晚期非小细胞肺癌精准治疗课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,16-11-4,#,Click to edit Master text styles,Second level,Third level,Fourth level,单击此处编辑母版标题样式,Click to edit Master text styles,Second level,Third level,Fourth level,单击此处编辑母版标题样式,周彩存，医学博士，博士生导师，主任医师，教授；上海市领军人才，享受国务院特殊津贴,中国医促会胸部肿瘤分会主委，中国抗癌协会肺癌专业委员会常委，上海市抗癌协会肺癌分子靶向和免疫治疗专业委员会主委，,中国抗癌协会肿瘤药物临床研究专业委员会,副主任委员，,上海市医学会分子诊断专委会副主任委员,，中国医师协会肿瘤分会常委，上海市医师协会肿瘤分会副会长,周彩存，医学博士，博士生导师，主任医师，教授；上海市领军人才,1,晚期非小细胞肺癌的精准治疗,Caicun Zhou,Shanghai Pulmonary Hospital,Shanghai,Tongji University, P.R.China,晚期非小细胞肺癌的精准治疗Caicun Zhou,2,肺癌是我国发病率和死亡率,最高,的恶性肿瘤，,5,年,生存率仅为,16,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,生存期短,过度治疗,无效,治疗,患 者,家 庭,国 家,失去家庭成员的巨大痛苦,高昂治疗费用的压力,治与不治的艰难选择,不断增加的高昂医疗负担,肺癌是我国发病率和死亡率最高的恶性肿瘤，5年生存率仅为16,3,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):768-777,Seo 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,KRAS,25%,无已知,的肿瘤,驱动,基因,36%,EGFR,23%,ALK,7.9%,MEK1,0.3%,ERBB2,2.7%,BRAF,2.6%,PIK3CA,0.8%,NRAS,0.7%,MET,0.7%,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？,高加索肺腺癌驱动基因图谱亚裔肺腺癌驱动基因图谱Sholl L,4,Precision Medicine in Advanced NSCLC,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl. Med. 2013,Target therapy,(,1,st, 2,nd, and 3,rd,generation),New targets,Increase of biomarker testing,Immunotherapy,1,50%,Mutation load200,Squamous Carcinoma,Smoking adenocarcinoma,No actionable,driver mutation,Avastin,Chemo,Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,Precision Medicine in Advanced,5,US Lung Cancer Mutational Consortium (LCMC),Collaboration of 14 US Cancer Centers,Multiplex genotyping of 1007 adenocarcinomas (full genotyping 733),Close link to clinical trial platform,Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014,US Lung Cancer Mutational Cons,6,LCMC: Benefit in overall survival,for,personalized treatment,Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014,LCMC: Benefit in overall survi,7,IPASS,开启了,EGFR-TKI,的肺癌精准医学时代,0,4,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,Gefitinib EGFR M+ (n=132),Gefitinib EGFR M- (n=91),Carboplatin / paclitaxel EGFR M+ (n=129),Carboplatin / paclitaxel EGFR M- (n=85),Probabilityof PFS,EGFR M+ HR (95% CI) 0.48 (0.36, 0.64), p0.0001,EGFR M- HR (95% CI) 2.85 (2.05, 3.98), p0.0001,Primary Cox analysis with covariates; ITT population;,HR,1 implies a lower risk of progression on gefitinib,Treatment by subgroup interaction test, p50%,Mutation load200,Squamous Carcinoma,Smoking adenocarcinoma,No actionable,driver mutation,Avastin,Chemo,Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,Precision Medicine in Advanced,25,E4599,：贝,伐珠单,抗一线,联合卡铂,/,紫杉醇,显著延长,PFS,、,OS,及,ORR,ECOG 4599,HR=0.66,p0.001 (95% CI: 0.570.77),0 6 12 18 24 30,4.5,6.2,1.0,0.8,0.6,0.4,0.2,0,PFS,贝伐珠单抗,+,卡铂,/,紫杉醇,卡铂,/,紫杉醇,10,9,8,7,6,5,4,3,2,1,0,0 6,1,2 18,2,4 30 36 42,OS,HR=0.79(0.670.92),P=0.003,12.3,10.3,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,HR,P,中位,PFS,(,月,),6.2,4.5,0.66,0.001,6,个月,PFS,55%,33%,1,年,PFS,15%,6%,中位,OS (,月,),12.3,10.3,0.79,0.003,ORR,35%,15%,E4599：贝伐珠单抗一线联合卡铂/紫杉醇显著延长PFS、,26,BEYOND,：,贝伐珠单,抗在中国人群疗效的验证,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,-,1,n=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=138,6,个周期,R,进展,*,安慰剂,d1+,紫杉醇,/,卡铂,3,周方案, n=138,1:1,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 (%),0,34 (2,5,),27 (,20,),1,104 (75),111 (80),组织学, n (%),腺癌,137 (99),136 (98),疾病分期, n (%),复发,4 (,3,),3 (2),IIIB,8 (,6,),9 (,7,),IV,126 (91),125 (9,1,),未知,0 (0.0),1 (,1,),EGFR,突变状态,*, n (%),85,6,6,EGFR,突变阳性, n (%),23 (27),17 (2,6,),EGFR,野生型, n (%),62 (7,3,),50 (74),研究设计,* 进展揭盲后,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,BEYOND：贝伐珠单抗在中国人群疗效的验证安慰剂单药中国I,27,BEYOND,：,贝,伐珠单,抗联,合卡铂,/,紫杉醇显著延长,PFS,及,OS,PFS,(,主要终点,),中位,PFS 9.2,月,vs 6.5,月,HR 0.40,(95,% CI,0.290.54),p0.001,1.0,0.8,0.6,0.4,0.2,0,6,12,18,24,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,进展风险,60%,2.7,时,间,(,月,),1.0,0.8,0.6,0.4,0.2,0,6,12,18,24,30,36,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=0.0154,死亡风险,32%,24.3,月,17.7,月,6.6,数据截止时间,2013,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 adenocarcinoma,No actionable,driver mutation,Avastin,Chemo,Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,Precision Medicine in Advanced,29,Activity in pretreated patients,Nivolumab,Pembrolizumab,Atezolizumab,Durvalumab,Avelumab,N,129,475,175,228,184,RR,鳞癌,非鳞癌,17%,18%,23.5%,19%,27%,21%,21%,13%,14%,药物相关,AE,所有级别,级,41%,4.7%,71%,9.5%,66%,11%,50%,8%,77%,12%,RR,PDL-1,阳性,PDL-1,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, ESMO 2013,;,Garon,E, NEJM 2015; 372: 2018-28; Rizvi N, ASCO 2015; Guley LJ, ASCO 2015,Activity in pretreated patient,30,Nivolumab vs docetaxel in advanced NSCLC,Overall survival,Sqamous Adenocarcinoma,HR 0.59 (95% CI 0.44-0.79) HR 0.73 (95% CI 0.59-0.89),P0.001p=0.002,Brahmer J et al. NEJM 2015, 373, 123Borghaei H et al. NEJM 2015,Nivolumab vs docetaxel in adva,31,Pembrolizumab (2 or 10 mg/kg) versus docetaxel in advanced NSCLC: Overall Survival,Herbst R et al.,Lancet Oncology 2015, online December 18,PD-L1 50% or more,Pembrolizumab 10 mg /kg every 3 weeks:,HR 0.50 (95% CI 0.36-0.70) p0.0001,Pembrolizumab 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=0.0001,Pembrolizumab 2 mg /kg every 3 weeks:,HR 0.71 (95% CI 0.58-0.88) p=0.0008,Pembrolizumab (2 or 10 mg/kg),32,晚期非小细胞肺癌精准治疗课件,33,晚期非小细胞肺癌精准治疗课件,34,Slide 16,Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting,探索性汇总无进展生存,K-M,曲线,Slide 16Presented By Gideon Bl,35,Slide 17,Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting,探索性汇总总生存,K-M,曲线,Slide 17Presented By Gideon Bl,36,一线策略？,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,一线策略？ Monotherapy 免疫治疗一线研发策略,37,Primary endpoint,: P,rogression-free survival (independent,radiology review,committee) in patients with,strongly,PD-L1 positive tumors,535 patients,Nivolumab,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),vs,Primary endpoint: Progression-,38,晚期非小细胞肺癌精准治疗课件,39,晚期非小细胞肺癌精准治疗课件,40,Pembrolizumab as first-line therapyin patients with high levels of PD-L1 KEYNOTE-024,Mercks 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.r,Press release, Thursday, June 16, 2016 6:45 am EDT,Pembrolizumab as first-line th,41,晚期非小细胞肺癌精准治疗课件,42,晚期非小细胞肺癌精准治疗课件,43,晚期非小细胞肺癌精准治疗课件,44,晚期非小细胞肺癌精准治疗课件,45,34% of Patients were TPS,1%,34% of Patients were