晚期NSCLC整體治療策略revised

1、Any reproduction, adaptation, distribution, dissemination or making available of such copyright works to the public is strictly prohibited 健擇在中國(guó)批準(zhǔn)的適應(yīng)癥為： 局部晚期或已轉(zhuǎn)移的非小細(xì)胞肺癌 局部晚期或已轉(zhuǎn)移的胰腺癌 與紫杉醇聯(lián)合，可用于治療經(jīng)輔助/新輔助化療后復(fù)發(fā)，不能切除的、局部復(fù)發(fā)或轉(zhuǎn)移新乳腺癌 力比泰在中國(guó)批準(zhǔn)的適應(yīng)癥為：聯(lián)合順鉑用于治療不可手術(shù)的惡性胸膜間皮瘤 宋宋 勇勇南京軍區(qū)南京總醫(yī)院肺癌中心南京軍區(qū)南京總醫(yī)院肺癌中心晚期晚期NSCLC

2、的整體治療策略的整體治療策略Where Are We?Azzoli CG, et al. J Clin Oncol 2009; 27(36): 6251-66.吉非替尼吉非替尼吉非替尼吉非替尼History of Therapy in Advanced NSCLC First-lineSecond-lineThird-lineNot approvedMedianoverallsurvival,months12+810624Best supportive careSingle-agent platinumDoubletsTriplets FDA Approval重要的重要的NSCLC一線臨床試驗(yàn)

3、一線臨床試驗(yàn)含鉑兩藥方含鉑兩藥方案案臨床試驗(yàn)臨床試驗(yàn)治療方案治療方案中位中位OS （月）（月）(95% CI)中位中位TTP （月）（月）(95% CI)ILCP(Scagliotti 20021)吉西他濱+順鉑紫杉醇+卡鉑長(zhǎng)春瑞濱+順鉑 9.8 10.0 9.5 5.3 5.5 4.6 TAX 326 (Fossella 20032)多西他賽+順鉑長(zhǎng)春瑞濱+順鉑多西他賽+卡鉑11.3 10.1 9.4 5.1 5.4 4.7 SWOG 9509(Kelly 20013)長(zhǎng)春瑞濱+順鉑紫杉醇+卡鉑8.1 8.6 4.0*4.0*FACS(Ohe 20074)伊力替康+順鉑紫杉醇+卡鉑吉西他濱+

4、順鉑長(zhǎng)春瑞濱+順鉑13.912.314.011.44.74.54.04.1* PFS值. 非鱗癌=腺癌+大細(xì)胞癌+其他. 95% CI沒(méi)有報(bào)道. 原來(lái)報(bào)道的是周，月是按照周7/30計(jì)算的。1.Scagliotti GV, et al. J Clin Oncol. 2002;20:4285-4291.2.Fossella F, et al. J Clin Oncol. 2003;21:3016-3024. 3.Kelly K, et al. J Clin Oncol. 2001;19:3210-3218.4.Ohe Y, et al. Ann Oncol. 2007; 18: 317-323.化

5、療療效達(dá)到平臺(tái)化療療效達(dá)到平臺(tái)ECOG 1594藥物藥物ORRmOS mTTP順鉑/紫杉醇217.8m3.4m順鉑/吉西他濱228.1m4.2m順鉑/多西他賽177.4m3.7m卡鉑/紫杉醇17%8.1m3.1mECOG 1594 Schiller JH et al. N Engl J Med 2002;346:92-8.突破雙藥化療療效的瓶頸突破雙藥化療療效的瓶頸Right Drug, Right Time, Right Patient聯(lián)合治療聯(lián)合治療? 三藥聯(lián)合化療 化療聯(lián)合靶向治療: 抗VEGF, 抗EGFR單抗個(gè)體化選擇個(gè)體化選擇? 臨床因素 分子/藥物基因組學(xué)方法續(xù)貫續(xù)貫? 化療與靶

6、向藥物順序我們的探索我們的探索增加化療藥物沒(méi)有提高療效增加化療藥物沒(méi)有提高療效, 毒性加重毒性加重Delbaldo C, et al. JAMA 2004 4項(xiàng)期臨床研究顯示厄洛替尼或吉非替尼聯(lián)合化療與單用化療相比，均未有額外臨床獲益化療聯(lián)合小分子化療聯(lián)合小分子TKI?臨床研究臨床研究入組人數(shù)入組人數(shù)研究分組研究分組PFS/TTP(m)mST(m)INTACT 11093順鉑+健擇+吉非替尼 500 mg/d順鉑+健擇+吉非替尼 250 mg/d順鉑+健擇+安慰劑5.55.86.09.99.910.9INTACT 21097卡鉑+紫杉醇+吉非替尼 500 mg/d卡鉑+紫杉醇+吉非替尼 250

