晚期非小细胞肺癌一线和维持治疗的选择

晚期非小细胞肺癌一线和维持治疗的选择病例讨论患者女性，46岁，气短和持续性咳嗽就诊无咯血及痰中带血不吸烟

无体重下降KPS:100分既往史无高血压、糖尿病、呼吸和心血管疾病无肺癌家族史没有药物过敏史查体无异常发现化验血常规、肝肾功能正常肿瘤标志物正常没有药物过敏史无感染诊断：晚期非小细胞肺癌（T1N2M1b，Ⅳ期），低分化腺癌。PET/CT检查右肺上叶3cm肿块肺门及纵隔淋巴结转移，T5溶骨性破坏以上病变君FDG高代谢细针穿刺活检病理（右肺上叶）低分化腺癌CK7（+）、CK20（-）、TTF-1（+）头颅MRI检查未发现颅内占位组织少未行EGFR及ALK基因状态检测选择哪种治疗方案？紫杉醇+卡铂培美曲塞+卡铂+贝伐单抗吉西他滨+卡铂答案B为最佳选择晚期肺腺癌，无手术指征EGFR状态不明的非鳞NSCLC，无咯血，NCCN优先推荐化疗联合贝伐单抗ECOGE4599表明，非鳞NSCLC，化疗（例如，紫杉醇+卡铂）联合贝伐单抗效果优于单纯化疗。非鳞NSCLC，培美曲塞+铂方案优于吉西他滨+铂。培美曲塞+贝伐单抗+卡铂方案是有效的，它结合了两者的优点，延长生存期和较低的毒性答案A为次选可以作为一线治疗晚期NSCLCECOGE4599实验研究证明了贝伐单抗联合紫杉醇联+卡铂方案的优越性。答案C为次选吉西他滨联合铂类方案治疗NSCLC鳞癌优于培美曲塞联合铂类方案治疗非鳞癌细胞NSCLC劣于，培美曲塞联合铂类方案。诱导化疗患者接受贝伐单抗/培美曲塞/卡铂方案治疗2周期叶酸、维生素B12及地塞米松预防培美曲塞的毒副作用两周期治疗后，疗效评价为PR无出血、高血压、血液学毒性及蛋白尿继续原方案2周期，再次评价疗效趋于稳定是否需要维持治疗？若需要，采用何种维持治疗方案贝伐单抗单药培美曲塞单药厄洛替尼单药答案A为最佳选择一线贝伐单抗+培美曲塞+卡铂方案有效，NCCN指南推荐维持治疗的1类证据E4599研究证明贝伐单抗用于维持治疗有效贝伐单抗和培美曲塞联合使用，近延长了PFS，总生存并没有获益答案B为次选单药培美曲塞作为维持治疗也是可以的，这是由于患者是腺癌，而且患者的EGFR状况未知。培美曲塞不是最好的选择（2011年NCCN指南2B类证据推荐），2012年以后1类证据推荐。答案C为次选如果EGFR（外显子19或21）突变，单药厄洛替尼维持治疗合理。此患者EGFR状态未知维持治疗患者接受3个月的贝伐单抗维持治疗。耐受了良好，但是现在出现了疲劳和气短。胸腹部CT显示：肺部病灶增大，肿大淋巴结增多。下一步如何做多西他赛二线治疗厄洛替尼二线治疗肺穿刺活检的突变研究答案C为最佳选择患者为女性、不吸烟、腺癌，肺穿刺活检基因突变研究是最好的选择。若EGFR基因突变阳性（19缺失或21外显子L858R，可应用厄洛替尼或吉非替尼治疗。答案A为合理的选择NSCLC二线治疗的药物包括多西他赛、培美曲塞、厄洛替尼、吉非替尼、阿法替尼多西他赛疗效与培美曲塞和厄洛替尼相似多西他赛毒性较强。答案B为亦为合理选择EGFR状态未知情况下，厄洛替尼作为二线治疗也是一个理性的选择BR.21试验显示EGFR野生型者有效率约9%EGFR敏感性突变患者的有效率更高二线诊断和治疗肺穿刺活检行分子病理诊断示：KRAS野生型、EGFR19外显子缺失突变。厄洛替尼150mg口服1/日，治疗2个月后影像学检查疗效评价PR毒性反应：腹泻（每日大便3-4次），颜面部和躯干痤疮样皮疹，轻微疲劳。下一步该怎么做？厄洛替尼原剂量继续厄洛替尼减量为100mg停用厄洛替尼答案B为合理的选择厄洛替尼减量至100mg继续口服1/日是最佳治疗选择厄洛替尼150mg口服1/日出现了明显的毒性减量33％可降低毒性提高耐受性，且疗效不变值得注意的是皮疹的情况反映药物疗效。答案A为次选厄洛替尼150mg口服1/日出现明显的毒性反应如果毒性继续，尽管有效，患者可能因不能耐受而停止治疗。再次以较低的剂量开始治疗答案C错误选择停用厄洛替尼可缓解不良反应终止治疗，病情会反复应该在较低剂量开始治疗厄洛替尼减量后持续用药将厄洛替尼减量至100mg口服1/日，患者临床症状改善了，能正常生活。患者继续接受较低剂量的厄洛替尼治疗，1.5年后病情仍然处于缓解状态。

