晚期非小细胞肺癌的精准治疗课件

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,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,

2、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,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

3、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？,4,Precision Medicine in Advanced NSCLC,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl. Med. 2013,Target therapy(1st, 2nd, and 3rd generatio

4、n) New targets Increase of biomarker testing,Immunotherapy 1 50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma,No actionable driver mutation,AvastinChemo Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,5,.,US Lung Cancer Mutational Consortium (LCMC),Collaboration of 14 US C

5、ancer 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 2014,6,.,LCMC: Benefit in overall survival for personalized treatment,Kris et al., ASCO 2011, # 7506, Kris et al., JAMA 2014,7,.,IP

6、ASS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),

7、p0.0001,Primary Cox analysis with covariates; ITT population; HR 1 implies a lower risk of progression on gefitinib,Treatment by subgroup interaction test, p0.0001,Mok et al 2009,Time from randomisation (months),8,.,九项临床研究验证TKI是EGFR突变阳性患者一线治疗的最佳选择,ROSsi A, et al. Cancer Treatment Reviews 2013; 39:48

8、9-497. Zhou CC, et al. Lancet Oncol 2011; 12: 73542.Wu YL, et al. Auunal of Onco 2015. Han JY, et al. J Clin Oncol 2012; 30:1122-1128.,9,NCCN指南明确单药TKI是目前EGFR突变阳性患者标准治疗,10,.,阿法替尼 40mg/天*,易瑞沙 250mg/天,主要研究终点 无进展生存期(PFS) -独立评估 治疗失败时间(TTF) 总生存期(OS),次要研究终点 客观缓解率(ORR) 至客观缓解的时间 客观缓解持续时间 疾病控制持续时间 肿瘤缩小 健康相关生活

9、质量评估（HRQoL),分层因素：突变类型（19/21); 是否有脑转移,如果研究者认为有获益则允许进展后持续治疗 第4、8、随后每8周直至第64周、随后每12周评估疗效(RECIST) 入组：2011年12月-2013年8月 中位PFS随访时间：27.3个月,Park K, et al. 2015 ESMO Asia.,*Del19和/或L858R(肿瘤组织)，local或central检测 a根据处方信息，允许剂量调整为50, 30, 20mg,LUX-Lung7研究：对于EGFR突变阳性患者的新一代EGFR-TKI 探索以易瑞沙为基础对照进行,LUX-Lung 7: PFS (独立评估)

10、,Park K, et al. 2015 ESMO Asia.,12,.,AZD9291用于经治T790M+的NSCLC： AURA2 ( II期研究 ),主要终点： 评估AZD9291疗效（ORR）,关键入组标准： 年龄18岁(日本20岁) 确认EGFRm+ 至少有一个可重复评估病灶 PS：0/1 脏器功能可接受 允许有稳定脑转移,不符合入组条件,既往接受过EGFR-TKI治疗出现进展或转移的患者经中心确认EGFRm+,疾病进展时再次活检经中心检测确认T790M+,T790M+ (n=210),T790M-,AZD9291 80mg,QD,Tetsuya Mitsudomi,et al.20

11、15 WCLC MINI16.08,13,.,AURA17研究：AZD9291 中国注册临床研究,AZD9291 80mg 每日一次 (n=175),每6周进行RECIST 1.1 评估指导出现疾病进展,基于最近一次治疗后进展的肿瘤标本经中心实验室检测出T790M突变阳性,EGFRm+的局部晚期或转移性 NSCLC 患者，且T790M突变阳性,设计： 本研究预计入组225例患者，其中包括180例中国患者 （占总入组人数80%）,主要终点: ORR 次要终点: PFS, OS,Confidential for AZD9291. Internal Use only. Not for interna

12、l or external distribution,期待2016WCLC结果！,14,.,AZD9291一线治疗EGFR突变NSCLC数据令人期待,注： 数据录入截止时间：2015年8月1日 对距最后一次评估14周以内的疾病进展事件进行监察 反应持续时间是距离第一次有记录的反应到Recist评估出现进展或死亡的时间,Suresh S.,et al.2015 WCLC MINI16.07,15,.,AZD9291，对比吉非替尼或厄洛替尼治疗EGFR-TKI敏感突变的初治晚期NSCLC的随机III期临床研究(FLAURA),Ramalingam SS, et al. 2015 ASCO Abst

