周彩存晚期非小細(xì)胞肺癌的精準(zhǔn)治療

1、周彩存,周彩存，醫(yī)學(xué)博士，博士生導(dǎo)師，主任醫(yī)師，教授；上海市領(lǐng)軍人才，享受?chē)?guó)務(wù)院特殊津貼現(xiàn)任同濟(jì)大學(xué)附屬上海市肺科醫(yī)院腫瘤科主任，醫(yī)學(xué)院腫瘤研究所所長(zhǎng)中國(guó)醫(yī)促會(huì)胸部腫瘤分會(huì)主委，中國(guó)抗癌協(xié)會(huì)肺癌專業(yè)委員會(huì)常委，上海市抗癌協(xié)會(huì)肺癌分子靶向和免疫治療專業(yè)委員會(huì)主委，中國(guó)抗癌協(xié)會(huì)腫瘤藥物臨床研究專業(yè)委員會(huì)副主任委員，上海市醫(yī)學(xué)會(huì)分子診斷專委會(huì)副主任委員，中國(guó)醫(yī)師協(xié)會(huì)腫瘤分會(huì)常委，上海市醫(yī)師協(xié)會(huì)腫瘤分會(huì)副會(huì)長(zhǎng),晚期非小細(xì)胞肺癌的精準(zhǔn)治療,C

2、aicun ZhouShanghai Pulmonary Hospital,Shanghai Tongji University, P.R.China,,肺癌是我國(guó)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(duì)患者、家庭、國(guó)家都是一種災(zāi)難,,,,生存期短過(guò)度治療無(wú)效治療,,患 者,,家 庭,國(guó) 家,,失去家庭成員的巨大痛苦高昂治療費(fèi)用的壓力治與不治的艱難選擇,不斷增加的高昂醫(yī)療負(fù)擔(dān),,,高

3、加索肺腺癌驅(qū)動(dòng)基因圖譜,亞裔肺腺癌驅(qū)動(dòng)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(qū)動(dòng)基因譜明確，精準(zhǔn)治療條件最成熟,,,,,,,,,,,KRAS25%,無(wú)已知的腫瘤驅(qū)動(dòng)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(diǎn)突變,未知,,,,,肺腺癌（n=200）,外顯子跳躍,精準(zhǔn)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(kāi)啟了EGFR-TKI的肺癌精準(zhǔn)醫(yī)學(xué)時(shí)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(xiàng)臨床研究驗(yàn)證TKI是EGFR突變陽(yáng)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(yáng)性患者標(biāo)準(zhǔn)治療,,阿法替尼40mg/天*,易瑞沙250mg/天,主要研究終點(diǎn)無(wú)進(jìn)展生存期(PFS) -獨(dú)立評(píng)估

12、治療失敗時(shí)間(TTF)總生存期(OS),次要研究終點(diǎn)客觀緩解率(ORR)至客觀緩解的時(shí)間客觀緩解持續(xù)時(shí)間疾病控制持續(xù)時(shí)間腫瘤縮小健康相關(guān)生活質(zhì)量評(píng)估（HRQoL),分層因素：突變類型（19/21); 是否有腦轉(zhuǎn)移,如果研究者認(rèn)為有獲益則允許進(jìn)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(píng)估療效(RECIST)入組：2011年12月-2013年8月中位PFS隨訪時(shí)間：27.3個(gè)月,Park K, et

13、al. 2015 ESMO Asia.,*Del19和/或L858R(腫瘤組織)，local或central檢測(cè)a根據(jù)處方信息，允許劑量調(diào)整為50, 30, 20mg,LUX-Lung7研究：對(duì)于EGFR突變陽(yáng)性患者的新一代EGFR-TKI 探索以易瑞沙為基礎(chǔ)對(duì)照進(jìn)行,LUX-Lung 7: PFS (獨(dú)立評(píng)估),Park K, et al. 2015 ESMO Asia.,AZD9291用于經(jīng)治T790M+的NSCLC： AURA

