周彩存晚期非小細胞肺癌的精準治療

1、周彩存,周彩存，醫(yī)學博士，博士生導師，主任醫(yī)師，教授；上海市領軍人才，享受國務院特殊津貼現(xiàn)任同濟大學附屬上海市肺科醫(yī)院腫瘤科主任，醫(yī)學院腫瘤研究所所長中國醫(yī)促會胸部腫瘤分會主委，中國抗癌協(xié)會肺癌專業(yè)委員會常委，上海市抗癌協(xié)會肺癌分子靶向和免疫治療專業(yè)委員會主委，中國抗癌協(xié)會腫瘤藥物臨床研究專業(yè)委員會副主任委員，上海市醫(yī)學會分子診斷專委會副主任委員，中國醫(yī)師協(xié)會腫瘤分會常委，上海市醫(yī)師協(xié)會腫瘤分會副會長,晚期非小細胞肺癌的精準治療,C

2、aicun ZhouShanghai Pulmonary Hospital,Shanghai Tongji University, P.R.China,,肺癌是我國發(fā)病率和死亡率最高的惡性腫瘤，5年生存率僅為16％發(fā)病率和死亡率仍在上升肺癌對患者、家庭、國家都是一種災難,,,,生存期短過度治療無效治療,,患 者,,家 庭,國 家,,失去家庭成員的巨大痛苦高昂治療費用的壓力治與不治的艱難選擇,不斷增加的高昂醫(yī)療負擔,,,高

3、加索肺腺癌驅動基因圖譜,亞裔肺腺癌驅動基因圖譜,Sholl LM, et al. J Thorac Oncol. 2015;10(5):768-777Seo JS, Genome Res. 2012, 22(11):2109-2119,肺癌驅動基因譜明確，精準治療條件最成熟,,,,,,,,,,,KRAS25%,無已知的腫瘤驅動基因36%,EGFR23%,ALK7.9%,MEK10.3%,ERBB2 2.7%,BRAF

4、2.6%,PIK3CA 0.8%,NRAS0.7%,MET0.7%,,,,,融合基因,點突變,未知,,,,,肺腺癌（n=200）,外顯子跳躍,精準治療，路在何方？,Precision Medicine in Advanced NSCLC,,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl. Med. 2013,Tar

5、get therapy(1st, 2nd, and 3rd generation)New targets Increase of biomarker testing,Immunotherapy ＰＤ－Ｌ1 ＴＰＳ >50% Mutation load>200 Squamous Carcinoma Smoking adenocarcinoma,No actionabled

6、river mutation,,,,Avastin＋Chemo 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 1007 adenocarc

7、inomas (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

8、 et al., JAMA 2014,IPASS開啟了EGFR-TKI的肺癌精準醫(yī)學時代,,,,,,,,,,,,,,,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 EG

9、FR M- (n=85),,,,,,,,,Probabilityof PFS,EGFR M+ HR (95% CI) 0.48 (0.36, 0.64), p<0.0001EGFR M- HR (95% CI) 2.85 (2.05, 3.98), p<0.0001,Primary Cox analysis with covariates; ITT population; HR <1 implies a lower

10、 risk of progression on gefitinib,Treatment by subgroup interaction test, p<0.0001,Mok et al 2009,Time from randomisation (months),,九項臨床研究驗證TKI是EGFR突變陽性患者一線治療的最佳選擇,ROSsi A, et al. Cancer Treatment Reviews 2013; 39:489

11、-497.Zhou CC, et al. Lancet Oncol 2011; 12: 735–42.Wu YL, et al. Auunal of Onco 2015.Han JY, et al. J Clin Oncol 2012; 30:1122-1128.,NCCN指南明確單藥TKI是目前EGFR突變陽性患者標準治療,,阿法替尼40mg/天*,易瑞沙250mg/天,主要研究終點無進展生存期(PFS) -獨立評估

12、治療失敗時間(TTF)總生存期(OS),次要研究終點客觀緩解率(ORR)至客觀緩解的時間客觀緩解持續(xù)時間疾病控制持續(xù)時間腫瘤縮小健康相關生活質量評估（HRQoL),分層因素：突變類型（19/21); 是否有腦轉移,如果研究者認為有獲益則允許進展后持續(xù)治療第4、8、隨后每8周直至第64周、隨后每12周評估療效(RECIST)入組：2011年12月-2013年8月中位PFS隨訪時間：27.3個月,Park K, et

13、al. 2015 ESMO Asia.,*Del19和/或L858R(腫瘤組織)，local或central檢測a根據處方信息，允許劑量調整為50, 30, 20mg,LUX-Lung7研究：對于EGFR突變陽性患者的新一代EGFR-TKI 探索以易瑞沙為基礎對照進行,LUX-Lung 7: PFS (獨立評估),Park K, et al. 2015 ESMO Asia.,AZD9291用于經治T790M+的NSCLC： AURA

