2顺铂+长春地辛64CZarogoulidis[16]199574NRNRNR8环磷酰胺+干扰素维持到疾病进展8CSmith[3]20013086366NR0丝裂霉素+长春碱+顺铂63B1Socinski[4]20022306363NR0泰素+卡铂维持到疾病进展4B1Belani[17]20031306662泰素+卡铂4泰素维持到疾病进展4B1Westeel[18]20051816393丝裂霉素+异磷酰胺+顺铂4长春瑞滨维持到疾病进展4B1vonPlessen[19]20062976463NR0卡铂+长春瑞滨63ABrodowicz[7]20062065773健择+卡铂4健择维持到疾病进展4B1Park[9]20073145867顺铂+泰素或泰索帝或健择2顺铂+泰素或泰索帝或健64B1Fidias[20]200730766NR健择+卡铂4泰索帝维持到疾病进展4B1Barata[8]20072206478NR0健择+卡铂64B1Ciuleanu[11]20086636173顺铂/卡铂+泰素或泰索帝或健择4力比泰®维持到疾病进展4B1A,较少争议;B1,少量争议;B2,中等争议;C,较大争议;NR:未报道

SoonYYetal,JClinOncol2009;27(20):3277-83维持化疗在一定程度上延长了生存期(HR0.92；95%CI，0.86-0.99；P=0.03)同样维持化疗明显延长PFS(HR0.75；95%CI，0.69-0.81；P=0.00001)SoonYYetal,JClinOncol2009;27(20):3277-83指南推荐更新--一线治疗靶向药物对IV期患者的总生存期、无进展生存期、毒性和生活质量/症状改善的获益如何？2003年指南推荐：如果IV期NSCLC患者2个周期治疗无效，可选择性的让患者参加临床研究进行治疗2009年指南推荐A7：不推荐厄洛替尼或吉非替尼联合化疗一线治疗未经选择的患者没有充分证据推荐厄洛替尼或吉非替尼一线单药治疗未经选择的患者对于EGFR突变的患者，一线使用吉非替尼可能是一种选择如果患者EGFR突变阴性或状态未知，应首选化疗AzzoliCG,etal.JClinOncol2009;27(36):6251-66.phaseIII,randomized,open-label,first-linestudyofgefitinibvscarboplatin

/paclitaxelinclinicallyselectedpatientswithadvancednon-smallcelllungcancerinAsia(IPASS)*Neversmokers,<100cigarettesinlifetime;ex-lightsmokers,stopped15yearsagoandsmoked10packyears;#limitedtoamaximumof6cycles.Carboplatin(AUC5or6)/paclitaxel

(200mg/m2)

3weekly#1:1randomization

PatientsChemo-naïveAge≥18yearsAdenocarcinomahistologyNeverorex-lightsmokers*Lifeexpectancy

≥12weeksWHOPS0-2MeasurablestageIIIB/IVdiseasePrimaryProgression-freesurvival

(non-inferiority)SecondaryObjectiveresponserateOverallsurvivalQualityoflifeDisease-relatedsymptomsSafetyandtolerabilityExploratoryBiomarkersEGFRmutationEGFR-gene-copynumberEGFRproteinexpression

EndpointsConductedinChina,Japan,Thailand,Taiwan,Indonesia,Malaysia,Philippines,HongKongandSingaporeMoketalNEnglJMed2009;361.Gefitinib

(250mg/day)Progression-freesurvival609453(74.4%)608497(81.7%)NEventsHR(95%CI)=0.74(0.65,0.85)p<0.0001GefitinibGefitinibdemonstratedsuperiorityrelativetocarboplatin/paclitaxelintermsofPFSPrimaryCoxanalysiswithcovariates;HR<1impliesalowerriskofprogressionongefitinib;ITTpopulation

PFS,progression-freesurvival;ITT,intent-to-treat;HR,hazardratio;CI,confidenceinterval;C/P,carboplatin/paclitaxelCarboplatin/paclitaxelC/PGefitinibMedianPFS(months)

