1、Caicun ZhouShanghai Pulmonary Hospital,Shanghai Tongji University,P.R.China肺癌是我国发病率和死亡率肺癌是我国发病率和死亡率最高最高的恶性肿瘤，的恶性肿瘤，5 5年年生存率仅为生存率仅为1616发病率和死亡率仍在上升发病率和死亡率仍在上升肺癌对患者、家庭、国家都是一种灾难肺癌对患者、家庭、国家都是一种灾难生存期短生存期短过度治疗过度治疗无效无效治疗治疗患 者家 庭国 家失去家庭成员的巨大痛苦失去家庭成员的巨大痛苦高昂治疗费用的压力高昂治疗费用的压力治与不治的艰难选择治与不治的艰难选择不断增加的高不断增加的高昂医疗负担昂医
2、疗负担高加索肺腺癌驱动基因图谱亚裔肺腺癌驱动基因图谱Sholl LM,et al.J Thorac Oncol.2015;10(5):768-777Seo JS,Genome Res.2012,22(11):2109-2119肺癌驱动基因谱明确，精准治疗条件最成熟肺癌驱动基因谱明确，精准治疗条件最成熟KRAS25%无已知的肿瘤驱动基因36%EGFR23%ALK7.9%MEK10.3%ERBB2 2.7%BRAF 2.6%PIK3CA 0.8%NRAS0.7%MET0.7%融合基因点突变未知肺腺癌（n=200）外显子跳跃精准治疗，路在何方？精准治疗，路在何方？Precision Medicine
3、 in Advanced NSCLCClinical Lung Cancer Genome Project and Network Genomic Medicine,Science Transl.Med.2013Target therapy(1st,2nd,and 3rd generation)New targets Increase of biomarker testing Immunotherapy 1 50%Mutation load200 Squamous Carcinoma Smoking adenocarcinomaNo actionabledriver mutationAvast
4、inChemo Non-squamous NSCLC Adeno CaSquamous Ca.SCLCNOSLarge cell US Lung Cancer Mutational Consortium(LCMC)Collaboration of 14 US Cancer CentersMultiplex genotyping of 1007 adenocarcinomas(full genotyping 733)Close link to clinical trial platform Kris et al.,ASCO 2011,#7506,Kris et al.,JAMA 2014 LCM
5、C:Benefit in overall survival for personalized treatmentKris et al.,ASCO 2011,#7506,Kris et al.,JAMA 2014 048121620240.00.20.40.60.81.0Gefitinib EGFR M+(n=132)Gefitinib EGFR M-(n=91)Carboplatin/paclitaxel EGFR M+(n=129)Carboplatin/paclitaxel EGFR M-(n=85)Probabilityof PFSEGFR M+HR(95%CI)0.48(0.36,0.
6、64),p0.0001EGFR M-HR(95%CI)2.85(2.05,3.98),p0.0001Primary Cox analysis with covariates;ITT population;HR 1 implies a lower risk of progression on gefitinibTreatment by subgroup interaction test,p50%Mutation load200 Squamous Carcinoma Smoking adenocarcinomaNo actionabledriver mutationAvastinChemo Non
7、-squamous NSCLC Adeno CaSquamous Ca.SCLCNOSLarge cell ECOG 4599HR=0.66,p0.001(95%CI:0.570.77)0 6 12 18 24 304.56.21.00.80.60.40.20PFS贝伐珠单抗+卡铂/紫杉醇卡铂/紫杉醇 1098765432100 6 12 18 24 30 36 42OSHR=0.79(0.670.92)P=0.00312.310.3贝伐珠单抗+卡铂/紫杉醇卡铂/紫杉醇 Sandler,et al.N Engl J Med 2006 贝伐联合卡铂紫杉醇卡铂紫杉醇HRP中位PFS(月)6.24.