UpdatedfromGandaraDR,etal.ClinLungCancer.2009;10:392-394.SystemicTherapyforNSCLCin2014

*Withdocetaxel,paclitaxel,gemcitabine,vinorelbine.PoorPSFirstlineMaintenanceSecondlineProposedTreatmentAlgorithmEGFRmutationpositiveorALKpositiveGoodPSErlotinib,gefitinib,afatinib,orcrizotinibNonsquamousSquamousBevacizumabeligibleBevacizumabineligiblePlatinum/pemetrexed

(orother*)±bevacizumabPlatinum/pemetrexed

(orother*)ErlotiniborpemetrexedorobservationBasedonPriorTherapyProgressionChemotherapybyalgorithmBasedonpriortherapyBasedonpriortherapyBasedonpriortherapyEndoffirst-linechemotherapySingle-agentorcombinationchemotherapyBevacizumab,erlotinib,pemetrexedorobservationAdenoLCC-NOSSCCSCLCEGFRmutantsALKROS/RETHER2BRAFKRASKRASIV期肺癌的治疗模式的改变:2002-2014TissuesenttopathologyMorphologicanalysisIHC,specialstainsTumorgenotypingTumorbiomarkers病理学诊断模式的演变...InteractiveDecisionSupportTool:

1Tool;6ExpertRecommendationsIntheIDST(Availableat:/WorldNSCLCtool),theabove6variableswereusedtomaketreatmentdecisions.ExpertsWereAskedHowTheyWouldTreatPatients,WiththeFollowingOptionsTargetedTherapyPlatinumChemotherapyNonplatinumChemotherapyAfatinibCisplatinPaclitaxelBevacizumabCarboplatinDocetaxelCrizotinibNoneAlbumin-boundpaclitaxelErlotinibEtoposideGefitinibGemcitabineNonePemetrexedVinorelbineNoneAnExpertInsightIsShownWithEachExpert’sTreatmentRecommendationsEGFR敏感性突变患者一线EGFR-TKI和化疗的比较StudyTreatmentNMedianPFS,Mos(PValue)MedianOS,Mos(PValue)NEJ002[1,2]Gefitinibvscarbo/pac23010.8vs5.4(<.001)30.5vs23.6(.31)WJTOG3405[3,4]Gefitinibvscis/doc1779.2vs6.3(<.0001)36vs39(.443)OPTIMAL[5,6]Erlotinibvscarbo/gem16513.7vs4.6(<.0001)22.7vs28.9(.69)EURTAC[7]Erlotinibvsplt-basedCT1749.7vs5.2(<.0001)19.3vs19.5(.87)LUX-Lung3[8]Afatinibvscis/pem34511.1vs6.9(.001)NotreportedLUX-Lung6[9]Afatinibvscis/gem36411.0vs5.6(<.0001)Notreported1.InuoeA,etal.AnnOncol.2013;24:54-59.2.MaemondoM,etal.NEnglJMed.2010;362:2380-2388.3.MitsudomiT,etal.LancetOncol.2010;11:121-128.4.MitsudomiT,etal.ASCO2012.Abstract7521.5.ZhouC,etal.LancetOncol.2011;12:735-742.6.ZhangC,etal.ASCO2012.Abstract7520.7.RosellR,etal.LancetOncol.2012;13:239-246.8.SequistLV,etal.JClinOncol.2013;31:3327-3334.9.WuYL,etal.LancelOncol.2014;15:213-222.LeeCK,etal.JNatlCancerInst.2013;105:595-605FavorsEGFRTKIFavorsChemo一线EGFR-TKIRCTs研究Meta分析:改善PFSStudyHR