14、2 ( II期研究 ),主要終點：評估AZD9291療效（ORR）,關鍵入組標準：年齡≥18歲(日本≥20歲)確認EGFRm+至少有一個可重復評估病灶PS：0/1臟器功能可接受允許有穩(wěn)定腦轉移,不符合入組條件,既往接受過EGFR-TKI治療出現(xiàn)進展或轉移的患者經中心確認EGFRm+,疾病進展時再次活檢經中心檢測確認T790M+,T790M+(n=210),T790M-,AZD9291 80mg,QD,Tetsuya M

15、itsudomi,et al.2015 WCLC MINI16.08,AURA17研究：AZD9291 中國注冊臨床研究,AZD9291 80mg 每日一次 (n=175),每6周進行RECIST 1.1 評估指導出現(xiàn)疾病進展,基于最近一次治療后進展的腫瘤標本經中心實驗室檢測出T790M突變陽性,EGFRm+的局部晚期或轉移性 NSCLC 患者，且T790M突變陽性,設計：本研究預計入組225例患者，其中包括180例中國患者 （占總

16、入組人數80%）,主要終點: ORR次要終點: PFS, OS,Confidential for AZD9291. Internal Use only. Not for internal or external distribution,期待2016WCLC結果！,AZD9291一線治療EGFR突變NSCLC數據令人期待,注：數據錄入截止時間：2015年8月1日對距最后一次評估14周以內的疾病進展事件進行監(jiān)察反應持續(xù)時間是距離

17、第一次有記錄的反應到Recist評估出現(xiàn)進展或死亡的時間,Suresh S.,et al.2015 WCLC MINI16.07,AZD9291，對比吉非替尼或厄洛替尼治療EGFR-TKI敏感突變的初治晚期NSCLC的隨機III期臨床研究(FLAURA),Ramalingam SS, et al. 2015 ASCO Abstract 8102.,2016年ASCO公布肺癌最新液態(tài)活檢數據（II/II）,組織、血漿、尿液中T790M陽性

18、患者對CO-1686的應答率比較接近，在預測療效上有著相同的功能。,17,Presented by David at 2016 ASCO,Slide 8,Presented By Jacob Chabon at 2016 ASCO Annual Meeting,Phase III trials comparing crizotinib with chemotherapy in ALK+ lung cancer (PROFILE 1007

19、 and 1014),Presented By Tetsuya Mitsudomi at 2016 ASCO Annual Meeting,ALK陽性病人：ALK抑制劑,Limitations of crizotinib,Presented By Tetsuya Mitsudomi at 2016 ASCO Annual Meeting,J-ALEX: Study Design,Presented By Shirish Gadgeel

20、at 2016 ASCO Annual Meeting,Primary Endpoint: PFS by IRF (ITT Population),Presented By Shirish Gadgeel at 2016 ASCO Annual Meeting,Efficacy results for ALK+ patients,Presented By Tetsuya Mitsudomi at 2016 ASCO Annual Mee

21、ting,3rd Generation ALKi: Loratinib,如何優(yōu)化？,使用順序：一代與新的TKI群體的選擇及其治療策略優(yōu)化 Bim 豐度 其它基因的改變,Precision Medicine in Advanced NSCLC,,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science Transl. M

22、ed. 2013,Target therapy(1st, 2nd, and 3rd generation)New targets Increase of biomarker testing,Immunotherapy ＰＤ－Ｌ1 ＴＰＳ >50% Mutation load>200 Squamous Carcinoma Smoking adenocarcinoma,No

23、actionabledriver mutation,,,,Avastin＋Chemo Non-squamous NSCLC,,Adeno Ca,Squamous Ca.,SCLC,NOS,Large cell,,E4599：貝伐珠單抗一線聯(lián)合卡鉑/紫杉醇顯著延長PFS、OS及ORR,ECOG 4599,HR=0.66, p<0.001 (95% CI: 0.57–0.77),Sandler, et al. N E

24、ngl J Med 2006,BEYOND：貝伐珠單抗在中國人群療效的驗證,主要終點：PFS：證實在中國人群中的療效與E4599研究療效一致(HR臨界 ≤0.83)次要終點：OS，ORR，疾病緩解時間，安全性，血漿生物標志物(VEGF-A，VEGFR-2),Zhou C, et al. J Clin Oncol 2015; 33:2197-2204.,研究設計,* 進展揭盲后, 僅貝伐珠單抗組可選擇使用貝伐珠單抗聯(lián)合已被批準的二、

