晚期NSCLC维持治疗策略课件

晚期晚期NSCLCNSCLC维持治疗策略维持治疗策略中山医科大学肿瘤医院张 力 晚期NSCLC维持治疗策略中山医科大学肿瘤医院晚期肺癌治疗的模式晚期肺癌治疗的模式诊断诊断缓解或稳定缓解或稳定PDPD死亡死亡1 1线化疗线化疗(4-6(4-6周期周期)2-32-3线化疗线化疗晚期肺癌治疗的模式诊断缓解或稳定PD死亡1线化疗2-3线化疗问题问题1 1：为什么要停下来休息为什么要停下来休息?问题1：为什么要停下来休息?继续一线两药化疗药物直到6个周期Socinski MA,et al.J Clin Oncol 2002;20:13351343.Socinski MA,et al.J Clin Oncol 2002;20:13351343.Park JO,et al.J Clin Oncol 2007;25:52335239.Park JO,et al.J Clin Oncol 2007;25:52335239.von Plessen et al.Br J Cancer 2006;95:966973.von Plessen et al.Br J Cancer 2006;95:966973.Park JO,et al.J ClinOncol 2007;25:52335239Park JO,et al.J ClinOncol 2007;25:52335239 第一作者第一作者年份年份化疗化疗治疗组治疗组(n)TTPMST1YSSmith2001MVP3周期周期(155)6周期周期(153)5月月5月月6月月7月月22%25%Socinski2002CP4周期周期(114)持续持续(116)NRNR6.6月月8.5月月28%34%Von Plessen2006CV3 周期周期(150)6周期周期(147)16周周21周周7月月8月月25%25%Park2007铂类铂类4周期周期(156)6周期周期(158)4.6月月6.2月月15.9月月14.9月月62.4%59%继续一线两药化疗药物直到6个周期Socinski MA,e继续一线两药化疗药物直到6个周期Smith et al：6周期=31%Socinsk et al:6周期=13%Park et al：6周期=68%Von Plessen et al:6周期=54%继续一线两药化疗药物直到6个周期Smith et al：6周一线化疗因为毒性退出化疗的比例Socinski MA,et al.J Clin Oncol 2002;20:13351343Socinski MA,et al.J Clin Oncol 2002;20:13351343一线化疗因为毒性退出化疗的比例Socinski MA,et一线化疗时间的一线化疗时间的MetaMeta分析分析JCO 2009;27:3277-3283JCO 2009;27:3277-3283一线化疗时间的Meta分析JCO 2009;27:3277ASCO GuidelineASCO Guideline的变化的变化199720042009ASCO Guideline的变化199720042009ASCO Educational Book 2003ASCO Educational Book 2003ASCO Educational Book 2003问题：问题：停下来休息的后果是什么？停下来休息的后果是什么？问题：停下来休息的后果是什么？晚期肺癌治疗的模式晚期肺癌治疗的模式诊断诊断缓解或稳定缓解或稳定PDPD死亡死亡1 1线化疗线化疗(4-6(4-6周期周期)2-32-3线化疗线化疗？病人病人 :肿瘤治疗好了吗？肿瘤治疗好了吗？医生：没有！医生：没有！病人病人 :以后不用再治疗了吗？以后不用再治疗了吗？医生：不是！医生：不是！晚期肺癌治疗的模式诊断缓解或稳定PD死亡1线化疗2-3线化疗晚期肺癌治疗的模式晚期肺癌治疗的模式诊断诊断缓解或稳定缓解或稳定PDPD死亡死亡1 1线化疗线化疗(4-6(4-6周期周期)2-32-3线化疗线化疗？病人病人 :什么时候再回来治疗？什么时候再回来治疗？医生：。医生：。晚期肺癌治疗的模式诊断缓解或稳定PD死亡1线化疗2-3线化疗晚期晚期NSCLCNSCLC维持治疗研究中对照组维持治疗研究中对照组PFSPFS结果汇总结果汇总方式研究维持药物MedianPFS(月)对照组原药维持Brodowics吉西他滨2IFCT-GFPC吉西他滨1.9Belani吉西他滨7.7Parament培美曲赛2.6换药维持WesteelVinorelbine3Fidias多西他赛2.7Ciuleanu培美曲赛2JMEN培美曲赛1.8靶向维持SATURN厄洛替尼2.6INFORM吉非替尼2.6Fidias JCO 27:591-8,2009Ciuleanu Lancet 374:1432-40,2009Capuzzo Lancet Oncol 11:521-529,2010 J Clin Oncol 29:2011(suppl;abstr CRA7510)Belani,ASCO 2010Perol,ESMO,2010Ciuleanu,et al.The Lancet 2009Cappuzzo,et al.ASCO 2009Zhang L,et al.2011 ASCO Abstract 7511.晚期NSCLC维持治疗研究中对照组PFS结果汇总方式研究维持近近50%50%患者无法进入二线治疗患者无法进入二线治疗 主要原因主要原因PSPS差差(58%)(58%)一线治疗疗效差一线治疗疗效差 (24%)(24%)合并症合并症 (24%)(24%)痌变范围痌变范围 (22%)(22%)29%29%仅接受仅接受 BSCBSC 接受一线治疗的患者100%100%54%54%接受二线治疗的患者来自来自306306位欧盟医师的资料位欧盟医师的资料 46%46%未接受未接受二线治疗二线治疗 17%17%死亡死亡TNS Healthcare,Brand Tracking Study,December 2007100806040200近50%患者无法进入二线治疗 29%仅接受 BSC 接受一多个多个IIIIII期临床期临床研究中，研究中，330%0%的患者未接受二线治疗的患者未接受二线治疗1.J Clin Oncol 2002;20:133543;2.J Clin Oncol 2003;21:293339;3.Lung