(95%CI)HR

(95%CI)EGFRmut

(first-linetherapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUXLUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal0.37(0.25-0.54)0.54(0.27-1.10)1.08(0.24-4.90)0.55(0.19-1.60)0.48(0.36-0.64)0.58(0.43-0.78)0.32(0.24-0.44)0.16(0.11-0.26)0.59(0.21-1.67)0.90(0.39-2.06)0.49(0.20-1.20)0.52(0.38-0.72)0.43(0.38-0.49)OutcomePROFILE1001[1]

(N=143)PROFILE1005[2]

(N=259)PROFILE1007[3]

(N=173)Bestoverallresponse,n(%)CR3(2)4(2)1(1)PR84(59)151(58)112(65)SD31(22)*69(27)32(18)PDNR19(7)11(6)Objectiveresponserate,%(95%CI)60.8(52.3-68.9)59.8(53.6-65.9)65(58-72)Mediandurationofresponse,

wks(95%CI)49.1(39.3-75.4)45.6(35.3-53.6)32.1(2.1-72.4)†Mediandurationoftreatment,

wks(range)43.1(0.1-138.6)N/A15.9(2.9-73.4)MedianPFS,mos(95%CI)9.7(7.7-12.8)8.1(6.8-9.7)7.7(6.0-8.8)克唑替尼治疗ALK阳性NSCLC的疗效1.CamidgeDR,etal.LancetOncol.2012;10:1011-1019.2.KimDW,etal.ASCO2012.Abstract7533.3.ShawAT,etal.NEnglJMed.2013;368:2385-2394*AtWk8.†Range.针对驱动基因改变的靶向治疗：“癌基因依赖性”Gefitinib[1,2]Erlotinib[3,4]Afatinib[5,6]Crizotinib[7-9]ActivityEGFREGFREGFR(ErbBfamily)ALK,ROS1,METTargetEGFRALKRR,%60-8050-80~60~60PFS,mos10-1110-14~11~10TRD,%1~21~21.7<1EGFRmutantsALKROS/RET1.MaemondoM,etal.NEnglJMed.2010;362:2380-2388.2.MitsudomiT,etal.LancetOncol.2010;11:121-128.3.RosellR,etal.LancetOncol.2012;13:239-246.4.ZhouC,etal.LancetOncol.2011;12:735-742.5.SequistLV,etal.JClinOncol.2013;31:3327-3334.6.WuYL,etal.LancelOncol.2014;15:213-222.7.CamidgeDR,etal.LancetOncol2012;10:1011-1019.8.KimDW,etal.ASCO2012.Abstract7533.9.ShawAT,etal.NEnglJMed2013;368:2385-2394.NSCLCAdenocarcinoma:BeyondEGFRMutationsandALKTranslocationEGFRBRAFKRASNoneERBB2(1.7%)HRAS(0.4%)NRAS(0.4%)RETfusion(0.9%)MAP2K1(0.9%)ALKfusion(1.3%)ROS1fusion(1.7%)NF1MET