4monthsprogression-free

6monthsprogression-free

12monthsprogression-free5.7

61%

48%

25%5.8

74%

48%

7%6092127624506081182231036341204812162024Months0.00.20.40.60.81.0Probability

ofPFSPatientsatrisk:MoketalNEnglJMed2009;361.TKI药物需用于EGFR突变的人群IPASS研究显示：吉非替尼的疗效随EGFR突变的不同而有显著差异；而EGFR突变状态对化疗的疗效影响不明显Moketal,NEnglJMed2009;361(3):947-57.TKI药物需用于EGFR突变的人群IPASS研究显示:EGFR突变野生型的患者缓解率只有1.1%，和安慰剂没有区别GefitinibCarboplatin/paclitaxelEGFRM+oddsratio(95%CI)=2.75

(1.65,4.60),p=0.0001EGFRM-oddsratio(95%CI)=0.04

(0.01,0.27),p=0.0013总体反应率(%)(n=132)(n=129)(n=91)(n=85)71.2%47.3%1.1%23.5%Moketal,NEnglJMed2009;361(3):947-57.First-SIGNAL：studydesignGemcitabine1250mg/m2(D1,D8)Cis80mg/m2(D1)q3wx9PatientsChemotherapynaive18-75

Ade

Non-smokerECOGPS0-2IIIB/IV

Gefitinib250mg/day

P.O./dq3wPDPD1:1随机分组女性vs.男性PS0,1vs.2Ⅲb期vs.Ⅳ期2009WCLCPrimaryendpoint:OverallsurvivalSecondaryendpoint:ProgressionfreesurvivalFirst-SIGNAL：OverallsurvivalandProgression-freesurvivalGefitinib(N=159)GP(N=150)MedianPFS(Mon)6.16.66-monthPFS(%)50.258.81-yearPFS(%)20.35.02-yearPFS(%)4.20.7Gefitinib(N=159)GP(N=150)MedianOS(Mon)21.323.36-monthOS(%)92.593.91-yearOS(%)74.276.2OS(Mon)HR=1.00395%CI:0.749~1.343P=0.428HR=0.81395%CI:0.641~1.031P=0.044(Mon)PFSSurvivalratePFSrate2009WCLCFirst-SIGNAL:PFSbyEGFRmutationstatuswithintreatmentarmHR(95%CI)=0.613(0.308~1.221)P=0.084(logrank)HR(95%CI)=1.517(0.880~2.615)P=0.071(logrank)PFSrate(Month)EGFR+EGFR-ArmGefitinib(N=26)GP(N=16)PFS(month)8.46.7ArmGefitinib(N=27)GP(N=27)PFS(month)2.16.42009WCLCFirst-SIGNAL：ConclusionEGFRmutationsisastrongpredictivemarkerforoverallresponseandPFSwithGefitinibGefitinibdidnotimproveOSoverthestandardGPchemotherapy,buthavehighORRandbettertoxicityprofiles.2009WCLCFirstlineGefitinibversusCaboplatinpluspaclitaxleinNSCLCpatientswithEGFRmutations:NorthEastJapan(NEJ)002GefitinibStudyGroupCBDCAAUC6andTXL200mg/m2N=991:1randomization

PatientssensitiveEGFRmutations(PNA-LNAPCRclamptest)measurablesite(s)ECOGPS0-1,ageof20-75years,NopriorchemotherapyPrimaryProgression-freesurvivalSecondaryQolOverallsurvivalEndpointsGefitinib

(250mg/day)N=98Balancedbyinstitution;sex,stageKobayashiK,etal.2009ASCOAbstract8016ResponseGefitinibCaboplatinpluspaclitaxle98100CR40PR6929SD1350PD815NE46CR+PR73(74.5%)29(29%)Fisher’sexactP<0.001ResponseConclusionThisisthefirstphaseIIIstudytocomparefirstlinegefitinibwithfirstlinechemotherapyforadvancedNSCLCpatientswithEGFRmutationTherewereseveraldifferencesintoxicitiesbetweenGefitinibArmandChemotherapyArmgrade4neutropenia:1%vs.29%grade3-4liverdysfunction:24%vs.1%grade3neuropathy:0%vs.5%,respectively,p<0.01Theindependentsafetycommitteehasdecidedtostopaccumulationpatientsupto31st,May,2009GefitinibversuscisplatinplusdocetaxelinpatientswithNSCLCharbouringEGFRmutations(WJTOG3405):anopenlabel,randomisedphaseIIItrialdocetaxel(60mg/m2,D1)followedbycisplatin(80mg/m2,D11:1randomization