8、50.660.0016个月PFS55%33%1年PFS15%6%中位OS(月)12.310.30.790.003ORR35%15%安慰剂单药中国IIIB/IV期非小细胞肺癌患者既往未接受治疗组织学或细胞学证实为非鳞癌年龄 18岁ECOG PS 0-1n=276贝伐珠单抗 15 mg/kg d1 卡铂 AUC6 d1 紫杉醇 175 mg/m2 d1 3周方案,n=1386个周期R进展*安慰剂 d1+紫杉醇/卡铂 3周方案,n=1381:1进展贝伐珠单抗单药主要终点：PFS：证实在中国人群中的疗效与E4599研究疗效一致(HR临界 0.83)次要终点：OS，ORR，疾病缓解时间，安全性，血浆生物
9、标志物(VEGF-A，VEGFR-2)Zhou C,et al.J Clin Oncol 2015;33:2197-2204.主要基线特征Bev+CP(n=138)Pl+CP(n=138)ECOG PS,n(%)034(25)27(20)1104(75)111(80)组织学,n(%)腺癌137(99)136(98)疾病分期,n(%)复发 4(3)3(2)IIIB8(6)9(7)IV126(91)125(91)未知0(0.0)1(1)EGFR 突变状态*,n(%)85 66 EGFR 突变阳性,n(%)23(27)17(26)EGFR 野生型,n(%)62(73)50(74)n研究设计*进展揭盲
10、后,仅贝伐珠单抗组可选择使用贝伐珠单抗联合已被批准的二、三线治疗PFS(主要终点)中位 PFS 9.2 月 vs 6.5 月HR 0.40(95%CI 0.290.54)p0.0011.00.80.60.40.206121824贝伐珠单抗+卡铂紫杉醇(n=138)卡铂+紫杉醇(n=138)时间(月)9.2月 6.5月2.7时间(月)1.00.80.60.40.2061218243036总生存贝伐珠单抗+卡铂紫杉醇(n=138)卡铂+紫杉醇(n=138)中位 OS 24.3月 vs 6.5月HR 0.68(95%CI 0.500.93)p=0.015424.3月17.7月6.6数据截止时间 20
11、13年1月27日Zhou C,et al.J Clin Oncol 2015;33:2197-2204.研究终点Bev+CP(n=136)Pl+CP(n=133)ORR,%(95%CI)54(45.462.9)26(19.234.8)P值50%Mutation load200 Squamous Carcinoma Smoking adenocarcinomaNo actionabledriver mutationAvastinChemo Non-squamous NSCLC Adeno CaSquamous Ca.SCLCNOSLarge cell NivolumabPembrolizumab
12、AtezolizumabDurvalumabAvelumabN129475175228184RR鳞癌鳞癌非鳞癌非鳞癌17%18%23.5%19%27%21%21%13%14%药物相关药物相关AE所有级别所有级别 级级41%4.7%71%9.5%66%11%50%8%77%12%RRPDL-1 阳性阳性PDL-1 阴性阴性16%13%42%(50%)10%(1%)34%IC2/3 or TC 2/3(half if 3 used)Gettinger S,J Clin Oncol 2015;33:2004-2012;Herbst R,Nature 2014;515:563-7;Soria JC,E
13、SMO 2013;Garon E,NEJM 2015;372:2018-28;Rizvi N,ASCO 2015;Guley LJ,ASCO 2015Sqamous AdenocarcinomaHR 0.59(95%CI 0.44-0.79)HR 0.73(95%CI 0.59-0.89)P0.001p=0.002Brahmer J et al.NEJM 2015,373,123Borghaei H et al.NEJM 2015PD-L1 50%or morePembrolizumab 10 mg/kg every 3 weeks:HR 0.50(95%CI 0.36-0.70)p0.000
14、1Pembrolizumab 2 mg/kg every 3 weeks:HR 0.54(95%CI 0.38-0.77)p=0.0002 Total Pembrolizumab 10 mg/kg every 3 weeks:HR 0.61(95%CI 0.49-0.75)p=0.0001Pembrolizumab 2 mg/kg every 3 weeks:HR 0.71(95%CI 0.58-0.88)p=0.0008Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting探索性汇总无进展生存K-M曲线Presented By G
15、ideon Blumenthal at 2016 ASCO Annual Meeting探索性汇总总生存K-M曲线 Monotherapy High PD-L1 expression In combination with chemotherapy Low PD-L1 expression In combination with other agents Targeted therapies？Bevacizumab Immune checkpoint inhibitors Other immunotherapies免疫治疗一线研发策略Primary endpoint:Progression-f
16、ree survival(independent radiology review committee)in patients with strongly PD-L1 positive tumors535 patientsNivolumab 3 mg/kg i.v.every 2 weeks(until disease progression,unacceptable toxicity,withdrawal of consent or study closure)Chemotherapy(investigators choice,up to 6 cycles)vsPembrolizumab a
17、s first-line therapyin patients with high levels of PD-L1 KEYNOTE-024Mercks KEYTRUDA(pembrolizumab)demonstrates superior-progression-free survival and overall survival compared to chemotherapy as first-line therapy in patients with advanced non-small cell lung cance.rPress release,Thursday,June 16,2