7、 mg/d卡鉑+紫杉醇+安慰劑4.65.35.08.79.89.9TRIBUTE1059組1:卡鉑+紫杉醇+厄洛替尼 150 mg/d組2: 卡鉑+紫杉醇+安慰劑6周后組1用厄洛替尼，組2用安慰劑維持治療5.14.910.610.5TALENT1172順鉑+健擇+厄洛替尼 150 mg/d順鉑+健擇+安慰劑66.210.811Giaccone G, et al. J Clin Oncol 2004; 22(5): 77784. Herbst RS, et al. J Clin Oncol 2004; 22(5): 78594. Herbst RS, et al. J Clin Oncol 20

8、05; 23(25): 58929.Park JO, et al. J Clin Oncol 2007; 25(12): 154552. 亞洲厄洛替尼與化療序貫一線治療的研究亞洲厄洛替尼與化療序貫一線治療的研究: FAST-ACTPlaceboTarceva 150mg/dayPreviously untreated stage IIIb/IV NSCLC (n=150)R11PDSix cycles gemcitabine + cisplatin OR carboplatin + placeboSix cycles gemcitabine + cisplatin OR carboplatin

9、 + Tarceva starting on day 15PDStratified by centre, stage, histology, smoking statusTreatmentPost-treatmentScreeningPost-studyGemcitabine 1250mg/m2 (d1,8); cisplatin 75mg/m2 OR carboplatin 5AUC (d1); Tarceva 150mg/day (d1527)Primary end point: Non progression rate (CR+PR+SD16 wks)Asian patientsonly

10、MO18633Secondary endpoints:RR + duration; TTP; PFS; OS; safety Fully recruitedFAST-ACT: PFS31.3 wksGC-Tarceva23.7 wksGC-PlaceboMedian PFSLog-rank test p=0.01751.00.80.60.40.2002468 10 12 14 1618 20 22 24 26 28 30 32 34 36Time (weeks)38 40 42 44 46 48 50 52 54 56 5876 74 73 73 65 62 60 59 59 53 51 51

11、 47 38 37 33 27 17 1578 77 77 76 67 60 58 57 51 44 43 42 35 25 24 22 16 8713 11 109866631054211111110No. at riskTarcevaPlacebo23.731.3HR=0.57 (95% CI: 0.380.84)Lee JS, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I):431s (Abs. 8031)JMDB: 培美曲塞培美曲塞/順鉑順鉑 vs. 吉西他濱吉西他濱/順鉑順鉑Scagliotti et al J Clin Oncol 2008順

12、鉑 75 mg/m2 D1+吉西他濱 1250 mg/m2 D1&8隨機(jī)因素 分期 體力狀態(tài)性別 組織學(xué)vs.細(xì)胞學(xué)診斷腦轉(zhuǎn)移史R順鉑75 mg/m2 D1+培美曲塞500 mg/m2 D1兩組均接受維生素B12，葉酸和地塞米松補(bǔ)充給藥l 預(yù)先設(shè)定的亞組分析：隨機(jī)因素以及年齡、種族、吸煙狀態(tài)與組織學(xué)類(lèi)型主要終點(diǎn)：總生存期15% 非劣效性上限 (HR 1.17)Q3w, 最多6周期RRPFSOS1YSR2YSR31%4.810.344%19%28%5.110.342%14%HR1.04(0.94, 1.15)0.94(0.84, 1.05)培美曲塞在培美曲塞在PFS, OS均達(dá)到非劣效均

13、達(dá)到非劣效JMDB: 組織學(xué)類(lèi)型與總生存期的前瞻性分析組織學(xué)類(lèi)型與總生存期的前瞻性分析* 非鱗癌包括腺癌、大細(xì)胞癌和其他/未確定的NSCLC組織學(xué)類(lèi)型非鱗癌* (n=1252)培美曲塞+順鉑中位生存11.0月吉西他濱+順鉑中位生存10.1月HR=0.844(95% CI: 0.740.96) p=0.011 生存時(shí)間 (月)生存概率鱗癌 (n=473)HR=1.229(95% CI: 1.001.51)p=0.051 生存時(shí)間 (月)培美曲塞+順鉑中位生存9.4月吉西他濱+順鉑中位生存10.8月生存概率Ciuleanu et al ASCO 2008 Abstract 8011Scagliot