Cancer 2006;52:15563;4.Br J Cancer 2006;95:96673;5.J Thorac Oncol 2007;2(Suppl.4):S666(Abs.P2-235);6.J Clin Oncol 2007;25:523339;7.Lancet 2009;374:143240;8.J Clin Oncol 2008;26(Suppl.15):6s(Abs.3);9.J Clin Oncol 2008;26:354351;10.J Clin Oncol 2009;27:591980255075100Socinski et al.20021Belani et al.20032Brodowicz et al.20063von Plessen et al.20064Barata et al.20075Park et al.20076Ciuleanu et al.20097Pirker et al.20088Scagliotti et al.20089Fidias et al.200910接受二线治疗的患者接受二线治疗的患者(%)(%)多个III期临床研究中，30%的患者未接受二线治疗1.JIn our opinion,treatment-free intervals remain In our opinion,treatment-free intervals remain an option;however,patients must be observed an option;however,patients must be observed closely with serial radiographic examinations closely with serial radiographic examinations because the median PFS is approximately 2 to 3 because the median PFS is approximately 2 to 3 months.months.The optimal timing and method of observing The optimal timing and method of observing patients for disease progression are unclear,patients for disease progression are unclear,and patients should be informed of the risks and patients should be informed of the risks associated with a treatment-free inteassociated with a treatment-free interval.rval.一线化疗后停下来休息一线化疗后停下来休息Stinchcombe,Socinski,JTO 2011Stinchcombe,Socinski,JTO 2011In our opinion,treatment-free问题：问题：有没有其他的治疗选择？有没有其他的治疗选择？问题：有没有其他的治疗选择？诊断诊断PD二线治疗直到PD死亡一线治疗一线治疗含铂两药化疗(46周期)CR/PR/SDCR/PR/SD维持治疗新的治疗模式：维持治疗新的治疗模式：维持治疗 进展前尽可能拖延无进展生存期进展前尽可能拖延无进展生存期 缓解症状复发或恶化缓解症状复发或恶化 改善总生存期改善总生存期诊断PD二线治疗死亡一线治疗含铂两药化疗CR/PR/SD维晚期晚期NSCLCNSCLC维持治疗的不同治疗策略维持治疗的不同治疗策略晚期NSCLC维持治疗的不同治疗策略晚期晚期NSCLCNSCLC维持治疗维持治疗PFSPFS结果汇总结果汇总方式研究维持药物MedianPFS(月)HR(95%CL)forPFS对照组维持组原药维持Brodowics吉西他滨23.60.69(0.56-0.86)IFCT-GFPC吉西他滨1.93.80.56(0.44-0.72)Belani吉西他滨7.77.41.09(0.81-1.45)Parament培美曲赛2.63.90.64(0.51-0.81)换药维持WesteelVinorelbine350.77(0.55-1.07)Fidias多西他赛2.75.70.71(0.55-0.92)JMEN培美曲赛1.84.40.47(0.420.61)靶向维持SATURN厄洛替尼2.62.90.71(0.620.82)INFORM吉非替尼2.64.80.42(0.33-0.55)Fidias JCO 27:591-8,2009Ciuleanu Lancet 374:1432-40,2009Capuzzo Lancet Oncol 11:521-529,2010 J Clin Oncol 29:2011(suppl;abstr CRA7510)Belani,ASCO 2010Perol,ESMO,2010Ciuleanu,et al.The Lancet 2009Cappuzzo,et al.ASCO 2009Zhang L,et al.2011 ASCO Abstract 7511.晚期NSCLC维持治疗PFS结果汇总方式研究维持药物MediINFORMINFORM研究中的研究中的PFSPFSZhang L,et al.2011 ASCO Abstract 7511.0312 1521 25时间(月)无进展生存率(%)02040608010018698.5 易瑞沙(n=105)2.6 安慰剂(n=104)中位 PFS(月)AstraZeneca Data On File.16.6 易瑞沙(n=15)2.8 安慰剂(n=15)中位 PFS(月)01696112PFS概率(%)04060801002032486480自随机时间(周)4.8 易瑞沙(n=148)2.6 安慰剂(n=148)中位 PFS(月)HR=HR=0.420.42HR=HR=0.170.17全组人群全组人群腺癌亚组腺癌亚组EGFR M+EGFR M+亚组亚组INFORM研究中的PFSZhang L,et al.2IressaPlacebo051015202530LCSLCSOdds Ratio=3.31(95%CI 1.60-6.82,p=0.0012).