18、016 6:45 am EDT 34%of Patients were TPS1%KEYNOTE-021(phase/):study designStage IIIB/IV NSCLCNo systemic therapy for recurrent disease ECOG PS 0-1(n=308)Cohort A:Pembrolizumab+carboplatin+paclitaxel(n=25)Cohort B:Pembrolizumab+carboplatin+paclitaxel+bevacizumab(n=25)Cohort C:Pembrolizumab+carboplatin
19、+pemetrexed(n=25)MaintenancepembrolizumabMaintenancepembrolizumab+bevacizumabMaintenancepembrolizumab+pemetrexedPembrolizumab dose:2 or 10mg/kg i.v.q3w;Carboplatin dose:AUC 6 i.v.(cohort A and B),AUC 5 i.v.(cohort C);Paclitaxel dose:200mg/m2 i.v.q3w;Bevacizumab dose:15mg/kg i.v.q3w;Pemetrexed dose:5
20、00mg/m2 i.v.q3wPrimary endpointORRSecondary endpointOS PFS DoRGadgeel,et at.ASCO 2016KEYNOTE-021:ResponseCohort A:Pembrolizumab+carboplatin+paclitaxel(n=25)Cohort B:Pembrolizumab+carboplatin+paclitaxel+bevacizumab(n=25)Cohort C:Pembrolizumab+carboplatin+pemetrexed(n=25)*Parients with TPS50%Gadgeel,e
21、t at.ASCO 2016KEYNOTE-021:OSKEYNOTE-021:OSNR=not reachedGadgeel,et at.ASCO 2016CheckMate 012 Study Design:Nivolumab Plus Ipilimumab in First-line NSCLCPrimary endpoint:safety and tolerabilitySecondary endpoints:ORR(RECIST v 1.1)and PFS rate at 24 wksExploratory endpoints:OS;efficacy by PD-L1 express
22、ionStage IIIB/IV NSCLC(any histology);no prior chemotherapy for advanced disease;ECOG PS 0 or 1 Nivo 3 mg/kg IV Q2W until disease progression or unacceptable toxicityaNivo 1 mg/kg IV Q3W x 4+Ipi 1 mg/kg IV Q3W x 4Nivo 1 mg/kg IV Q2W+Ipi 1 mg/kg IV Q6WNivo 3 mg/kg IV Q2W+Ipi 1 mg/kg IV Q12WNivo 3 mg/
23、kg IV Q2W+Ipi 1 mg/kg IV Q6WUntil disease progression or unacceptable toxicitya Here,we report results from new cohorts explored to permit synergistic activity and acceptable safety pro combination treatment with nivolumab and ipilimumabaPatients tolerating study treatment permitted to continue trea
24、tment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefitCheckmate 012:Nivo+Chemo1a期:DLT评估(n=6-12)主要终点:安全性,耐受性次要终点:PKSchedule 1:胃癌/GEJ,胆管癌 3+3 设计(n=3-6)Ram 8 mg/kg,D1,8Pembro 200 mg fixed,D1Both IV 每3周1b期:队列扩展(n=155)主要终点:安全性和耐受性次要终点:PK及初步疗效探索性终点:生物标志物和免疫原性中期分析Schedul
25、e 2:胃癌/GEJ,NSCLC,UC3+3 设计(n=3-6)Ram 10 mg/kg,D1Pembro 200 mg fixed,D1Both IV 每3周队列A:15 Gastric/GEJ(2nd-3rd Line)队列A1:25 BTC(2nd-3rd Line)队列A2:25 Gastric/GEJ(1st Line)队列B:15 Gastric/GEJ(2nd-3rd Line)队列C:25 NSCLC(2nd-4th Line)队列D:25 UC(2nd-4th Line)队列E:25 NSCLC(1st Line)Herbst,et al.2016 ASCO,abstract
26、 3056.NCT02443324NSCLC On treatment20Off treatment7 Progressive Disease5 Death1 AE1Any grade TRAE19Grade 3/4 TRAE1Treatment related SAE3AE leading to death0Any GradeGrade 3/4IRR21Elevated ALT2-Elevated AST2-Proteinuria2-Hypertension2-Hypothyroidism1-Mouth hemorrhage1-Elevated CPK1-Stomatitis1-AE概况引起关注的治疗相关AEHerbst,et al.2016 ASCO,abstract 3056.NCT02443324肿瘤缓解肿瘤缓解随时间变化Herbst,et al.2016 ASCO,abstract 3056.NCT02443324谢谢谢谢