13、ract 8102.,16,.,2016年ASCO公布肺癌最新液态活检数据（II/II）,组织、血浆、尿液中T790M阳性患者对CO-1686的应答率比较接近，在预测疗效上有着相同的功能。,17,Presented by David at 2016 ASCO,.,Slide 8,Presented By Jacob Chabon at 2016 ASCO Annual Meeting,18,.,Phase III trials comparing crizotinib with chemotherapy in ALK+ lung cancer (PROFILE 1007 and 1014),P

14、resented By Tetsuya Mitsudomi at 2016 ASCO Annual Meeting,ALK阳性病人：ALK抑制剂,19,.,Limitations of crizotinib,Presented By Tetsuya Mitsudomi at 2016 ASCO Annual Meeting,20,.,J-ALEX: Study Design,Presented By Shirish Gadgeel at 2016 ASCO Annual Meeting,21,.,Primary Endpoint: PFS by IRF (ITT Population),Pre

15、sented By Shirish Gadgeel at 2016 ASCO Annual Meeting,22,.,Efficacy results for ALK+ patients,Presented By Tetsuya Mitsudomi at 2016 ASCO Annual Meeting,3rd Generation ALKi: Loratinib,23,.,如何优化？,使用顺序：一代与新的TKI 群体的选择及其治疗策略优化 Bim 丰度 其它基因的改变,24,.,Precision Medicine in Advanced NSCLC,Clinical Lung Cancer

16、 Genome Project and Network Genomic Medicine, Science Transl. Med. 2013,Target therapy(1st, 2nd, and 3rd generation) New targets Increase of biomarker testing,Immunotherapy 1 50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma,No actionable driver mutation,AvastinChemo Non-squamous NSCLC,

17、Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,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),Sandler, et al. N Engl J Med 2006,26,.,BEYOND：贝伐珠单抗在中国人群疗效的验证,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

18、Clin Oncol 2015; 33:2197-2204.,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,27,.,BEYOND：贝伐珠单抗联合卡铂/紫杉醇显著延长PFS及OS,数据截止时间 2013年1月27日 Zhou C, et al. J Clin Oncol 2015; 33:2197-2204.,28,.,Precision Medicine in Advanced NSCLC,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl

19、. Med. 2013,Target therapy(1st, 2nd, and 3rd generation) New targets Increase of biomarker testing,Immunotherapy 1 50% Mutation load200 Squamous Carcinoma Smoking adenocarcinoma,No actionable driver mutation,AvastinChemo Non-squamous NSCLC,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,29,.,Activity in p

20、retreated patients,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 2015,30,.,Nivolumab vs docetaxel in advanced NSCLCOverall survival,Sqamous Adenocarcinoma HR 0.59 (95% CI 0.4

21、4-0.79) HR 0.73 (95% CI 0.59-0.89) P0.001p=0.002Brahmer J et al. NEJM 2015, 373, 123Borghaei H et al. NEJM 2015,31,.,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 more Pembrolizumab 10 mg /kg ev

22、ery 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=0.0008,32,.,33,.,34,.,Slide 16,

23、Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting,探索性汇总无进展生存K-M曲线,35,.,Slide 17,Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting,探索性汇总总生存K-M曲线,36,.,一线策略？,Monotherapy High PD-L1 expression In combination with chemotherapy Low PD-L1 expression In combination with other agents Target

24、ed therapies？ Bevacizumab Immune checkpoint inhibitors Other immunotherapies,免疫治疗一线研发策略,37,.,Primary endpoint: Progression-free survival (independent radiology review committee) in patients with strongly PD-L1 positive tumors,38,.,39,.,40,.,Pembrolizumab as first-line therapyin patients with high le

25、vels 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 ,41,.,42,.,43,.,44,.,

26、45,.,34% of Patients were TPS1%,46,.,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); Paclitaxel dose: 200mg/m2 i.v. q3w; Bevacizumab dose:15mg/kg i.v.q3w; Pemetrexed dose: 500mg/m2 i.v.q3w,Primary endpoi

27、nt ORR,Secondary endpoint OS PFS DoR,Gadgeel,et at. ASCO 2016,47,.,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.

28、 ASCO 2016,48,.,KEYNOTE-021: OS,KEYNOTE-021: OS,NR=not reached,Gadgeel,et at. ASCO 2016,49,.,50,.,51,.,52,.,53,.,54,.,55,.,CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC,Here, we report results from new cohorts explored 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,56,.,57,.,58,.,59,.,60,.,61,.,Checkmate 012: Nivo + Che