中位症状恶化时间(LCS):4.3月(gefitinib)v 2.3月(placebo).INFORM生活质量改善Han BH,et al WCLC 2011Odds Ratio=3.31(95%CI 1.60-6.晚期晚期NSCLCNSCLC维持治疗维持治疗OSOS结果汇总结果汇总方式研究维持药物MedianOS(月)HR(95%CL)forOS对照组维持组原药维持Brodowics吉西他滨11.013.0p=0.195IFCT-GFPC吉西他滨10.812.10.86(0.66-1.12)Belani吉西他滨8.09.30.97(0.72-1.30)Parament培美曲赛NRNRNR换药维持WesteelVinorelbine12.312.3p=0.65Fidias多西他赛9.712.30.84(0.651.08)JMEN培美曲赛10.613.40.70(0.56-0.88)靶向维持SATURN厄洛替尼11.012.00.81(0.700.95)INFORM吉非替尼16.918.70.84(0.621.14)Fidias JCO 27:591-8,2009Ciuleanu Lancet 374:1432-40,2009Capuzzo Lancet Oncol 11:521-529,2010 J Clin Oncol 29:2011(suppl;abstr CRA7510)Belani,ASCO 2010Perol,ESMO,2010Ciuleanu,et al.The Lancet 2009Cappuzzo,et al.ASCO 2009Zhang L,et al.2011 ASCO Abstract 7511.晚期NSCLC维持治疗OS结果汇总方式研究维持药物Media问题：问题：如何解释没有如何解释没有OSOS的改善？的改善？问题：如何解释没有OS的改善？维持治疗研究的设计维持治疗研究的设计维持治疗研究的设计研究分组中位PFS(月)中位OS(月)任何后续治疗(%)后续为维持治疗药物(%)JMEN培美曲塞413.4511安慰剂210.66718SATURN特罗凯2.912555安慰剂2.6116416Fidias多西他赛维持5.712.395多西他赛二线2.79.763IFCT-GFPC特罗凯2.9682观察组1.98254INFORM吉非替尼4.818.750.78.1观察组2.616.966.931.8研究分组中位PFS中位OS任何后续后续为维持JMEN培美曲塞SATURNSATURN研究研究Time(weeks)0 8 16 24 32 40 48 56 64 72 80 88 96PFS probabilityHR=0.10(0.040.25)Log-rank p0.0001 1.00.80.60.40.20PFSErlotinib(n=22)Placebo(n=27)Cappuzzo,et al.ASCO 2009Coudert,etal.ELCC2010SATURN研究Time(weeks)0 Randomized studies on first line EGFR Randomized studies on first line EGFR TKI in patients with EGFR mutationTKI in patients with EGFR mutationAuthorStudyN(EGFR mut+)RR Median PFSOSMok et alIPASS13271.2%vs 47.39.8 vs 6.4 months阴性Lee et alFirst-SIGNAL2784.6%vs 37.5%8.4 vs 6.7 months阴性Mitsudomi et alWJTOG 34058662.1%vs 32.2%9.2 vs 6.3 months阴性Maemondo et alNEJGSG00211473.7%vs 30.7%10.8 vs 5.4 months阴性Zhou et alOPTIMAL15483%vs 36%13.1 vs 4.6 months阴性Rosell et alEURTAC135NANA阴性Mok et al NEJM 2009,Lee et al WCLC 2009,Mitsudomi et al Lancet Oncology 2010,Maemondo NEJM 2010Zhou et al ESMO 2010，Rosell et al ASCO 2011Randomized studies on first liJMEN JMEN 研究的后续治疗研究的后续治疗Ciuleanu,et al.The Lancet 2009JMEN 研究的后续治疗Ciuleanu,et al.TIFCT-GFPC 0502IFCT-GFPC 0502研究研究PerolM,etal.ESMO:abstr370PD.IFCT-GFPC 0502研究PerolM,etal.ES二线培美曲塞的治疗情况二线培美曲塞的治疗情况观察组(N=155)吉西他滨(N=154)特罗凯(N=155)培美曲塞(%)766063中位周期(范围)3(1-14)3(1-21)3(1-14)二线培美曲塞疗效可评估患者796267 CR(%)001.5 PR(%)15.28.110.4 SD(%)43.046.840.3 PD(%)41.847.247.8Perol M,et al.J Clin Oncol 2010;28(s):abstr 7507.