amp

(2.2%)ERBB2amp

(0.9%)RIT1

(2.2%)8.3%4.3%7.0%METex1411.3%32.2%24.4%GovindanR.ISLAC2013.AbstractPL05.1.JohnsonB,etal.ASCO2013.Abstract8019.肺癌突变联盟：突变和治疗对OS的影响Drivermutation+targetedtherapy(n=313)Drivermutation+notargetedtherapy(n=265)Nodrivermutation(n=361)100806040200OS(%)012345YrsKRASKRASIV期肺癌的治疗模式的改变:2002-2014组织病理学仍然指导大多数病人的治疗选择AdenoLCC-NOSSCCIV期肺癌的治疗模式的改变:2002-2014NON-SQUAMOUSNSCLCAdenoLCC/NOSSCCKRASKRAS组织病理学仍然指导大多数病人的治疗选择IHC对NSCLC-NOS的诊断具有重要意义

NSCLCSquamousAdenocaOccasionalraretypesNSCLCprobablyadenoNSCLCprobablysquamous87%accuracy80%accuracy83%accuracyImmunohistochemistrytopredictsubtype50%Adenoca37%Largecell13%Squamouswhenresected~20%to35%ofcasesoverall60%to75%ofcasesTTF1,p63,CK5/6&AB/PAS25%to40%ofcases1.EdwardsS,etal.JClinPathol.2000;53:537-540.2.LooPS,etal.JThoracOncol.2010;5:442-447.NSCLC-NOSIHCnotpredictive6%ofcasesoverallNSCLC-NOS组织病理学类型决定C/PvsC/G治疗晚期NSCLC的OSMosSurvivalProbabilitySquamousNonsquamousMosSurvivalProbabilityScagliottiGV,etal.JClinOncol.2008;26:3543-3551.C/P

C/G

C/PvsC/GMedianSurvival11.8mos10.4mosAdjustedHR:0.81(95%CI:0.70-0.94)C/P

C/G

C/PvsC/GMedianSurvival9.4mos10.8mosAdjustedHR:1.23(95%CI:1.00-1.51)1.0030061218241.003006121824培美曲赛的III临床研究表明组织学类型影响OSNSCLCHistology

Second-line

PemvsDocetaxel[1]First-linePem/Cis

vsGem/Cis[1]Maintenance

PemvsPlacebo[2]PemDocCis/PemCis/GemPemPlaceboNonsquamous,*n205194618634325156 MedianOS,mos9.38.011.010.115.510.3 AdjustedHR

(95%CI;Pvalue)0.78(0.61-1.00;

.048)0.84(0.74-0.96;

.011)0.70(0.56-0.88;

.002)Squamous,n789424422911666 MedianOS,mos10.89.910.8 AdjustedHR

(95%CI;Pvalue)1.56(1.08-2.26;

.018)1.23(1.00-1.51;

.050)1.07(0.77-1.50;

.678)*Adenocarcinoma,largecellcarcinoma,orother/indeterminateNSCLChistology1.ScagliottiGV,etal.Oncologist.2009;14:253-263.2.Pemetrexed[packageinsert].2009.NSCLC中ERCC1、RRM1和TSmRNA表达存在异质性MausMKH,etal.JThoracOncol.2013;8:582-586.ERCC1RRM1TS*Geneexpressionlevelcutofffordrugsensitivity.ERCC1

(Reference<1.7forplatinum)*%BelowReferenceLevelNSCLC-total43.4NSCLC-AC46.0NSCLC-SCCA30.7RRM1

(Reference<0.97forgemcitabine)*%BelowReferenceLevelNSCLC-total39.6NSCLC-AC42.2NSCLC-SCCA13.0TS

