肺癌內(nèi)科治療進展

1、化療進展,早期術(shù)后輔助化療：個體化？局部晚期 同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;　ND優(yōu)于DP非鱗癌 分子靶向治療 貝伐單化療優(yōu)于化療 培美優(yōu)于健擇 連續(xù)維持治療改善總體生存免疫治療,輔助治療的必要性,輔助化療,是淋巴結(jié)陽性完

2、全切除早期NSCLC的標(biāo)準(zhǔn)治療在淋巴結(jié)陰性病人,仍存在爭議順鉑為基礎(chǔ)方案是標(biāo)準(zhǔn)卡鉑為基礎(chǔ)方案未得到批準(zhǔn),但經(jīng)常使用證據(jù)最多的是NPECOG1505允許所有未批準(zhǔn)的方案,BRCA1水平和含鉑藥物化療的相關(guān)性,Yang Y et al.J Exp Clin Cancer Res,2013,Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT),Presente

3、d By Mark Socinski at 2015 ASCO Annual Meeting,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT),SLIDES ARE THE PROPERTY OF THE AUTHOR.PERMISSION REQUI

4、RED FOR REUSE.,實驗組的OS,Massuti B, et al. 2015 ASCO Abstract 7507.,BRCA1高水平患者DFS和OS,BRCA1高表達者未顯示順鉑耐藥。,Massuti B, et al. 2015 ASCO Abstract 7507.,BRCA1低表達患者DFS和OS,BRCA1低表達者多見于腺癌、非吸煙和女性患者。,分子學(xué)分析指導(dǎo)下的晚期NSCLC患者全球III期研究：研究設(shè)計,分層因

5、素：PS、性別、既往(新)輔助治療治療：6周期、無維持治療、無貝伐單抗主要入組條件：IIIB(濕性)/IV期NSCLC，PS 0-1，可測量疾病，F(xiàn)FPE組織塊并有蛋白表達數(shù)據(jù)計劃入組：267例 (254個事件),Bepler G, et al. 2013 ASCO Abstract 8001.,招募：運輸組織塊，篩選符合條件受試者,主要終點：無進展生存,,,2 : 1,N=275,,研究結(jié)果：PFS和OS,Beple

6、r G, et al. 2013 ASCO Abstract 8001.,OS,So what can we conclude from this study and what are the issues?,Presented By Mark Socinski at 2015 ASCO Annual Meeting,BRCA1 does not appear to be a robust biomarker in this smal

7、l 4-arm trialRT-PCR - is it a valid method to quantitate BRCA1 function?Three different treatments given - how do you separate the treatment effects from the biology? Terciles were not balanced for known prognostic fac

8、torsRaises the hypothesis that different cisplatin-based doublets may have differing effects in different subsetsCompliance to therapy important (but reasons for non-compliance not delineated),化療進展,早期術(shù)后輔助化療：個體化？局部晚期

9、同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;　ND優(yōu)于DP非鱗癌 分子靶向治療 貝伐單化療優(yōu)于化療 培美優(yōu)于健擇 連續(xù)維持治療改善總體生存免疫治療,Unresectable Stage III NSCLC,Presented By Mark

10、 Socinski at 2015 ASCO Annual Meeting,Chemoradiation established as the standard of care over a decade agoConcurrent superior to sequential chemoradiationOptimal chemotherapy regimen/strategy still unclearFull-dose as

11、 well as low-dose strategies accepted as a standard of careCommon full-dose regimens - cisplatin + etoposide, vinorelbine, vinblastine, docetaxelCommon low-dose regimen – weekly carboplatin/paclitaxel,,除了EP同步化放為2B證據(jù)外，其

12、他都為2A級證據(jù)。,不可手術(shù)的III期NSCLC,過去10年,III期臨床研究所致力解決的問題:誘導(dǎo)治療的作用；鞏固治療的作用；新藥 vs. 老藥；放療的劑量（60 vs. 74Gy);Cetuximab的作用；Tecemotide的作用；,Is CisPem “worthy” of a Phase III Trial in stage III NSCLC?,Presented By Mark Socinski at 201

13、5 ASCO Annual Meeting,Pre-clinical synergism of pemetrexed with RT11 ph I trials with either cisplatin or carboplatin all using RT doses of 40-70 Gy (most common 66 Gy)8 ph II trials of various strategies showed high O

14、RR (46-86%) and med OS of 18-34 monthsAII ph I/II trials used "systemic" dosesPh II trials reported rates of gr 3-4 esophagitis and pnemonitis of 0-16% and 3-23%, respectively,PROCLAIM: Study Design,Presented

