肺癌免疫治疗进展培训ppt课件

本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Future OutlookUpdate of checkpoint Inhibitors in lung cancer therapyCancer Immunotherapy123 OutlineFuture OutlookUpdate of checkp1本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Future OutlookUpdate of checkpoint Inhibitors in lung cancer therapyCancer Immunotherapy123 OutlineFuture OutlookUpdate of checkp2本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。肿瘤免疫治瘤免疫治疗攻克攻克肿瘤的新希望瘤的新希望人类抗击肿瘤的历史肿瘤免疫治疗具有特异性和靶向性，一直为临床医师高度关注，近年进步显著，使得免疫治疗成为更具期待的领域靶向治疗靶向治疗进入21世纪，分子靶向治疗如火如荼肿瘤免疫治疗攻克肿瘤的新希望人类抗击肿瘤的历史靶向治疗3本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。eKeyeventsinthehistoryofcancerimmunotherapy1890s 1st CA vaccine developed(coley)1973 discovery of the dendritic cell(steinman)1976 1st study with BCG in bladder CA1978 Discovery of tumor specific mABs1985 1st study with adoptive T-ce ll transfer in CA1986 IFN(cytokine)approved for CA1990s Discovery of role of checkpoints in CA1992 Il-2(Cytokine)approved for CA1997 1st mAB approved for CA2010 1st cellular immunotherapy approved for CA2011 1st checkpoint inhibitor approved for CA2014 2nd checkpoint inhibitor approved for CAEnthusiasm phase1976-1985Skepticism phase1986-1992Renaissance phase1997-eKey events in the history 1894本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。美国Science杂志:2013年六大值得关注的科学领域单细胞测序“普朗克”探测微波背景辐射人类连接组计划探索南极冰下世界癌症免疫疗法基础植物研究美国Science杂志:5本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Breakthrough of year 2013Science.2013 Dec 20;342(6165):1432-3Breakthrough of year 2013Scie6本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Immunity.39(1)25 July 2013,Pages 110Stimulatory and Inhibitory Factors in the Cancer-Immunity CycleImmunity.39(1)25 July 2013,P7本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。CTLA-4 and PD-1/PD-L1 checkpoint blockade for cancer treatmentCTLA-4 and PD-1/PD-L1 checkpoi8本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment Immune checkpoint blockade includes agents targeting the negative regulators CTLA-4 and PD-1 CTLA-4 attenuates the early activation of naive and memory T cells in the lymph nodes Agents targeting CTLA-4 include ipilimumab and tremelimumab In contrast,PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2 Agents targeting PD-1 include nivolumab and MK-3475 Agents targeting PD-L1 include MPDL3280A and MEDI4736Kyi C,et al.FEBS Lett.2014;588:368-376CTLA-4 and PD-1/PD-L1 Checkpo9本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Comparing CTLA-4 and PD-1CTLA-4PD-1Biological functionInhibitory receptorInhibitory receptorExpression onT cells at the time of initial response to antigen(activated CD8+T cells)Activated T cells,B cells,NK cellsTILs in different tumor typesMajor roleRegulates the early stage of T-cell activationLimits T-cell activity in peripheral tissue after inflammatory responseLimits autoimmunityLigandsB7.1(CD80)B7.2(CD86)PD-L1(B7-H1/CD274)PD-L2(B7-CD/CD273)Mechanism