PatientsLocaladvanced/metastatic(IIIB/IVdisease)Chemo-naïve(adjuvantOK)Age≥20yearsEvaluablediseasePS0-1PrimaryProgression-freesurvivalSecondaryObjectiveresponserateOverallsurvivalThirdDCRSafetyEndpointsGefitinib

(250mg/day)EGFRmutationExon19deletionorL858R200patientswithmutationTetsuyaMitsudomi,etal.Lancet,December21,2009Gefitinib(N=86)Cisplusdoc(N=86)Age(years;median;range)64·0(34–74)64·0(41–75)SmokinghistoryNever6157Former/current2529EGFRmutationExon19deletion5037L858R3649StagePostoperativerecurrence3536Withpostoperativeadjuvantchemotherapy1923Withoutpostoperativeadjuvantchemotherapy1613IIIB109IV4141DemographyTetsuyaMitsudomi,etal.Lancet,December21,2009Progression-freesurvivalintheoverallpopulationTetsuyaMitsudomi,etal.Lancet,December21,2009OverallsurvivalintheoverallpopulationTetsuyaMitsudomi,etal.Lancet,December21,2009Gefitinib(n=87)CisplatinplusdocetaxelAllCTCgrade≥3AllCTCgrade≥3Rash*74270AST*6114171ALT*6124352Dryskin*47030Diarrhoea471350Fatigue*342732Paronychia*28110Stomatitis190130Nausea*151833Constipation*140390Alopecia*80670Sensorydisturbance*71230CTCGrade¾Non-haematologicaltoxicityTetsuyaMitsudomi,etal.Lancet,December21,2009Gefitinib(n=87)CisplatinplusdocetaxelAllCTCgrade≥3AllCTCgrade≥3Leucocytopenia*1308243Thrombocytopenia*120290Neutropenia*708174Anaemia*3307915CTCGrade¾haematologicaltoxicityTetsuyaMitsudomi,etal.Lancet,December21,2009PatientgroupNMedianPFS(months)MedianOS(months)GefChemoHR(95%CI)GefChemoSubsetanalysesofthephase3trialsforpatientsselectedaccordingtoclinicalbackgroundsIPASSEastAsian,light-non-smoker,adenocarcinoma2619·56·30·48(0·36–0·64)~20~20FirstSIGNALKorean,non-smoker,adenocarcinoma428·46·70·61(0·31–1·22)30·626·5Phase3trialsofpatientsselectedaccordingtoEGFRmutationstatusNEJ002Japanese,EGFRmutation19410·45·50·357(0·252–0·507)28·023·6WJTOG3405Japanese,EGFRmutation1729·26·30·489(0·336–0·710)SummaryConclusionGefitinibsignificantlyprolongedtheprogression-freesurvivalofpatientswithNSCLCwhocarryEGFRmutationscomparedwithchemotheray指南推荐更新--一线治疗靶向药物对IV期患者的总生存期、无进展生存期、毒性和生活质量/症状改善的获益如何？2009年指南推荐A8：在选择性患者中推荐贝伐单抗15mg/kg每三周方案与卡铂紫杉醇的联合治疗选择性患者应排除：鳞癌、脑转移、有临床意义的咯血、器官功能不足、ECOGPS>1、接受治疗性抗凝血药物、伴临床显著性心血管疾病或控制不佳的高血压贝伐单抗可持续给药直至疾病进展或出现不可耐受的毒性AzzoliCG,etal.JClinOncol2009;27(36):6251-66.BevacizumabBevacizumabAVAiL:Cis/GemPDPDPDBevacizumab15mg/kg+CGBevacizumab7.5mg/kg+CGPlacebo+CGPreviouslyuntreated,stageIIIB,IVorrecurrentnon-squamousNSCLCRANDOMISEPlacebo+CG2211PreviouslyuntreatedstageIIIB/IVnon-squamousNSCLCCPAvastin(15mg/kg)every3weeks+CPPDPDAvastinevery