15、 By Mark Socinski at 2015 ASCO Annual Meeting,Primary Endpoint: OS (superiority)*Stratified for. ECOG PS (0 vs 1);PET scan staging(yes vs no);gender, and disease stage(IIIA vs IIIB).↑AJCC Cancer Staging Manual(ed 6),2

16、002.?Folic acid, vitamin B12,and dexamethasone administered in Arm A TRT=thoracic radiotherapy.,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Primary Endpoint: OS (superiority)*Stratified for. ECOG PS (0 vs 1)

17、;PET scan staging(yes vs no);gender, and disease stage(IIIA vs IIIB).↑AJCC Cancer Staging Manual(ed 6),2002.?Folic acid, vitamin B12,and dexamethasone administered in Arm A TRT=thoracic radiotherapy.,PROCLAIM: Study Des

18、ign,PROCLAIM: Primary Endpoint, OS,Presented By Mark Socinski at 2015 ASCO Annual Meeting,HR(95% CI): 0.98(0.79,1.20)Lag-rank p=0.831Median OS (95% CI),mosPem-Cis: 26.8 (20.4,30.9)Eto-Cis: 25.0 (22.2,29.8)Median fo

19、llow-up times(mos­[range])All patients:Pem-Cis,22.2(0.1-66.6)Eto-Cis,22.6 (0.0-71.4)Patients alive: Pem-Cis,32.9(0.1-66.6)Eto-Cis, 35.7(0.0-71.4)Total events:357Pem-Cis:177 events/301 patientsEto-Cis: 180 e

20、vents/297patients,PROCLAIM in the wake of RTOG 0617,Presented By Mark Socinski at 2015 ASCO Annual Meeting,*p<0.05, includes 2 gr 5 events; + Bradley JD et al.Lancet Oncol 16:187-99,2015PET Staging -82% PROCLAIM,~90%

21、 in RTOG 0617,化療進展,早期術(shù)后輔助化療：個體化？局部晚期 同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;　ND優(yōu)于DP非鱗癌 分子靶向治療 貝伐單化療優(yōu)于化療 培美優(yōu)于健擇 連續(xù)維持治療改善總體生存免疫治療,WJOG520

22、8L: Study design,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,主要終點：OS;次人終點: PFS, RR, AEs初期樣本大小250例； 修改后樣本350例，power 由80%變?yōu)?0%,WJOC 5208L: 比較nedaplatin與順鉑聯(lián)合多烯紫杉醇一線治療晚期或復(fù)發(fā)肺鱗癌,Chemo-naive PS 0-1 Age 2

23、0-74Stage IIIb/IV orrecurrent SqLCN:350,Docetaxel 60 mg/m2 dlNedaplatin 100 mg/m2 dlq3w,4-6 cyclesN=175,Docetaxel 60 mg/m2 dlCisplatin 80 mg/m2 dlq3w,4-6 cyclesN=175,1:1,Stratification factors:S

24、tage(IIIb, IV or recurrent)GenderInstitutions,Baseline characteristics,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,Primary endpoint: Overall survival,Presented By Takehito Shukuya at 2015 ASCO Annual Meet

25、ing,Progression-free survival,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,Objective tumor response,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,RECIST ver. 1.1,*Fisher’s exact test,Treatment ex

26、posure,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,*One and 2 patients withdrew before study treatment in ND and CD, respectively,Post-Study Systemic Therapy,Presented By Takehito Shukuya at 2015 ASCO Annua

27、l Meeting,CA031試驗設(shè)計,初次化療PS 0-1Ⅲb/ Ⅳ期NSCLCN=1,050,1：1,白蛋白結(jié)合型紫杉醇： 100mg/m2 ，第1、8、15天卡鉑：AUC 6，第1天無預(yù)處理N=525,溶劑型紫杉醇： 200mg/m2 ，第1天卡鉑：AUC 6，第1天地塞米松+抗組胺藥預(yù)處理N=525,分層因素：分期(Ⅲb或 Ⅳ期)年齡(＜70或＞70)性別組織學(xué)(鱗狀細(xì)胞\非鱗狀

28、細(xì)胞)區(qū)域,三周重復(fù),Abstract # LBA7511, 2010 ASCO,主要終點ORR--所有組織學(xué)類型,,RR = 1.31(1.082-1.593)P = 0.005,33%,25%,緩解率,獨立影像學(xué)評價,,Nab-P/C (n=521),,P/C (n=531),37%,30%,研究者評價,RR = 1.26(1.060-1.496)P = 0.008,Abstract # LBA7511, 2010 ASC

