1、周彩存,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现任同济大学附属上海市肺科医院肿瘤科主任，医学院肿瘤研究所所长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,晚期非小细胞肺癌的精准治疗,Caicun ZhouShanghai Pulmonary Hospital,Shanghai Tongji University, P.R.China,肺癌是我国发
2、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,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,KRAS25%,无已知的肿瘤驱动基因36%,EGFR23%,ALK7.9%,MEK1
3、0.3%,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？,Precision Medicine in Advanced NSCLC,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl. Med. 2013,Target therapy(1st, 2nd, and 3rd generation)New targets Increase of biomarke
4、r testing,Immunotherapy 1 50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma,No actionabledriver mutation,AvastinChemo Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,US Lung Cancer Mutational Consortium (LCMC),Collaboration of 14 US Cancer CentersMultiplex genotyping of 100
5、7 adenocarcinomas (full genotyping 733)Close link to clinical trial platform,Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014,LCMC: Benefit in overall survival for personalized treatment,Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014,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,
6、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), p0.0001EGFR M- HR (95% CI) 2.85 (2.05, 3.98), p0.0001,Primary Cox analysis with covariates; ITT po
7、pulation; HR 1 implies a lower risk of progression on gefitinib,Treatment by subgroup interaction test, p50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma,No actionabledriver mutation,AvastinChemo Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,E4599：贝伐珠单抗一线联合卡铂/紫杉醇显著延长PFS、
8、OS及ORR,ECOG 4599,HR=0.66, p50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma,No actionabledriver mutation,AvastinChemo Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,Activity in pretreated patients,Gettinger S, J Clin Oncol 2015; 33: 2004-2012; Herbst R, Nature 2014; 515:
9、563-7; Soria JC, ESMO 2013; Garon E, NEJM 2015; 372: 2018-28; Rizvi N, ASCO 2015; Guley LJ, ASCO 2015,Nivolumab vs docetaxel in advanced NSCLCOverall survival,Sqamous 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
10、. NEJM 2015,Pembrolizumab (2 or 10 mg/kg) versus docetaxel in advanced NSCLC: Overall SurvivalHerbst R et al. Lancet Oncology 2015, online December 18,PD-L1 50% or morePembrolizumab 10 mg /kg every 3 weeks:HR 0.50 (95% CI 0.36-0.70) p0.0001Pembrolizumab 2 mg/kg every 3 weeks:HR 0.54 (95% CI 0.38-0.7
11、7) 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=0.0008,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 17,Presented By Gideon Blumenthal at 2016 ASCO
12、 Annual Meeting,探索性汇总总生存K-M曲线,一线策略？,Monotherapy High PD-L1 expressionIn combination with chemotherapyLow 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-free survival (indepe
13、ndent radiology review committee) in patients with strongly PD-L1 positive tumors,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 firs
14、t-line therapy in patients with advanced non-small cell lung cance.rPress release, Thursday, June 16, 2016 6:45 am EDT ,34% of Patients were TPS1%,KEYNOTE-021(phase /):study design,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);Paclitaxe
15、l dose: 200mg/m2 i.v. q3w; Bevacizumab dose:15mg/kg i.v.q3w; Pemetrexed dose: 500mg/m2 i.v.q3w,Primary endpointORR,Secondary endpointOS PFS DoR,Gadgeel,et at. ASCO 2016,KEYNOTE-021: Response,Cohort A:Pembrolizumab+carboplatin+paclitaxel(n=25),Cohort B:Pembrolizumab+carboplatin+paclitaxel+bevacizumab
16、 (n=25),Cohort C:Pembrolizumab+carboplatin+pemetrexed (n=25),*Parients with TPS50%,Gadgeel,et at. ASCO 2016,KEYNOTE-021: OS,KEYNOTE-021: OS,NR=not reached,Gadgeel,et at. ASCO 2016,CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC,Here, we report results from new cohorts explo
17、red to permit synergistic activity and acceptable safety profile of combination treatment with nivolumab and ipilimumab,aPatients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit,Checkmate 012: Nivo + Chem
18、o,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, D1,8Pembro 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,Schedule 2: 胃癌/GEJ, NSCLC, UC3+3 设计 (n=3-6)Ram 10 mg/kg, D1Pembro 200 mg fix
19、ed, 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 3056. NCT02443324,JVDF：NSCLC患者安全性,AE概况,引起关
20、注的治疗相关AE,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,Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,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。,谢谢,