14、ti et al. J Clin Oncol 2008 第一個(gè)NSCLC預(yù)設(shè)不同組織學(xué)亞型的前瞻性III期臨床試驗(yàn) JMDB證實(shí)培美曲塞/順鉑在非鱗癌中的療效顯著優(yōu)于鱗癌 首個(gè)以NSCLC組織學(xué)亞型適應(yīng)癥進(jìn)入NCCN指南的藥物一線化療一線化療(+抗抗VEGF)：非鱗癌：非鱗癌紫杉醇紫杉醇/卡鉑卡鉑貝伐單抗貝伐單抗 (E4599)Sandler A, et al. NEJM 355:2542-50, 2006020406080100Patients with PFS, %Carboplatin/paclitaxelCarbo/paclitaxel + bevacizumab06121824303

15、6(m)Treatment groupHazard ratio = 0.62, P 0.0001Median PFS: 6.4 vs 4.5 monthsPFS at 6 months: 55% vs 33%PFS at 1 year: 15% vs 6%Progression-Free Survival061218243036020406080100Hazard ratio = 0.77, P = 0.007Median surv.: 12.5 vs 10.2mo.Survival at 1 year: 52% vs 44%Survival at 2 years: 22% vs 17%Pat

16、ients surviving, %Overall Survival Response rate: 15% for CbP vs 35% for CbP+ B Tx-related death: 0.5% for CbP vs 1.9% for CbP+B(m)一線化療一線化療(+抗抗VEGF)：非鱗癌：非鱗癌吉西他濱吉西他濱/順鉑順鉑貝伐單抗貝伐單抗 (AVAiL)1.00.80.60.40.20.01.00.80.60.40.20.006121839151.00.80.60.40.20.01.00.80.60.40.20.006121839151.00.80.60.40.20.01.00.

17、80.40.20.0012183915CG + Bevacizumab 7.5 mg/kgCG + Placebo PFSGC vs B(7.5)0612183915CG + Bevacizumab 15 mg/kgCG + Placebo PFSGC vs B(15)GC+PlaceboGC+ B (7.5)GC + B (15)PFS6.1m6.7m6.5mHR=0.750.62-0.91; P=0.003HR=0.820.68-0.98; P=0.03OS13.1m13.6m13.4mHR=0.930.78-1.11; P=0.42HR=0.930.86-1.23; P=0.76RR20

18、.1%34.1% (P28.0Sequist34EGFR mutationIGefitinib559.217.5Yang55EGFR mutationIGefitinib69824Sugio20EGFR mutationI/IIGefitinib63.27.120Sunaga21EGFR mutationI/IIGefitinib7612.9Not reachedSutani38EGFR mutationI/IIGefitinib789.415.4Yoshida27EGFR mutationI/IIGefitinib90.57.7Not reachedHan17EGFR mutationI/I

19、I+Gefitinib64.721.730.5Tamura28EGFR mutationI/II/IIIGefitinib7511.5Not reached選擇性人群選擇性人群: 一線使用一線使用TKI帶來(lái)獲益帶來(lái)獲益1. Mok et al 2008 ASCO; 2. Lee et al 2009 WCLC; 3.Kobayashi et al 2009 ASCO; 4.Tsurutani et al 2009 ESMO+:直到腫瘤進(jìn)展；直到腫瘤進(jìn)展；#最多最多9 周期周期; &:最多最多6周期周期NEJ002 (日本日本)3未未經(jīng)經(jīng)化化療療 EGFR 突突變變 ECOG PS 01

20、吉非替尼吉非替尼250mg/d卡卡鉑鉑 AUC 6 紫杉醇紫杉醇 200 mg/m2 每每3周周*主要主要終終點(diǎn)點(diǎn)PFS (優(yōu)優(yōu)效性效性)次要次要終終點(diǎn)點(diǎn)OS, ORR, QoL, 疾病相關(guān)癥狀，安全性和耐受性疾病相關(guān)癥狀，安全性和耐受性吉非替尼吉非替尼250 mg/d吉西他吉西他濱濱1250mg/m2 順鉑順鉑 80 mg/m2每每3周周#主要主要終終點(diǎn)點(diǎn)OS次要次要終終點(diǎn)點(diǎn)PFS, ORR, QoL, 疾病相關(guān)癥狀，安全性和耐受性疾病相關(guān)癥狀，安全性和耐受性First-SIGNAL (韓國(guó)韓國(guó))2未未經(jīng)經(jīng)化化療療 腺癌且非吸煙腺癌且非吸煙 ECOG PS 02吉非替尼吉非替尼250 mg/