14、2 ( II期研究 ),主要終點(diǎn)：評(píng)估AZD9291療效（ORR）,關(guān)鍵入組標(biāo)準(zhǔn)：年齡≥18歲(日本≥20歲)確認(rèn)EGFRm+至少有一個(gè)可重復(fù)評(píng)估病灶PS：0/1臟器功能可接受允許有穩(wěn)定腦轉(zhuǎn)移,不符合入組條件,既往接受過(guò)EGFR-TKI治療出現(xiàn)進(jìn)展或轉(zhuǎn)移的患者經(jīng)中心確認(rèn)EGFRm+,疾病進(jìn)展時(shí)再次活檢經(jīng)中心檢測(cè)確認(rèn)T790M+,T790M+(n=210),T790M-,AZD9291 80mg,QD,Tetsuya M

15、itsudomi,et al.2015 WCLC MINI16.08,AURA17研究：AZD9291 中國(guó)注冊(cè)臨床研究,AZD9291 80mg 每日一次 (n=175),每6周進(jìn)行RECIST 1.1 評(píng)估指導(dǎo)出現(xiàn)疾病進(jìn)展,基于最近一次治療后進(jìn)展的腫瘤標(biāo)本經(jīng)中心實(shí)驗(yàn)室檢測(cè)出T790M突變陽(yáng)性,EGFRm+的局部晚期或轉(zhuǎn)移性 NSCLC 患者，且T790M突變陽(yáng)性,設(shè)計(jì)：本研究預(yù)計(jì)入組225例患者，其中包括180例中國(guó)患者 （占總

16、入組人數(shù)80%）,主要終點(diǎn): ORR次要終點(diǎn): PFS, OS,Confidential for AZD9291. Internal Use only. Not for internal or external distribution,期待2016WCLC結(jié)果！,AZD9291一線治療EGFR突變NSCLC數(shù)據(jù)令人期待,注：數(shù)據(jù)錄入截止時(shí)間：2015年8月1日對(duì)距最后一次評(píng)估14周以內(nèi)的疾病進(jìn)展事件進(jìn)行監(jiān)察反應(yīng)持續(xù)時(shí)間是距離

17、第一次有記錄的反應(yīng)到Recist評(píng)估出現(xiàn)進(jìn)展或死亡的時(shí)間,Suresh S.,et al.2015 WCLC MINI16.07,AZD9291，對(duì)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(jī)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(shù)據(jù)（II/II）,組織、血漿、尿液中T790M陽(yáng)性

18、患者對(duì)CO-1686的應(yīng)答率比較接近，在預(yù)測(cè)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(yáng)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(zhǎng)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(guó)人群療效的驗(yàn)證,主要終點(diǎn)：PFS：證實(shí)在中國(guó)人群中的療效與E4599研究療效一致(HR臨界 ≤0.83)次要終點(diǎn)：OS，ORR，疾病緩解時(shí)間，安全性，血漿生物標(biāo)志物(VEGF-A，VEGFR-2),Zhou C, et al. J Clin Oncol 2015; 33:2197-2204.,研究設(shè)計(jì),* 進(jìn)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(zhǔn)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(zhǎng)PFS及OS,數(shù)據(jù)截止時(shí)間 2013年1月27日Z(yǔ)hou 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(wú)進(jìn)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(yàn),1a期: DLT評(píng)估 (n=6-12),主要終點(diǎn): 安全性, 耐受性次要終點(diǎn): PK,Schedule 1: 胃癌/GEJ, 膽管癌 3+3 設(shè)計(jì) (n=3-6)Ram 8 mg/kg, D1,8Pembro 200 mg fixed, D1Both IV 每3周,1b期: 隊(duì)列擴(kuò)展 (n=155),主要終點(diǎn): 安全性和耐受性次要終點(diǎn): PK及初步療效探索性終點(diǎn): 生物標(biāo)志物和免疫原性,中期分

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

43、3rd Line)隊(duì)列C: 25 NSCLC (2nd-4th Line)隊(duì)列D: 25 UC (2nd-4th Line)隊(duì)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(guān)注的治療相關(guān)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(shí)間變化,Herbst, et al. 2016 ASCO, abstract 3056. NCT02443324,結(jié)論,精準(zhǔn)分子診斷是精準(zhǔn)醫(yī)學(xué)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(qū)動(dòng)基因陰性，非鱗癌NSCLC：抗血管生成聯(lián)合化療驅(qū)動(dòng)基因陰性鱗癌和吸煙腺