3weeksuntilprogressionECOG4599:Carbo/TaxolBevacizumabstudies-DesignofECOG4599+AVAiL-贝伐单抗的应用ECOG4599显示卡铂紫杉醇联合贝伐单抗可改善PFS和OSECOG4599CPCP+BEV15OS(月)10.312.3HR=0.79;P=0.003PFS(月)4.56.2HR=0.66;P<0.001RR(%)1535P<0.001SandlerA,etal.NEnglJMed2006,355(24):2542-50.注：贝伐单抗在中国还未上市AVAiL:GlobalversusAsianpopulations

GroupGlobalpopulationAsian*populationPlacebo+

cisplatin/gemcitabine32433Bevacizumab7.5mg+

cisplatin/gemcitabine32338Bevacizumab15mg+

cisplatin/gemcitabine33234*IncludespatientsofAsianorigin(Taiwan65,HongKong14,Thailand12,

Canada11,Germany1,Belgium1andAustralia1)AVAiL:AsianpatientdemographicsAVAiLAsianpopulationPlacebo+CG(n=33)Bevacizumab7.5mg/kg

+CG(n=38)Bevacizumab15mg/kg

+CG(n=34)Sex(%)Male/Female

55/4550/5053/47Age(years)Median5756.556.5ECOGPS(%)0/145/5547/5353/47Smokingstatus(%)Never/Current/Past58/9/3366/8/2656/6/38Histology(%)Adenocarcinoma889585Largecell336Mixed*303Other636Stage(%)Recurrent953IIIB151315IV768282*PredominantlyadenocarcinomaHigherproportioninAsiansascomparedtooverallstudypopulationAVAiL:PFSoutcomeforAsianandglobalpopulationsNote:analyseswereexploratoryandoflowstatisticalpowerduetosmallsamplesizesRochedataon,etal.ESMO2008Asianpopulation(n=105)Globalpopulation(n=1,043)PFSPlacebo

+CG

(n=33)Bev7.5mg/kg

+CG

(n=38)Bev15mg/kg

+CG

(n=34)Placebo

+CG

(n=347)Bev7.5mg/kg

+CG

(n=345)Bev15mg/kg

+CG

(n=351)MedianPFS(months)

6.1

8.88.7

6.2

6.8

6.6HR

(95%CI)0.49

(0.29–0.83)0.61

(0.36–1.04)0.75

(0.64–0.87)0.85

(0.73–1.00)AVAiL:overallsurvivalforAsianandglobalpopulationsNote:analyseswereexploratoryandoflowstatisticalpowerduetosmallsamplesizesAsiansubpopulation(n=105)Globalpopulation(n=1,043)OverallsurvivalPlacebo

+CG

(n=33)Bev7.5mg/kg

+CG

(n=38)Bev15mg/kg

+CG

(n=34)Placebo

+CG

(n=347)Bev7.5mg/kg

+CG

(n=345)Bev15mg/kg

+CG

(n=351)MedianOS(months)17.428.225.813.113.613.4HR

(95%CI)0.46

(0.22–0.97)0.79

(0.40–1.57)0.93

(0.78–1.11)1.03

(0.86–1.23)Rochedataon,etal.ESMO2008AVAiL:responseratesintheAsianpopulationAsianpopulation(n=105)Bestresponse%Placebo

+CG

(n=33)Bev7.5mg/kg

+CG

(n=38)Bev15mg/kg

+CG

(n=34)CR000PR15.247.441.2SD57.642.150.0PD21.200Rochedataon,etal.ESMO2008AVAiL:summaryofAEsforAsianandglobalpopulationsAsianpopulation(n=99)Globalpopulation(n=986)Pl+CGBv7.5+CGBv15+CGPl+CGBv7.5+CGBv15+CGAnyAE31