29、O,主要終點ORR--組織學(xué)分層,,鱗癌,,Nab-P/C,,P/C,非鱗癌,Abstract # LBA7511, 2010 ASCO,41%,24%,26%,25%,P<0.001,P=0.808,,n=228,,n=221,,n=292,,n=310,獨立影像學(xué)評價,緩解率,化療方案的選擇,JMDB研究：力比泰/順鉑對非鱗癌患者的療效更優(yōu),,Scagliotti GV, et al. J Clin Oncol. 2008

30、;26(21): 3543-51,OS(非鱗癌),OS(鱗癌),化療方案的選擇,,Pujol JL, et al. Oral abstract presented at 2012 ESMO. Vienna, Austria.,患者(%),惡心P=0.004,嘔吐p=1.0,脫水(任何分級)P=0.075,脫發(fā)(任何分級)P<0.001,疲乏P=0.143,發(fā)熱性中性粒細(xì)胞減少P=0.002,患者(%),3/4級非血

31、液學(xué)毒性反應(yīng),3/4級血液學(xué)毒性反應(yīng),力比泰/順鉑一線治療非鱗癌耐受性優(yōu)勢顯著,化療方案的選擇,晚期NSCLC非鱗癌（尤其EGFR突變狀態(tài)未知）患者：優(yōu)選力比泰,*非鱗癌包括：腺癌、大細(xì)胞癌和其他未確定類型的NSCLC,Scagliotti G. et al. J Thorac Oncol.2011; 6(1): 64-70.,PARAMOUNT研究：力比泰同藥維持治療顯著延長非鱗癌(EGFR突變狀態(tài)未知)患者PFS,力比泰同藥維持：顯

32、著降低患者疾病進展風(fēng)險40%,Paz-Ares L, et al. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Scagliotti GV, et al. Lung Cancer. 2014 Sep;85(3):408-14.,PFS（維持治療階段）,PFS（自誘導(dǎo)開始）,HR=0.60 (0.50-0.73)p<0.001,PARAMOUNT研究：力比泰同藥維持治療顯著延

33、長非鱗癌(EGFR突變狀態(tài)未知)患者OS,力比泰同藥維持：顯著降低患者死亡風(fēng)險22%,OS（維持治療階段）,OS（自誘導(dǎo)開始）,Paz-Ares L, et al. J Clin Oncol. 2013 Aug 10;31(23):2895-902.,Single-agent Pl,BEYOND study design,Secondary endpoints: OS, ORR, duration of response, s

34、afety, plasma biomarkers (VEGF-A, VEGFR-2)Exploratory biomarkers: tissue and plasma EGFR mutation statusStratification factors: gender, smoking status, age,Chinese patients with previously untreated, advanced, stage II

35、IB/IVnon-squamous NSCLCn=276,Bevacizumab (B) 15 mg/kg d1 Carboplatin (C) AUC6 d1 Paclitaxel (P) 175 mg/m2 d1 3-weekly cycle, n=138,6 cycles,R,PD,CP + Placebo (Pl)All on d1 3-weekly cycle, n=138,1:1,PD,Primary endpo

36、int: PFSto confirm efficacy in Chinese population through consistency with E4599 (HR threshold ≤0.83),,*,*Optional enrolment in post-progression phase of open-label B + approved 2nd-/3rd-line treatment for B+CP arm only

37、,PD = disease progression; R = randomised; ORR = objective response rate; HR = hazard ratio; VEGF-A = vascular endothelial growth factor-AVEGFR-2 = vascular endothelial growth factor receptor-2; EGFR = epidermal growth

38、factor receptor,Single-agent B,Exploratory EGFR biomarker analysis: PFS,A total of 152 patients provided tissue for biomarker analysis (n=85 B+CP; n=67 Pl+CP)EGFR mutation-positive rate was 27% in B+CP and 25% in Pl+CP

39、 patientsNo correlation was observed between EGFR mutation status and bevacizumab efficacya similar degree of treatment benefit was seen for mutation positive and wild-type groups (mutation-positive HR 0.27, 95% CI 0.1

40、2–0.63; wild-type HR 0.33, 95% CI 0.21–0.53Analyses of EGFR plasma data are ongoing,Mut+ = mutation-positive; WT = wild type,PFS (primary endpoint),Data cut-off 27 Jan 2013,1711100502500023178206249201

41、0,1.0,0.8,0.6,0.4,0.2,0.0,Median OS was 24.3 vs 27.5 months for B+CP vs Pl+CP in the EGFR mutation-positive subgroup (HR 0.90)In the EGFR wild-type subgroup, median OS was 20.3 vs 13.8 months for B+CP vs Pl+CP (HR 0.57

42、),Exploratory EGFR biomarker analysis: OS,Data cut-off 30 Apr 2014,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,1.0,0.8,0.6,0.4,0.2,0.0,05101520253035,,,,,Overall Survival,171615111091049452