25、三線治療,,,,BEYOND：貝伐珠單抗聯(lián)合卡鉑/紫杉醇顯著延長PFS及OS,數據截止時間 2013年1月27日Zhou C, et al. J Clin Oncol 2015; 33:2197-2204.,,Precision Medicine in Advanced NSCLC,,Clinical Lung Cancer Genome Project and Network Genomic Medicine, Science T

26、ransl. Med. 2013,Target therapy(1st, 2nd, and 3rd generation)New targets Increase of biomarker testing,Immunotherapy ＰＤ－Ｌ1 ＴＰＳ >50% Mutation load>200 Squamous Carcinoma Smoking adenocarci

27、noma,No actionabledriver mutation,,,,Avastin＋Chemo 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

28、; 515: 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

29、) HR 0.73 (95% CI 0.59-0.89) P<0.001p=0.002Brahmer J et al. NEJM 2015, 373, 123Borghaei H et al. NEJM 2015,Pembrolizumab (2 or 10 mg/kg) versus docetaxel in advanced NSCLC: Overall SurvivalHerbst R et al. L

30、ancet 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) p<0.0001Pembrolizumab 2 mg/kg every 3 weeks:HR 0.54 (95% CI 0.38-0.77) p=0.0002 Total

31、 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

32、索性匯總無進展生存K-M曲線,Slide 17,Presented By Gideon Blumenthal at 2016 ASCO Annual Meeting,探索性匯總總生存K-M曲線,一線策略？,Monotherapy High PD-L1 expressionIn combination with chemotherapyLow PD-L1 expression In combination with other a

33、gents Targeted therapies？ Bevacizumab Immune checkpoint inhibitors Other immunotherapies,免疫治療一線研發(fā)策略,Primary endpoint: Progression-free survival (independent radiology review committee) in patients with strongly PD-

34、L1 positive tumors,,,,,,Pembrolizumab as first-line therapyin patients with high levels of PD-L1 KEYNOTE-024,Merck‘s KEYTRUDA® (pembrolizumab) demonstrates superior-progression-free survival and overall survival

35、 compared to chemotherapy as first-line therapy in patients with advanced non-small cell lung cance.rPress release, Thursday, June 16, 2016 6:45 am EDT www.mercknewsroom.com,,,,,,,,,34% of Patients were TPS＜1%,KEYNOT

36、E-021(phase Ⅰ/Ⅱ):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; Pemetr

37、exed 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

38、+paclitaxel+bevacizumab (n=25),Cohort C:Pembrolizumab+carboplatin+pemetrexed (n=25),*Parients with TPS≥50%,Gadgeel,et at. ASCO 2016,KEYNOTE-021: OS,KEYNOTE-021: OS,NR=not reached,Gadgeel,et at. ASCO 2016,,,,,,,,,,,,,Ch

39、eckMate 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 nivolu

40、mab 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 + Chemo,,JVDF：Ra

41、m聯(lián)合Pembro I期試驗,1a期: DLT評估 (n=6-12),主要終點: 安全性, 耐受性次要終點: PK,Schedule 1: 胃癌/GEJ, 膽管癌 3+3 設計 (n=3-6)Ram 8 mg/kg, D1,8Pembro 200 mg fixed, D1Both IV 每3周,1b期: 隊列擴展 (n=155),主要終點: 安全性和耐受性次要終點: PK及初步療效探索性終點: 生物標志物和免疫原性,中期分

42、析,Schedule 2: 胃癌/GEJ, NSCLC, UC3+3 設計 (n=3-6)Ram 10 mg/kg, D1Pembro 200 mg fixed, D1Both IV 每3周,隊列A: 15 Gastric/GEJ (2nd-3rd Line)隊列A1: 25 BTC (2nd-3rd Line)隊列A2: 25 Gastric/GEJ (1st Line),隊列B: 15 Gastric/GEJ (2nd-

43、3rd Line)隊列C: 25 NSCLC (2nd-4th Line)隊列D: 25 UC (2nd-4th Line)隊列E: 25 NSCLC (1st Line),Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,JVDF：NSCLC患者安全性,AE概況,引起關注的治療相關AE,Herbst, et al. 2016 ASCO, abstract 3056. NCT

44、02443324,JVDF：NSCLC患者療效,腫瘤緩解,腫瘤緩解隨時間變化,Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,結論,精準分子診斷是精準醫(yī)學的前提，EGFR,ALK,ROS1, RET, HER2等靶向治療是首選，第三代EGFR TKI優(yōu)于第一二代，第二代及三代ALKI優(yōu)于克唑替尼， 驅動基因陰性，非鱗癌NSCLC：抗血管生成聯(lián)合化療驅動基因陰性鱗癌和吸煙腺