二线培美曲塞的治疗情况观察组 吉西他滨特罗凯培美曲塞(%)IFCT-GFPC 0502IFCT-GFPC 0502研究研究全组病人全组病人接受二线治疗的接受二线治疗的病人病人Perol M,et al.J Clin Oncol 2010;28(s):abstr 7507.IFCT-GFPC 0502研究全组病人接受二线治疗的病人PReal-World Considerations for Maintenance Real-World Considerations for Maintenance TherapyTherapyJTO 2011;6:365371Real-World Considerations for Because patients with stage IV NSCLC have longer OS Because patients with stage IV NSCLC have longer OS in clinical trials,the impact of any one drug,or in clinical trials,the impact of any one drug,or the timing of its use,on that survival becomes more the timing of its use,on that survival becomes more difficult to detect as patients receive sequential difficult to detect as patients receive sequential therapies.therapies.This complexity will increase the importance of PFS This complexity will increase the importance of PFS as an end point in future clinical trials of novel as an end point in future clinical trials of novel drugs in patients with stage IV NSCLC.drugs in patients with stage IV NSCLC.JCO 2011JCO 2011Because patients with stage IV问题：问题：怎样实现个体化维持治疗怎样实现个体化维持治疗?问题：怎样实现个体化维持治疗?如何合理地选择维持治疗？如何合理地选择维持治疗？1.哪些患者适合维持治疗？2.原药维持和换药维持如何选择？3.怎样实现个体化维持治疗?如何合理地选择维持治疗？哪些患者适合维持治疗？两项吉西他滨维持治疗研究显示两项吉西他滨维持治疗研究显示两项吉西他滨维持治疗研究显示两项吉西他滨维持治疗研究显示:对对对对PSPSPSPS评分好的患者进行维持治疗疗效显著评分好的患者进行维持治疗疗效显著评分好的患者进行维持治疗疗效显著评分好的患者进行维持治疗疗效显著吉西他滨/卡铂一线治疗后吉西他滨维持IFCT-GFPC0502研究吉西他滨维持组N=128BSCN=127吉西他滨维持组N=154BSCN=155中位年龄（岁）67.267.557.959.8ECOGPS2-3(%)565863对诱导化疗的反应:ORR/SD(%)28/3753/4753/47PFS(月)3.93.83.81.9P=0.838*P0.001OS(月)8.09.3NR*与安慰剂相比与安慰剂相比ASCO 2010 ASCO 2010 M.Perol,M.Perol,et al.,Abstract#7507et al.,Abstract#7507ASCO 2010 ASCO 2010 C.P.Belani,C.P.Belani,et al.,Abstract#7506et al.,Abstract#7506两项吉西他滨维持治疗研究显示:对PS评分好的患者进行维持HR=0.4795%CI:0.420.61)p0.00001Progression-free probability培美曲塞:中位=4.4个月安慰剂:中位=1.8个月1.0036912150.00.10.20.30.40.50.60.70.80.91.0培美曲塞:中位=3.9个月(3.0-4.2)安慰剂:中位=2.6个月(2.2-2.9)Log-rank P=0.0002未调整HR:0.64(0.51-0.81)JNENJNENParamountParamountTime Time（monthsmonths）Time Time（monthsmonths）Progression-free probabilityProgression-free probability病理类型对选择培美曲赛维持治疗的病理类型对选择培美曲赛维持治疗的从延长 PFS角度来看，两种治疗方式都是合理的选择。Ciuleanu,et al.The Lancet 2009HR=0.47 95%CI:0.420.61)PrSDSD的患者更适合换药维持的患者更适合换药维持Ciuleanu,et al.The Lancet 2009Cappuzzo,et al.ASCO 2009SD的患者更适合换药维持Ciuleanu,et al.TEGFR TKIs:EGFR mut+EGFR TKIs:EGFR mut+的病人的病人Cappuzzo et al.Lancet Oncol 2010;Brugger,et al.WCLC 2009Cappuzzo et al.Lancet Oncol 2010;Brugger,et al.WCLC 2009Time(weeks)0 8 16 24 32 40 48 56 64 72 80 88 96PFS probabilityHR=0.10(0.040.25)Log-rank p0.0001 1.00.80.60.40.20PFSErlotinib(n=22)Placebo(n=27)020406080100081624324048566472808896 104 112PFS(%)时间(周)HR(95%CI)=0.17(0.07,0.42)吉非替尼(n=15)中位 PFS,16.6 个月安慰剂(n=15)中位 PFS,2.8 个月EGFR TKIs:EGFR mut+的病人Cappuzzl维持治疗目标争取更多的病人能够接受后续的治疗维持治疗目标争取更多的病人能够接受后续的治疗l尽可能地延长患者尽可能地延长患者PFSPFS。l改善改善/保持较好的生活质量保持较好的生活质量(QoL)(QoL)l副作用小的药物更加适合作为维持治疗的选择。副作用小的药物更加适合作为维持治疗的选择。l很多因素影响患者的很多因素影响患者的OSOS。维持治疗用于晚期维持治疗用于晚期NSCLCNSCLC总体评价总体评价维持治疗目标争取更多的病人能够接受后续的治疗维持治疗用于晚期1.1.