(100%)34(97%)33(100%)322(98%)326(99%)326(99%)Grade≥3AE24

(77%)28

(80%)29

(88%)246

(75%)252

(76%)265

(81%)SeriousAE8

(26%)12

(34%)14

(42%)116

(35%)116

(35%)145

(44%)AEleading

todeath001

(3%)14

(4%)13

(4%)16

(5%)AEleadingtoanycomponentwithdrawal

4

(13%)

8

(23%)

10

(30%)

74

(23%)

86

(26%)

98

(30%)Clinicalcutoff7Oct2006(SAP)指南推荐更新--一线治疗靶向药物对IV期患者的总生存期、无进展生存期、毒性和生活质量/症状改善的获益如何？2009年指南推荐A9：免疫组化检测EGFR表达阳性的患者，可考虑一线给予顺铂长春瑞滨联合西妥昔单抗的治疗方案西妥昔单抗可持续给药直至疾病进展或出现不可耐受毒性AzzoliCG,etal.JClinOncol2009;27(36):6251-66.Pirkeretal.TheLancet,373,1525-1531,2009

CharacteristicCT+cetuximab(n=557)CT(n=568)Male/female%69/3171/29Medianage,years(range)≥65years%59(18–78)3160(20–83)32ECOGPS%012246017216018Stage%IIIBIV694694Histology%Adeno-ca.Squamouscellca.Other463420493318Neversmoker%2222Ethnicity%CaucasianAsianOther8411585105FLEX-Patientbaselinecharacteristics-Pirkeretal.TheLancet,373,1525-1531,2009西妥昔单抗的应用FLEX研究显示：加用cetuximab可延长NSCLC患者的OSPirkerR,etal.Lancet2009;373(9674):1525-31.MedianOSCT+cetuximab(n=557)11.3moCT(n=568)10.1moHR=0.87(95%CI;0.76–1.0)p=0.04MonthsOverallsurvival(%)指南推荐更新－二线治疗IV期患者拥有最佳的二线治疗吗？是否有证据能支持二线联合生物治疗？IV期患者二线治疗最佳的给药计划是什么？2003年指南推荐

：一线接受以铂类为基础化疗的患者进展后，如PS评分良好，可接受多西他赛的二线治疗。吉非替尼可用于铂类为基础的化疗及多西他赛治疗失败的患者2009年指南推荐B1：一线接受以铂类为基础化疗的患者进展后，如PS评分良好，可接受力比泰、多西他赛、厄洛替尼或吉非替尼的二线治疗AzzoliCG,etal.JClinOncol2009;27(36):6251-66.已经完成的全球二线III期临床研究化疗Vs.安慰剂TAX.317 (多西他赛对照BSC)化疗Vs.化疗TAX.320 (多西他赛Vs.长春瑞滨-异环磷酰胺)JMEI (培美曲塞Vs.多西他赛)EGFR-TKIVs.安慰剂ISEL (吉非替尼Vs.安慰剂)BR.21 (特罗凯Vs.安慰剂)EGFR-TKIVs.化疗INTEREST (吉非替尼Vs.多西他赛)V15-32(吉非替尼Vs.多西他赛)ISTANA(吉非替尼Vs.多西他赛)TITAN

(特罗凯Vs.多西他赛or培美曲塞)EGFR-TKIVs多靶点（Zactimavs.特罗凯）晚期NSCLC的二线治疗随机临床研究证实力比泰®、厄洛替尼或吉非替尼可用于NSCLC的二线治疗临床研究入组人数研究分组mPFS/TTF(月)mST(月)JMEI571力比泰®

vs.多西他赛2.9vs.2.98.3vs.7.9INTEREST1466吉非替尼vs.多西他赛2.2vs.2.77.6vs.8.0ISEL1129吉非替尼+BSCvs.安慰剂+BSC3.0vs.2.65.6vs.5.1BR.21731厄洛替尼vs.安慰剂2.2vs.1.86.7vs.4.7HannaN,etal.JClinOncol2004;22(9):1589–97.

KimESetal.Lancet2008;372(9652):1809-18.ThatcherN,etal.La