(Reference<2.33forpemetrexed)*%BelowReferenceLevelNSCLC-total41.3NSCLC-AC45.7NSCLC-SCCA25.9GeneExpressionLevelRelativetoβ-actin1086420ACSCCA1086420ACSCCA1086420ACSCCA选择性血管生成抑制剂在NSCLC中的应用DrugTargetRouteFrequencyClinicalStatusBevacizumabVEGFligandIVq3wApprovedRamucirumabVGFR-2IVq3wPhaseIIISorafenibRaf,Kit,Flt-3,VEGFR-2,VEGFR-3,PDGFR-POTwicedailyNotapprovedVandetanibVEGFR-2,VEGFR-3,RET,EGFRPODailyNotapprovedSunitinibVEGFR-1,VEGFR-2,VEGFR-3,PDGFR-α,PDGFR-,Flt-3,c-kitPOTwicedailyNotapprovedCediranibVEGFR-2,VEGFR-1,VEGFR-3,c-kit,Flt-3PODailyNotapprovedMotesanibVEGFR-1,VEGFR-2,VEGFR-3,PDGFR,RET,kitPODailyNotapprovedAxitinibVEGFR-1,VEGFR-2,VEGFR-3,PDGFR-,kitPOTwicedailyNotapprovedPazopanibVEGFR-2,VEGFR-2,VEGFR-3,PDGFR-α,PDGFR-,c-kitPODailyNotapprovedNintedanibVEGFR1-3;FGFR1,3;PDGFα,β

POTwicedailyPhaseIIIECOGE4599:Bev+CarboandPaclitaxelinMetastaticNonsquamousNSCLCSandlerA,etal.NEnglJMed.2006;355:2542-2550.SandlerA,etal.JThoracOncol.2010;5:1416-1423.OverallPopulationAdenocarcinoma1.00ProbabilityofOSMos10.30426121824303612.31.00ProbabilityofOSMos10.30426121824303614.2CP+bev(n=434)CP(n=444)

HR:0.79(95%CI:0.67-0.92;

P=.003)CP+bev(n=300)CP(n=302)HR:0.69(95%CI:0.58-0.83;P=.009)抗VEGF单抗治疗NSCLC的III期临床研究TrialTreatmentlineTreatmentArmsMedianSurvival,MosTrialOutcomeECOG4599[1]FirstlinePaclitaxel/carboplatin

+bevacizumabOS:12.3*PositivePaclitaxel/carboplatinOS:10.3AVAiL[2]FirstlineCisplatin/gemcitabine

+bevacizumabPFS

Highdose:6.5*

Lowdose:6.7*Positivefor

primaryendpointCisplatin/gemcitabine

+placeboPFS:6.1BETA[3]SecondlineBevacizumab+erlotinibOS:9.3NegativeErlotinib+placeboOS:9.2ATLAS[4]FirstlinemaintenanceBevacizumab+erlotinibPFS:4.8*Positivefor

primaryendpointBevacizumab+placeboPFS:3.71.SandlerA,etal.NEnglJMed.2006;355:2542-2550.2.ReckM,etal.JClinOncol.2009;27:1227-1234.

3.HerbstRS,etal.Lancet.2011;377:1846-1854.4.JohnsonBE,etal.JClinOncol.2013;31:3926-3934.*Significantlydifferentfromcomparator.抗血管生成治疗的生物标志物高血压是VEDF抑制剂获益的早期预测因素ICAM和VEGF-A水平的预后作用优于其预测意义VEGF多态性有望成为预测因子血浆细胞因子/血管生长因子引发关注IL-6,IL-12有可能仍需有真正预测意义的生物标志物帮助我们在抗血管生成治疗取得进展组织病理学仍然指导大多数病人的治疗选择对于鳞癌而言，含铂两药方案化疗仍然是标准的治疗IV期肺癌的治疗模式的改变:2002-2014AdenoLCC-NOSSCC卡铂/纳米紫杉醇vs卡铂/紫杉醇治疗晚期NSCLC的III期临床研究Primaryendpoint:ORRSecondaryendpoints:PFS,OS,safetyPatientswithstageIIIb/IVNSCLC,ECOGPS0-1,nopreviouschemotherapyformetastaticdisease(N=1050)Nab-Paclitaxel100mg/m2onDays1,8,15+CarboplatinAUC6onDay1NopremedicationPaclitaxel200mg/m2onDay1+CarboplatinAUC6onDay1Premedication:dexamethasone,antihistaminesStratifiedbystage(IIIbvsIV),