“Switch maintenanceSwitch maintenance”Tx with erlotinib or pemetrexed Tx with erlotinib or pemetrexed following completation of first-line CT is an option.following completation of first-line CT is an option.Decision factors for the use of Decision factors for the use of“switch maintenanceswitch maintenance”include histology,type and response to first line include histology,type and response to first line chemotherapy,residual toxicity,patientchemotherapy,residual toxicity,patients symptoms and s symptoms and preference.preference.2.Any patient whose tumor harbour an EGFR activating 2.Any patient whose tumor harbour an EGFR activating mutation should receive EGFR TKIs as maintenance,if not yet mutation should receive EGFR TKIs as maintenance,if not yet received as first-line.received as first-line.Strength of recommendationStrength of recommendation:B;Level of evidenceLevel of evidence:I 1.“Switch maintenance”Tx wit总总 结结 For patients with stable disease or response after four For patients with stable disease or response after four For patients with stable disease or response after four For patients with stable disease or response after four cycles,immediate treatment with alternative,single-cycles,immediate treatment with alternative,single-cycles,immediate treatment with alternative,single-cycles,immediate treatment with alternative,single-agent chemotherapy such as pemetrexed in patients with agent chemotherapy such as pemetrexed in patients with agent chemotherapy such as pemetrexed in patients with agent chemotherapy such as pemetrexed in patients with non-squamous histology,docetaxel in unselected patients,non-squamous histology,docetaxel in unselected patients,non-squamous histology,docetaxel in unselected patients,non-squamous histology,docetaxel in unselected patients,or erlotinib in unselected patients may be considered;or erlotinib in unselected patients may be considered;or erlotinib in unselected patients may be considered;or erlotinib in unselected patients may be considered;Limitations of this data are such that break from Limitations of this data are such that break from Limitations of this data are such that break from Limitations of this data are such that break from cytotoxic chemotherapy after fixed course is also cytotoxic chemotherapy after fixed course is also cytotoxic chemotherapy after fixed course is also cytotoxic chemotherapy after fixed course is also acceptable,with initiation of second-line chemotherapy acceptable,with initiation of second-line chemotherapy acceptable,with initiation of second-line chemotherapy acceptable,with initiation of second-line chemotherapy at disease progressionat disease progressionat disease progressionat disease progression总 结For patients with stable d THANKS !