TPS1%,46,KEYNOTE-021(phase,/,):study design,Stage IIIB/IV NSCLC,No 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+,pemetrexed (n=25),Maintenance,pembrolizumab,Maintenance,pembrolizumab+,bevacizumab,Maintenance,pembrolizumab+,pemetrexed,Pembrolizumab 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: 500mg/m2 i.v.q3w,Primary endpoint,ORR,Secondary endpoint,OS PFS DoR,Gadgeel,et at. ASCO 2016,KEYNOTE-021(phase /):study d,47,KEYNOTE-021: Response,Cohort 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,et at. ASCO 2016,KEYNOTE-021: ResponseCohort A:,48,KEYNOTE-021: OS,KEYNOTE-021: OS,NR=not reached,Gadgeel,et at. ASCO 2016,KEYNOTE-021: OSKEYNOTE-021: OS,49,晚期非小细胞肺癌精准治疗课件,50,晚期非小细胞肺癌精准治疗课件,51,晚期非小细胞肺癌精准治疗课件,52,晚期非小细胞肺癌精准治疗课件,53,晚期非小细胞肺癌精准治疗课件,54,晚期非小细胞肺癌精准治疗课件,55,CheckMate 012 Study Design:,Nivolumab Plus Ipilimumab in First-line NSCLC,Primary endpoint:,safety and tolerability,Secondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24,wks,Exploratory endpoints: OS; efficacy by PD-L1 expression,Stage 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 toxicity,a,Nivo,1 mg/kg IV Q3W x 4,+,Ipi 1 mg/kg IV Q3W x 4,Nivo,1 mg/kg IV Q2W,+,Ipi 1 mg/kg IV Q6W,Nivo,3 mg/kg IV Q2W,+,Ipi 1 mg/kg IV Q12W,Nivo,3 mg/kg IV Q2W,+,Ipi 1 mg/kg IV Q6W,Until disease progression or unacceptable toxicity,a,Here, we report results from,new,cohorts,explored to permit synergistic,activity and acceptable safety pro combination treatment with nivolumab and,ipilimumab,a,Patients,tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit,CheckMate 012 Study Design: Pr,56,晚期非小细胞肺癌精准治疗课件,57,晚期非小细胞肺癌精准治疗课件,58,晚期非小细胞肺癌精准治疗课件,59,晚期非小细胞肺癌精准治疗课件,60,晚期非小细胞肺癌精准治疗课件,61,Checkmate 012: Nivo + Chemo,Checkmate 012: Nivo + Chemo,62,晚期非小细胞肺癌精准治疗课件,63,JVDF,：,Ram,联合,Pembro I,期试验,1a,期,: DLT,评估,(n=6-12),主要终点,:,安全性,耐受性,次要终点,: PK,Schedule 1:,胃癌,/GEJ,胆管癌,3+3,设计,(n=3,-,6),Ram 8 mg/kg, D1,8,Pembro 200 mg fixed, D1,Both 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,Schedule 2:,胃癌,/GEJ,NSCLC, UC,3+3,设计,(n=3,-,6),Ram 10 mg/kg, D1,Pembro 200 mg fixed, D1,Both IV,每,3,周,队列,A: 15 Gastric/GEJ (2,nd,-3,rd,Line),队列,A1: 25 BTC (2,nd,-3,rd,Line),队列,A2: 25 Gastric/GEJ (1,st,Line),队列,B: 15 Gastric/GEJ (2,nd,-3,rd,Line),队列,C: 25 NSCLC (2,nd,-4,th,Line),队列,D: 25 UC (2,nd,-4,th,Line),队列,E: 25 NSCLC (1,st,Line),Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,JVDF：Ram联合Pembro I期试验1a期: DLT评,64,JVDF,：,NSCLC,患者安全性,NSCLC,O,n treatment,20,Off,treatment,7,Progressive Disease,5,Death,1,AE,1,A,ny grade,TRAE,19,Grade 3/4 TRAE,1,Treatment,related,SAE,3,AE leading to death,0,Any Grade,Grade 3/4,IRR,2,1,Elevated ALT,2,-,Elevated AST,2,-,Proteinuria,2,-,Hypertension,2,-,Hypothyroidism,1,-,Mouth hemorrhage,1,-,Elevated CPK,1,-,Stomatitis,1,-,AE,概况,引起关注的治疗相关,AE,Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,JVDF：NSCLC患者安全性NSCLC On treatm,65,JVDF,：,NSCLC,患者疗效,肿瘤缓解,肿瘤缓解随时间变化,Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,JVDF：NSCLC患者疗效肿瘤缓解肿瘤缓解随时间变化Her,66,结论,精准分子诊断是精准医学的前提，,EGFR,ALK,ROS1, RET, HER2,等靶向治疗是首选，,第三代,EGFR TKI,优于第一二代，第二代及三代,ALKI,优于克唑替尼，,驱动基因阴性，非鳞癌,NSCLC,：抗血管生成联合化疗,驱动基因阴性鳞癌和吸烟腺癌：免疫治疗希望所有，,免疫治疗与其它免疫治疗或化疗等联合可以改善疗效。,结论精准分子诊断是精准医学的前提，,67,谢谢,谢谢,68,