of actionAfter ligand binding:Binding with PI3K,phosphatases SHP-2 and PP2ABlockade of lipid-raft expressionBlockade of microcluster formationAfter ligand binding:Recruits inhibitory phosphatase,SHP-2Decreases expression of cell survival protein Bcl-xLInhibits kinases(PI3K/AKT)involved in T-cell activationCrit Rev Oncol Hematol.2014;89:140-165.CTLA-4 and PD-1 have separate but complimentary roles in immune responsesComparing CTLA-4 and PD-1CTLA-10本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Future OutlookUpdate of checkpoint Inhibitors in lung cancer therapyCancer Immunotherapy123 OutlineFuture OutlookUpdate of checkp11本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。CTLA-4 Checkpoint Inhibitor肺癌免疫治疗进展培训ppt课件12本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Anti-CTLA-4 antibodies can induce clinical response in a broad variety of cancerAdapted form Lebbe et al.ESMO 2008Presented By Lawrence Fong at 2014 ASCO Annual Meeting Bladder Renal Esophageal CNS Colorectal Glioblastoma LeukemiaSoft Tissue SarcomaAnti-CTLA-4 antibodies can ind13本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。J Clin Oncol.2012 Jun 10;30(17):2046-54Ann Oncol.2013 Jan;24(1):75-83J Clin Oncol.2012 Jun 10;30(114本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。J Clin Oncol.2012 Jun 10;30(17):2046-54Ipilimumab in combination with PC as first-line therapy in stage IIIB/IV NSCLCJ Clin Oncol.2012 Jun 10;30(115本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。KaplanMeier plots for OS J Clin Oncol.2012 Jun 10;30(17):2046-54Deaths/patients 51/66 51/68Median(95%CI),months 8.28(6.80 to 12.39)12.22(9.26 to 14.39)HR(95%CI)0.87 (0.59 to 1.28)Log-rank P 0.23ControlPhased IpiDeaths/patients 51/66 51/70Median(95%CI),months 8.28(6.80 to 12.39)9.69(7.59 to 12.48)HR(95%CI)0.99(0.67 to 1.46)Log-rank P 0.48Concurrent lpiControlKaplanMeier plots for OS J Cl16本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Events/patients 61/66 58/70Median(95%CI),mo 4.21(2.76 to 5.32)4.11(2.76 to 5.32)HR(95%CI)0.88(0.61 to 1.27)Log-rank P .25J Clin Oncol.2012 Jun 10;30(17):2046-54KaplanMeier plots for PFS per immune-related(ir)response criteria(irPFS)and modified WHO criteria(mWHO-PFS).Events/patients 56/66 54/68Median(95%CI),4.63m(4.14 to 5.52)5.68(4.76 to 7.79)HR(95%CI)0.72 (0.50 to 1.06)Log-rank P .05 ControlPhased IpiEvents/patients 56/66 55/70Median(95%CI),4.63m(4.14 to 5.52)5.52(4.17 to 6.74)HR(95%CI)0.81(0.55 to 1.17)Log-rank P .13ControlConcurrent lpiEvents/patients 61/66 56/68Median(95%CI),mo 4.21(2.76 to 5.32)5.13(4.17 to 5.72)HR(95%CI)0.69(0.48 to 1.00)Log-rank P .02ControlPhased IpiControlConcurrent lpiEvents/patients 17本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Adverse EventsJ Clin Oncol.2012 Jun 10;30(17):2046-54Adverse EventsJ Clin Oncol.2018本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Follow-UPEvery 12 wksFor survivalSCREENINGINDUCTIONMAINTENANCEFOLLOW-UPCA184-104:phase III trial comparing the the efficacy of ipilimumab(Ipi)with PC versus placebo with PC in patients(pts)with stage IV/recurrent NSCLC of squamous histologyTumor assessmentEvery 12 wksIpi 10mg/kg+PCWks 7,10,13,16stage IV/recurrent squamous NSCLCECOG1Placebo+PCWks 7,10,13,162 cycle PC Wks1,4Ipi 10mg/kgEvery 12 wksPlaceboEvery 12 wks RJ Clin Oncol 31,2013(suppl;abstr TPS8117)primary endpoint OSsecondary endpoints OS among pts who receive blinded therapy PFS best overall response rateTumor assessmentWks 7,13,19,25Exclusion Criteria:Exclusion Criteria:Brain MetastasesAutoimmune diseasesPC Paclitaxel(175 mg/m2,IV)+Carboplatin(AUC=6,IV)SCREENINGINDUCTIONMAINTENANCEF19本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。CA184-156:Phase III Trial Comparing the Efficacy of Ipi Plus Etoposide/Platinum Versus Etoposide/Platinum in Subjects With Newly Diagnosed ED-SCLC J Clin Oncol 30,2012(suppl;abstr TPS7113)Ipi+EPQ3W 2 cycleED-SCLC ECOG 0-1Placebo+EPQ3W 2cycleSCREENINGINDUCTIONMAINTENANCE2 cycle EP Ipi 10mg/kgQ12WPlaceboQ12WRprimary endpoint OSsecondary endpoints OS among pts who receive blinded therapy immune-related and mWHO PFS best overall response rate duration of responseExclusion Criteria:Exclusion Criteria:Prior systemic therapy for lung cancerSymptomatic CNS metastasesHistory of autoimmune diseaseIpi Q3W 2 cycleEP：etoposide(100 mg/m2,IV on Days 1-3 Q3W)+cisplatin(75 mg/m2,IV)or+carboplatin(AUC=5,IV)once Q3WIpi:(10 mg/kg,IV,Q3W)PlaceboQ3W 2cycleCA184-156:Phase III Trial Com20本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。A Phase III Study of Nivolumab in Combination with Yervoy in Patients with Advanced Non-Small Cell Lung Cancer A Phase III Study of Nivolumab21本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。PD-1/PD-L1 Checkpoint Inhibitors肺癌免疫治疗进展培训ppt课件22本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。PD-1 and PD-L1 antibodies in phase III development PD-1 and PD-L1 antibodies in p23本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Phase1 Nivolumab(anti-PD-1;BMS-936558,ONO-4538)multidose regimenEligibility:advcancedmelanoma,NSCLC,RCC,CRC,orCRPCwithPDafter1-5systemictherapiesPhase1 Nivolumab(anti-PD-1;B24本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Select Aes(1%)occuring in Pts with NSCLC treated with Nivolumab(N=129)Drug-related pneumonitis(any grade)occurred in 8 NSCLC Pts(6%)VS 12 Pts(4%)in the overall study population-3Pts(2%)with NSCLC had grade pneumonitis Select Aes(1%)occuring in Pt25本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Efficacy of Nivolumab monotherapy in Pts treated with NSCLC Efficacy of Nivolumab monothe26本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Nivolumab in combination with PT-DC in advanced NSCLCAntonia SJ,et al.2014 ASCO Abstract 8113.Nivolumab in combination with 27本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Results and Conclusions治治疗的前的前6周没有周没有发生生剂量限制毒性量限制毒性3-4级治治疗相关不良事件相关不良事件发生率生率为45%ORR：33-50%1年年OS：59-87%Nivo 10+gem/cis鳞癌Nivo 10+pem/cis非鳞癌Nivo 10+pac/carb鳞+非鳞癌Nivo 5+pac/carb鳞+非鳞癌N12151514ORR,n(%)4(33)7(47)7(47)7(50)mDOR(范围)，周20.9(12.1-41.7)32.0(13,1-42.1)25.6(11.4-39.0)NA(11.4-37.3)PD为BOR,n(%)003(20)1(7)24周时PFS,%367138571年OS,%598759NAAntonia SJ,et al.2014 ASCO Abstract 8113.Antonia SJ,et al.2014 ASCO Abstract 8113.Results and Conclusions治疗的前6周没28本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Ongoing Nivolumab Clinical Trials in Patients With NSCLCLine of therapyPhasePD-L1 SelectionComparatorSingle agent Nivolumab1st line1IIIYesChemotherapy2nd line,squamous2IIINoDocetaxel2nd line,adeno3IIIYesDocetaxel 2nd line,squamous4IINoNACombination Nivolumab 2nd line5INo+LAG3 2nd line6INo+lirilumab(KIR)1st line7INoSingle agent;+chemotherapy;+bevacizumab;+erlotinib;+ipilimumab1.ClinicalTrials.gov.NCT02041533.2.ClinicalTrials.gov.NCT01642004.3.ClinicalTrials.gov.NCT01673867.4.ClinicalTrials.gov.NCT01721759.5.ClinicalTrials.gov.NCT01968109.6.ClinicalTrials.gov.NCT01714739.7.ClinicalTrials.gov.NCT01454102.Ongoing Nivolumab Clinical Tr29本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Parts C to F:Additional MEL and NSCLC cohortsMK3475(Pembrolizumab,Anti-PD-1):Phase I Trial Design20112012AprNovDecJanFebMarAprMayJunJulAugSepOctNovDecIPI-N 10 q2w(n=41)IPI-N 10 q3w(n=24)Part A:Dose EscalationIPI-N 2 q3w(n=22)IPI-T 10 q2w(n=16)IPI-T 10 q3w(n=32)Part B:Metastatic or locally advanced,unresectable MELRibas A et al.ASCO 2013.Abstract 9009.Parts C to F:Additional MEL a30本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。KEYNOTE-001：NSCLC扩大大队列研究列研究设计 (N=307)非随机(N=33)PD-L1+2次治疗非随机(N=40)PD-L1+2次治疗至少1次含铂随机(N=144)PD-L1+1次治疗至少1次含铂随机(N=45)PD-L1+初治非随机(N=45)PD-L1+1次治疗至少1次含铂Pembro10mg/kgq3wPembro10mg/kgq2wPembro10mg/kgq3wPembro10mg/kgq2wPembro10mg/kgq2wPembro10mg/kgq3wPembro2mg/kgq3wPembro2mg/kgq3wR(3:2)R*(1:1:1)*前11例患者随机分入2mg/kg q3w和10mg/kg q3w组，剩余34例患者随机接受10mg/kg q2w和10mg/kg q3w组*非随机队列的45例接受2mg/kg q3w的患者分析截止日期为2014年9月11日数据截止日期：2014年3月3日Garon EB,et al.2014 ESMO Abstract LBA43.主要终点：主要终点：ORR(RECIST v1.1独立中心评估独立中心评估)次要终点：免疫相关疗效标准次要终点：免疫相关疗效标准(irRC)研究者评估研究者评估Pembrolizumab(MK3475)治疗持续直至治疗持续直至PD，不可接受的毒性或死亡，不可接受的毒性或死亡KEYNOTE-001：NSCLC扩大队列研究设计(N=31本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。KEYNOTE-001：基：基线特征特征特征特征特征特征N=262N=262年龄，中位年龄，中位(范围范围)，岁，岁65(28-86)男性男性50%ECOG PS：0/1/缺失缺失31%/68%/1%人种：白种人种：白种/黑人或非裔美国人黑人或非裔美国人/亚裔亚裔/其他其他83%/4%/11%/2%鳞癌鳞癌17%既往接受治疗次数：既往接受治疗次数：0/=117%/83%分期：分期：M0/M1a/M1b/未知未知13%/28%/49%/11%脑转移瘤史脑转移瘤史5%EGFR突变突变(N=250)16%KRAS突变突变(N=156)26%ALK基因重排基因重排(N=231)3%吸烟史：目前吸烟史：目前/曾经曾经/从不从不/未知未知5%/64%/28%/2%Garon EB,et al.2014 ESMO Abstract LBA43.KEYNOTE-001：基线特征特征N=262年龄，中位(32本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。KEYNOTE-001：治治疗暴露与治暴露与治疗相关不良事件相关不良事件汇总4例患者(1.5%)发生输注相关反应发生率1%的其他潜在免疫调节不良事件为结肠炎和低钠血症治疗暴露治疗暴露N=262中位中位(范围范围)治疗时间治疗时间(d)85.5(1-400)中位中位(范围范围)剂量剂量(n)5.5(1-23)治疗相关不良事件总结治疗相关不良事件总结(%)任何级别任何级别67%3-4级级9%死亡死亡0.4%终止终止3%不良事件发生率不良事件发生率N=262任何级别任何级别3-5级级治疗相关不良事件治疗相关不良事件(发生率发生率5%)乏力乏力20%1%瘙痒瘙痒9%0关节痛关节痛8%1%食欲减退食欲减退8%0腹泻腹泻7%0甲状腺功能减退甲状腺功能减退6%0发热发热6%0皮疹皮疹6%0恶心恶心5%1%其他关注的临床不良事件其他关注的临床不良事件(发生率发生率1%)肺炎肺炎4%2%甲状腺功能亢进甲状腺功能亢进2%=50%的肿瘤细胞PD-L1弱阳性：1-49%的肿瘤细胞染色阴性为PD-L1无表达Garon EB,et al.2014 ESMO Abstract LBA43.PD-L1强阳性患者较弱阳性/阴性患者的PFS更长(HR=0.52;95%CI:0.33-0.80)PD-L1强阳性患者较弱阳性/阴性患者的OS更长(HR=0.59;95%CI:0.35-0.99)KEYNOTE-001：生存期评估：PD-L1表达PD-L41本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。KEYNOTE-001：总结与与结论在初治在初治(ORR 26%)和复治和复治(ORR 20%)晚期晚期NSCLC患患者中，所有者中，所有剂量和方案都量和方案都观察到很好的抗察到很好的抗肿瘤活瘤活性性2mg/kg q3w剂量下，量下，ORR为20%(irRC)缓解持久解持久安全性及毒性可管理安全性及毒性可管理PD-L1强表达与表达与缓解率解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相关的改善相关在在KEYNOTE-001研究研究额外入外入组的的300例患者中将前例患者中将前瞻性瞻性验证PD-L1的截点的截点Garon EB,et al.2014 ESMO Abstract LBA43.KEYNOTE-001：总结与结论在初治(ORR 26%)42本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。4/49PD-L1 Identifies Pts With NSCLC Most Likely to Benefit From MK-3475(Pembrolizumab,Anti-PD-1)Strong PD-L1 positive staining was considered 50%of tumor cells,and weak was defined as staining between 1%to 49%of positively staining tumor cells.Negative had no tumor staining for PD-L1.Response Rate(%)3/427/4615/4125/129Gandhi L,et al.AACR 2014.Abstract CT105.Reprinted with permission.RR-RECIST 1.1504030201001937157Total1%-49%PD-L1 staining 50%PD-L1 staining PD-L1 negative Response Rate(%)4/5320/4428/146RR-irRC50403020100194688n/N:n/N:4/49PD-L1 Identifies Pts With 43本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Ongoing MK-3475(Pembrolizumab,Anti-PD-1)Clinical Trials in Patients With NSCLCLine of TherapyPhasePD-L1 SelectionComparatorSingle-agent MK-3475 1st line;2nd line1,2I/IIBothNA2nd line3IIIYesDocetaxel1st line4IIIYesChemotherapyCombination MK-3475NA5I/IINoSingle agent;+chemotherapy;+pemetrexed;+gefitinib;+erlotinib;+ipilimumab1.ClinicalTrials.gov.NCT02085070.2.ClinicalTrials.gov.NCT02129556.3.ClinicalTrials.gov.NCT01905657.4.ClinicalTrials.gov.NCT02142738.5.ClinicalTrials.gov.NCT02039674.Ongoing MK-3475(Pembrolizumab,44本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Examples of PD-L1 NSCLC Sample IHC Staining*PD-L1 NegativePD-L1 Positive*Clinical trial assay.Staining Intensity 0+1+2+3+PD-L1 Positivity,%0 2100100Gandhi L,et al.AACR 2014.Abstract CT105.Reprinted with permission.Examples of PD-L1 NSCLC Sampl45本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Phase I Study of MPDL3280A(Anti-PDL-1)in NSCLCMPDL3280A:antiPD-L1 antibody engineered for enhanced safety and efficacyPatients with metastatic solid tumorsEGFR and KRAS status assessed at baselineStudy design:MPDL3280A IV every 3 wks x 16 cycles(1 yr)Primary endpoint:safetySecondary endpoint:ORR by RECIST v1.1Baseline demographicsCharacteristicsCharacteristicsn=85*n=85*Median age,yrs(range)60(24-84)Sex,male/female,n(%)48(56)/37(44)ECOG PS,0/1,n(%)27(32)/58(68)Histology,n(%)Squamous20(24)Nonsquamous65(76)*Safety evaluable patients(n=85)with NSCLC.Data cutoff April 30,2013.Systemic regimens administered in the metastatic,adjuvant or neoadjuvant setting.3%of patients had no previous systemic regimens.Characteristics,n(%)Characteristics,n(%)n=85*n=85*Previous systemic regimens 1 or 236(42)347(55)Smoking status Current/previous68(80)Never17(20)Horn L,et al.WCLC 2013.Abstract MO18.Reprinted with permission.Phase I Study of MPDL3280A(An46本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。PD-L1 Status*(N=53)ORR,%(n/N)Pts With PD,%(n/N)IHC 3(n=6)83(5/6)17(1/6)IHC 2 and 3(n=13)46(6/13)23(3/13)IHC 1/2/3(n=26)31(8/26)38(10/26)All patients(IHC 0/1/2/3 and 7 patients with diagnostic unknown;N=53)23(12/53)40(21/53)Duration of Treatment and ResponseWkHistology IHCNS IHC 0S IHC 3NS IHC 0NS IHC 1NS IHC 0S IHC 2NS IHC 3S IHC 3NS IHC 3NS IHC 0NS IHC 3NS IHC 1*PD-LI status determined using proprietary Genentech Roche IHC.ORR includes investigator-assessed unconfirmed and confirmed(u/c)PR per RECIST 1.1.Patients first dosed at 1-20 mg/kg by October 1,2012.Data cutoff April 30,2013.MPDL3280A(Anti-PDL-1)in NSCLC:Best Response by PD-L1 Status and DOT/DORHorn L,et al.WCLC 2013.Abstract MO18.Reprinted with permission.0612182430364248546066727884On study,on treatmentOn study,post treatmentTreatment discontinuedOngoing responseFirst responseFirst PDPD-L1 Status*ORR,Pts With PD,47本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。*ORR includes investigator-assessed u/c PR by RECIST 1.1.Patients first dosed at 1-20 mg/kg by October 1,2012.Data cutoff April 30,2013.Former/Current SmokersNever SmokersResponse by Smoking Status(ORR*)Smoking Status(NSCLC;n=53)Pts With PR(%)EGFR MutantEGFR Status(NSCLC;n=53)UnknownResponse by EGFR Status(ORR*)Pts With PR(%)KRAS Status(NSCLC;n=53)Response by KRAS Status(ORR*)Pts With PR(%)KRAS MutantUnknownEGFR WT EGFR Mutant KRAS WT KRAS Mutant 11/431/109/401/68/271/10MPDL3280A(Anti-PDL-1)Phase Ia:Response by Smoking and Mutational StatusHorn L,et al.WCLC 2013.Abstract MO18.Reprinted with permission.504030201005040302010050403020100Former/Current Smokers Never Smokers26%10%23%17%30%10%51%30%19%76%13%11%81%19%KRAS WT EGFR WT *ORR includes investigator-ass48本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Majority of AEs were grade 1/2 and did not require interventionNo MTD or dose-limiting toxicitiesNo grade 3-5 pneumonitis observedTreatment-related death(cardio-respiratory arrest)in 1 patient with sinus thrombosis and large tumor mass invading the heart at baselineImmune-related grade 3.4 AEs:1 patient with large-cell neuroendocrine NSCLC(diabetes mellitus,1%)MPDL3280A(Anti-PDL-1):Treatment-Related Adverse Events in Patients With NSCLC*AEs occurring in 5%of patients.Grade 3/4 treatment-related AEs listed include treatment-related AEs for which the any grade occurrence was 5%of patients.Data cutoff April 30,2013.Adverse Event Adverse Event(n=85)(n=85)Treatment Related,%(n)Treatment Related,%(n)Any Grade*Grade 3/4Any AE66(56)11(9)Fatigue20(17)2(2)Nausea14(12)1(1)Decreased appetite12(10)0Dyspnea9(8)1(1)Diarrhea8(7)0 Asthenia7(6)0Headache7(6)0Rash7(6)0Pyrexia6(5)0Vomiting6(5)1(1)Upper respiratory tract infection5(4)0Horn L,et al.WCLC 2013.Abstract MO18.Reprinted with permission.Majority of AEs were grade 1/249本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Ongoing MPDL3280A(Anti-PDL-1)Clinical Trials in Patients With NSCLCLine of TherapyPhasePD-L1 SelectionComparatorSingle-agent MPDL3280A 1st line;2nd line1IIYesNA1st line;2nd line2IIYesNA2nd line3IINoDocetaxel 2nd line4IIINoChemotherapyCombination MPDL3280A Expansion:EGFRm TKI naive5INo+erlotinib Expansion:KRAS NSCLC6INo+cobimetinibNA7INo+chemotherapy;+bevacizumab1.ClinicalTrials.gov.NCT02108652.2.ClinicalTrials.gov.NCT01846416.3.ClinicalTrials.gov.NCT01903993.4.ClinicalTrials.gov.NCT01984242.5.ClinicalTrials.gov.NCT02013219.6.ClinicalTrials.gov.NCT01988896.7.ClinicalTrials.gov.NCT01633970.Ongoing MPDL3280A(Anti-PDL-1)50本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。MED14736(Anti-PD-L1):Emerging promising clinical activity in select tumors MED14736(Anti-PD-L1):Emerging 51本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。MED14736(Anti-PDL1)safety:No colitis,no high grade pneumonitis,no drug-related deaths MED14736(Anti-PDL1)safety:No52本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Ongoing MEDI4736(Anti-PDL-1)Clinical Trials in Patients With NSCLCLine of TherapyPhasePD-L1 SelectionComparatorSingle-agent MEDI4736 2nd line1IIYesNAPost chemo-RT for IIIA NSCLC2IIYesNACombination MEDI4736 NA3,4INo+tremelimumab 2nd line for EGFR+NSCLC5INo+gefitinibNA6INo+MEDI0680(PD-1)1.ClinicalTrials.gov.NCT02087423.2.ClinicalTrials.gov.NCT02125461.3.ClinicalTrials.gov.NCT01975831.4.ClinicalTrials.gov.NCT02000947.5.ClinicalTrials.gov.NCT02088112.6.ClinicalTrials.gov.NCT02118337.Ongoing MEDI4736(Anti-PDL-1)C53本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Future OutlookUpdate of checkpoint Inhibitors in lung cancer therapyCancer Immunotherapy123 OutlineFuture OutlookUpdate of checkp55本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Tumor Chemo,Targeted,Hormone Therapy Rapid Activity,Tumor Shrinkage Targeting tumor and tumor microenvironment Targeting host immune system highly specific anti-tumor immunity memory:Durable response(cure?)Understanding of Tumor Biology&Immunology Enables Rational Immuno-Combination?Targeting tumor and Targeting 56本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Effects of immunotherapy and targeted therapy on melanoma survival curvesClin Cancer Res.2012;18:336-341.Effects of immunotherapy and t57本文档所提供的信息仅供参考之用，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Combi