43、91913910232321171583062574641312150,Study Month,,Plasma samples were available from 274 patientsPlasma VEGF-A and VEGFR-2 baseline levels (high versus low compared to median levels) did not correlat

44、e with bevacizumab efficacy for PFS or OS,Plasma VEGF biomarker analysis,,Data cut-off 27 Jan 2013 for PFS; 30 Apr 2014 for OS,化療進展,早期術(shù)后輔助化療：個體化？局部晚期 同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;　ND優(yōu)于DP非鱗癌 分

45、子靶向治療 貝伐單化療優(yōu)于化療 培美優(yōu)于健擇 連續(xù)維持治療改善總體生存免疫治療,Mutational heterogeneity in cancer,Presented By Laura Chow at 2014 ASCO Annual Meeting,適應(yīng)性免疫應(yīng)答可以預(yù)測預(yù)后,Galon J, et.

46、al, Science,2006,313:1960-1964,克服免疫逃逸的根本 — 解除T細(xì)胞的抑制,T細(xì)胞效應(yīng)功能受到宿主和腫瘤微環(huán)境的影響而抑制 - 對于Treg細(xì)胞增多的患者，抗CTLA-4和PD-1是一種有效的方式 - 阻斷T細(xì)胞正常表達的CTLA-4，PD-L1，或LAG3可減少它們的抗原應(yīng)答 - 僅僅通過抑制CTLA-4和PD-1對CD8+T細(xì)胞增殖和生存是不夠的，加入LAG3抑制劑可進一

47、步增強T細(xì)胞的增殖和激活 - 對于具有MDSCs或調(diào)節(jié)性B細(xì)胞表型的患者，或腫瘤微環(huán)境相關(guān)的先天性免疫應(yīng)答缺陷的患者，另一種免疫檢測點抑制劑可能有效，比如OX40或ICOS,Lucas CL, et al. Blood.2011;117:5532-5540Twyman-Saint Victor C, et al. Nature. 2015;520:373-377,topalian, Drake, Pardoll, Curr

48、 Opin Immunol 2012,美國FDA批準(zhǔn)的免疫檢測點抑制劑,免疫檢查點及其抗體,腫瘤免疫逃避是腫瘤局部事件 TILs IFN-γ 誘導(dǎo)腫瘤細(xì)胞表達PD-L1免疫檢查點抗體 適用于多種腫瘤 大腫瘤有效 較長的反應(yīng)維持時間 不良反應(yīng)輕,,生存優(yōu)勢能否持續(xù)？,Nivolumab 二線治療肺鱗癌的III期臨床研究CheckMate 017,首要

49、終點：OS（預(yù)設(shè)一次中期分析，中期分析OS邊界為 p<0.03）次要終點：ORR、PFS、安全性、QoL、PD-L1表達與療效的關(guān)系,研究設(shè)計,David R.Spigel, et al. 2015 ASCO, abstract 8009,PD-L1表達量與OS/PFS的關(guān)系,Nivolumab帶來的生存獲益，不依賴于PD-L1表達水平,David R.Spigel, et al. 2015 ASCO, abstract 800

50、9,Nivolumab二線治療非鱗型NSCLC的III期臨床研究CheckMate 057,Luis Paz-Ares, et al. 2015 ASCO, abstract LBA109,患者根據(jù)既往維持治療和治療線數(shù)分層（二線 vs 三線）,研究設(shè)計,0.25,0.5,1.0,2.0,Nivolumab,多西他賽,PD-L1表達量與OS的關(guān)系,Luis Paz-Ares, et al. 2015 ASCO, abstract LBA

51、109,PD-L1的療效預(yù)測指標(biāo)并沒有在鱗癌體現(xiàn)（017研究）而在非鱗癌體現(xiàn)（057）,017研究鱗癌的突變負(fù)荷更多？ - 同樣的藥物，同樣的標(biāo)志物 - 近期/曾經(jīng)吸煙者的比例：017研究-92% 057研究-79% - 057研究：EGFR/ALK突變-19% 免疫系統(tǒng)對鱗狀上皮來源的腫瘤和腺體上皮來源的腫瘤的作用不同？ - 這兩種患者的免疫微環(huán)境可能存在差異

52、- 免疫調(diào)節(jié)機制可能存在差異 cut off值是否正確？ - 1%，5%和10%數(shù)值可能太低,KEYNOTE-001：根據(jù)PD-L1表達的OS,Garon EB, et al. N Engl J Med. 2015,結(jié)論,早期術(shù)后輔助化療：個體化×局部晚期 同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;　ND優(yōu)于DP非鱗癌 分子靶向治療：EGFR