age(<70yrsvs>70yrs),sex,

histology(squamousvsnonsquamous),geographicregion21-daycyclesSocinskiMA,etal.JClinOncol.2012;30:2055-2062.P=.005

RRR:1.3133%25%IntenttoTreatSocinskiMA,etal.JClinOncol.2012;30:2055-2062.卡铂/纳米紫杉醇vs卡铂/紫杉醇治疗晚期NSCLC：有效率*Carboplatin/nab-paclitaxel

Carboplatin/paclitaxelResponseRate(%)P<.001

RRR:1.680P=.808

RRR:1.03441%26%24%25%01020304050Squamous†Nonsquamous†n=229n=221n=292n=310*Independentradiologicalreview.†Notaprespecifiedendpoint.InteractionPvalueforhistology=.036n=521n=531NSCLC鳞癌中可作为靶点的癌基因通路的改变体细胞突变纯合性缺失高扩增水平基因表达的上调/下调CancerGenomeAtlasNetwork.Nature.2012;489:519-525.ReprintedbypermissionfromMacmillanPublishersLtd:Copyright2012.维持治疗的策略4周期化疗后继续原两药方案原方案以外的单药化疗（换药维持）卡铂+紫衫醇——培美曲塞卡铂+吉西他滨——多西他赛含铂两药方案——厄洛替尼靶向药物继续治疗卡铂+紫杉醇+贝伐珠单抗——贝伐珠单抗应用原方案中1种或2种药物继续治疗（原药维持）顺铂+培美曲塞——培美曲塞顺铂+吉西他滨——吉西他滨顺铂+培美曲塞—+贝伐珠单抗——贝伐珠单抗+培美曲塞ContinuationMaintenanceCaiH,etal.ClinLungCancer.2013;14:333-341.HR:0.54

(95%CI:0.46-0.63;P<.00001)HR:0.61

(95%CI:0.51-0.74;P<.00001)HR:0.65

(95%CI:0.59-0.72;P<.00001)NSCLC维持治疗的Meta分析：PFSSwitchMaintenance0.20.5125FavorsExperimentalFavorsControlBrodowicz2006Perol2010Barlesi2011Paz-Ares2012StudyorSubgroupPetoOddsRatioExp[O-E/V],Fixed,95%CI0.20.5125FavorsExperimentalFavorsControlStudyorSubgroupPetoOddsRatio

Exp[0-E)/V],Fixed,95%CI1.1CytotoxicAgents

Fidias2009

Ciuleanu20091.2MolecularlyTargetedAgents

Cappuzzo2010

Gaatar2010Perol2010Zhang2012HR:0.80

(95%CI:0.63-1.01);P=.06)HR:0.81

(95%CI:0.71-0.92);P=.001)TotalHR:0.80(95%CI:0.72-0.92);P=.0002)7trialsreportnodetrimentaleffectonQOLNSCLC维持治疗的Meta分析：OSCaiH,etal.ClinLungCancer.2013;14:333-341.ContinuationMaintenance0.20.5125FavorsExperimentalFavorsControlBrodowicz2006Perol2010Belani2010Barlesi2011Paz-Ares2012StudyorSubgroupPetoOdds

RatioExp[O-E/V],Fixed,95%CIHR:0.82

(95%CI: