1、肺癌免疫治疗进展肺癌免疫治疗进展123 Outline Outline123 Outline Outline肿瘤免疫治疗肿瘤免疫治疗攻克肿瘤的新希望攻克肿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1896年coley毒素应用于临床1899年放疗治愈第1例病人1946年氮芥治疗淋巴瘤获得成功免疫治疗免疫治疗放疗放疗化疗化疗靶向治疗靶向治疗进入21世纪，分子靶向治疗如火如荼eKey events in the history of cancer immunotherapy1890s 1st CA vaccine
2、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 CA19
3、97 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-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
4、疗法基础植物研究Breakthrough of year 2013Science.2013 Dec 20;342(6165):1432-3Immunity.39(1)25 July 2013,Pages 110StimulatoryStimulatory and and InhibitoryInhibitory Factors Factors in the Cancer-Immunity Cyclein the Cancer-Immunity CycleCTLA-4 and PD-1/PD-L1 checkpoint blockade for cancer treatmentCTLA-4 an
5、d PD-1/PD-L1 CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment 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 Agen
6、ts 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.FEB
7、S Lett.2014;588:368-376Comparing CTLA-4 and PD-1Comparing CTLA-4 and PD-1CTLA-4PD-1Biological function Inhibitory receptor Inhibitory receptorExpression on T cells at the time of initial response to antigen(activated CD8+T cells)Activated T cells,B cells,NK cells TILs in different tumor typesMajor r
8、ole Regulates the early stage of T-cell activation Limits T-cell activity in peripheral tissue after inflammatory response Limits autoimmunityLigands B7.1(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
9、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 comp
10、limentary roles in immune responses123 Outline OutlineAnti-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 Sarc
11、omaJ Clin Oncol.2012 Jun 10;30(17):2046-54Ann Oncol.2013 Jan;24(1):75-83J Clin Oncol.2012 Jun 10;30(17):2046-54Ipilimumab in combination with PC as first-line therapy in stage IIIB/IV NSCLCKaplanMeier plots for OS J Clin Oncol.2012 Jun 10;30(17):2046-54Deaths/patients 51/66 51/68Median(95%CI),months
12、 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 lpiControlEvents/patients 61/66 58/70Median(95%CI),mo 4.21(2.
13、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(KaplanMeier plots for PFS per immune-related(ir ir)response criteria()response criteria(irPFSirPFS)and)and modified WHO criteria(mWHO-PFS).Events/
14、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 56/68Me
15、dian(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 lpiAdverse EventsAdverse EventsJ Clin Oncol.2012 Jun 10;30(17):2046-54Follow-UPEvery 12 wksFor survivalSCREENINGINDUCTIONMAINTENANCEFOLLOW-UPCA184-104:CA184-104:phase III tr
16、ial comparing the thethe efficacy of efficacy of ipilimumabipilimumab(IpiIpi)with PC versus)with PC versus placebo with PC in patients(placebo with PC in patients(ptspts)with stage IV/recurrent NSCLC of squamous histology)with stage IV/recurrent NSCLC of squamous histologyTumor assessmentEvery 12 wk
17、sIpi 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 r
18、ateTumor assessmentWks 7,13,19,25Brain MetastasesAutoimmune diseasesPC Paclitaxel(175 mg/m2,IV)+Carboplatin(AUC=6,IV)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 TPS
19、7113)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 responsePrior systemic thera
20、py 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 2cycleA Phase III Study of Nivolumab in Combination with Yervoy in Patients with Ad
21、vanced Non-Small Cell Lung Cancer PD-1 and PD-L1 antibodies in phase III development Phase1 Nivolumab(anti-PD-1anti-PD-1;BMS-936558,;BMS-936558,ONO-4538)ONO-4538)multidose regimenEligibility:advcanced melanoma,NSCLC,RCC,CRC,or CRPC with PD after1-5 systemic therapies Select Aes(1%)occuring in Pts wi
22、th 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 Efficacy of Nivolumab monotherapy in Pts treated with NSCLC Nivolumab in combination with PT-DC in advanced NSCLCA
23、ntonia SJ,et al.2014 ASCO Abstract 8113.Results and ConclusionsResults and Conclusions 治疗的前治疗的前6周没有发生剂量限制毒性周没有发生剂量限制毒性 3-4级治疗相关不良事件发生率为级治疗相关不良事件发生率为45%ORR：33-50%1年年OS：59-87%NivoNivo 10+gem/10+gem/ciscis鳞癌NivoNivo 10+pem/10+pem/ciscis非鳞癌NivoNivo 10+pac/carb 10+pac/carb鳞+非鳞癌NivoNivo 5+pac/carb 5+pac/c
24、arb鳞+非鳞癌N N1212151515151414ORR,n(%)ORR,n(%)4(33)4(33)7(47)7(47)7(47)7(47)7(50)7(50)mDORmDOR(范围)，周20.920.9(12.1-41.7)(12.1-41.7)32.032.0(13,1-42.1)(13,1-42.1)25.625.6(11.4-39.0)(11.4-39.0)NANA(11.4-37.3)(11.4-37.3)PDPD为BOR,BOR,n(%)n(%)0 00 03(20)3(20)1(7)1(7)2424周时PFS,PFS,%36367171383857571 1年OS,%OS,
25、%595987875959NANAAntonia SJ,et al.2014 ASCO Abstract 8113.Antonia SJ,et al.2014 ASCO Abstract 8113.Ongoing Nivolumab Clinical Trials in Patients With NSCLCLine of therapyPhasePD-L1 SelectionComparatorSingle agent Nivolumab1st line1IIIYesChemotherapy2nd line,squamous2IIINoDocetaxel2nd line,adeno3IIIY
26、esDocetaxel 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.NCT
27、01721759.5.ClinicalTrials.gov.NCT01968109.6.ClinicalTrials.gov.NCT01714739.7.ClinicalTrials.gov.NCT01454102.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
28、: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.KEYNOTE-001：NSCLC扩大队列研究设计扩大队列研究设计(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
29、+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
30、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-001KEYNOTE-001：基线特征：基线特征年龄，中位年龄，中位(范围范围)，岁，岁65(28-86)65(28-86)男性男性50%50%ECOG PSECOG PS：0/1/0/1/缺失缺失31%/68%/1%31%/68%/1%人种：白种人种：白种/黑人或非裔
31、美国人黑人或非裔美国人/亚裔亚裔/其他其他83%/4%/11%/2%83%/4%/11%/2%鳞癌鳞癌17%17%既往接受治疗次数：既往接受治疗次数：0/=10/=117%/83%17%/83%分期：分期：M0/M1a/M1b/M0/M1a/M1b/未知未知13%/28%/49%/11%13%/28%/49%/11%脑转移瘤史脑转移瘤史5%5%EGFREGFR突变突变(N=250)(N=250)16%16%KRASKRAS突变突变(N=156)(N=156)26%26%ALKALK基因重排基因重排(N=231)(N=231)3%3%吸烟史：目前吸烟史：目前/曾经曾经/从不从不/未知未知5%/6
32、4%/28%/2%5%/64%/28%/2%Garon EB,et al.2014 ESMO Abstract LBA43.KEYNOTE-001KEYNOTE-001：治疗暴露与治疗相关不良事件汇总治疗暴露与治疗相关不良事件汇总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
33、N=262N=262任何级别任何级别3-53-5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%)5%)乏力乏力20%20%1%1%瘙痒瘙痒9%9%0 0关节痛关节痛8%8%1%1%食欲减退食欲减退8%8%0 0腹泻腹泻7%7%0 0甲状腺功能减退甲状腺功能减退6%6%0 0发热发热6%6%0 0皮疹皮疹6%6%0 0恶心恶心5%5%1%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%)1%)肺炎肺炎4%4%2%2%甲状腺功能亢进甲状腺功能亢进2%2%1%=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.
34、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-001KEYNOTE-001：总结与结论总结与结论 在初治在初治(ORR 26%)和复治和复治(ORR 20%)晚期晚期NSCLC患者中，所有剂量和方患者中，所有剂量和方案都观察到很好的抗肿瘤活性案都观察到很好的抗肿瘤活性 2mg/kg q3w剂量下，剂量下，ORR为为20%(irRC)缓解持久缓解持久 安全性及毒性可管理安全性及毒性
35、可管理 PD-L1强表达与缓解率强表达与缓解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相关的改善相关 在在KEYNOTE-001研究额外入组的研究额外入组的300例患者中将前瞻性验证例患者中将前瞻性验证PD-L1的的截点截点Garon EB,et al.2014 ESMO Abstract LBA43.4/49PD-L1 Identifies Pts With NSCLC Most Likely to Benefit From MK-3475(Pembrolizumab,Anti-PD-1)Strong PD-L1 positive staining was cons
36、idered 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 s
37、taining 50%PD-L1 staining PD-L1 negative Response Rate(%)4/5320/4428/146RR-irRC50403020100194688n/N:n/N: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 line3IIIYesDocetax
38、el1st 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.Exampl
39、es 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.Phase I Study of MPDL3280A(Anti-PDL-1)in NSCLCMPDL3280A:antiPD-L1 antibody engineered for en
40、hanced 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 demographicsMedian age,yrs(range)60(24-84)Sex,male/female,n(%)48(56)/37(
41、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.Previous systemic regimen
42、s 1 or 236(42)347(55)Smoking status Current/previous68(80)Never17(20)Horn L,et al.WCLC 2013.Abstract MO18.Reprinted with permission.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 p
43、atients 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 uncon
44、firmed 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 trea
45、tmentOn study,post treatmentTreatment discontinuedOngoing responseFirst responseFirst PD*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 S
46、tatus(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:Respons
47、e by Smoking and Mutational StatusHorn L,et al.WCLC 2013.Abstract MO18.Reprinted with permission.504030201005040302010050403020100Former/Current SmokersNever Smokers26%10%23%17%30%10%51%30%19%76%13%11%81%19%KRAS WT EGFR WT Majority of AEs were grade 1/2 and did not require intervention No MTD or dos
48、e-limiting toxicities No grade 3-5 pneumonitis observed Treatment-related death(cardio-respiratory arrest)in 1 patient with sinus thrombosis and large tumor mass invading the heart at baseline Immune-related grade 3.4 AEs:1 patient with large-cell neuroendocrine NSCLC(diabetes mellitus,1%)MPDL3280A(
49、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.Any Grade*Grade 3/4Any AE66(56)11(9)Fatigue20(17)2(2)
50、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.Ongoing MPDL3280A(Anti-PDL-1)Clinical Trials in Patients With NSCL