21、d多西他多西他賽賽60 mg/m2 順鉑順鉑 80 mg/m2每每3周周&主要主要終終點(diǎn)點(diǎn)PFS次要次要終終點(diǎn)點(diǎn)OS, ORR, QoL, 疾病相關(guān)癥狀，安全性和耐受性疾病相關(guān)癥狀，安全性和耐受性WJOG3405 (日本日本)4未未經(jīng)經(jīng)化化療療 EGFR 突突變變 ECOG PS 01吉非替尼吉非替尼250 mg/d紫杉醇紫杉醇200mg/m2 卡卡鉑鉑 AUC=5/6每每3周周#主要主要終終點(diǎn)點(diǎn)PFS次要次要終終點(diǎn)點(diǎn)OS, ORR, QoL, 疾病相關(guān)癥狀，安全性和耐受性疾病相關(guān)癥狀，安全性和耐受性IPASS (亞洲亞洲)1未未經(jīng)經(jīng)化化療療 腺癌且非腺癌且非/輕輕度吸煙度吸煙 ECO

22、G PS 02EGFR突變患者突變患者: 吉非替尼改善吉非替尼改善PFSIPASSWJTOG 3405NEJGCG 002First-SignalHR (95%CI)= 0.613 (0.308 1.221)P=0.084(log rank)Progression-free survival0.20.40.60.81.01020304050吉非替尼一線治療并未改善吉非替尼一線治療并未改善OSIPASSWJTOG 3405NEJGCG 002(月)HR=1.00395% CI: 0.7491.343P=0.428Probability of survivalFirst-Signal吉非替尼吉非替

23、尼卡鉑卡鉑/紫杉醇紫杉醇PHR95%CI全組全組 (N)609608中位中位OS (月月)18.817.40.1090.9010.793-1.023EGFR M+ (N)132129中位中位OS (月月)21.621.90.9901.0020.756-1.328EGFR M- (N)9185中位中位OS (月月)11.212.70.3091.1810.857-1.628EGFR M未知未知386394中位中位OS (月月)18.917.20.0150.8180.696-0.962IPASS的更新數(shù)據(jù)的更新數(shù)據(jù): OS最終結(jié)果沒(méi)有顯著獲益最終結(jié)果沒(méi)有顯著獲益EGFR M+ is prognost

24、icEGFR M+ is predictive of PFS not OSYang et al, ESMO 2010EURTC: 厄羅替尼一線治療厄羅替尼一線治療EGFR mut NSCLCPhase III study initiated by the Spanish Lung Cancer Group (GECP)Recruitment ongoing in Spain, Italy and FrancePrimary endpoint: PFSSecondary endpoints: ORR, 1-year survival, OS, safety, QoL, localisation

25、of PDErlotinib 150mg/dayuntil PDChemonave advanced NSCLC EGFR mutation-positive (exon 19 or L858R) ECOG PS 02 n150Platinum-based doublet chemotherapyRORR = objective response rate; QoL = quality of lifeOPTIMAL: 厄羅替尼一線治療厄羅替尼一線治療EGFR mut NSCLCPrimary endpoint: PFSSecondary endpoints: ORR, OS, QoL and

26、safetyPhase III study initiated by Tongji University, Shanghai, ChinaRecruitment in ChinaErlotinib 150mg/dayuntil PDChemonave advanced NSCLCl EGFR mutation-positive (exon 19 or 21) l ECOG PS 02 l n150Gemcitabine (1,000 mg/m2, IV, d1 and d8) plus carboplatin (AUC=5, IV d1) repeated every 3 weeks up t

27、o 4 cyclesRgem/carb = gemcitabine/carboplatin; AUC = area under curve Zhou et al: LBA 4799OPTIMAL: 主要終點(diǎn)主要終點(diǎn)PFSZhou C, et al. Ann Oncol 2010; 21(S8):viii1-viii12. LBA13.Wu YL, et al. Ann Oncol 2010; 21(S8):viii1-viii12. LBA14.E(n=82)GC(n=72)PCR/PR (%)2/810/36ORR (%)83360.0001SD (%)1346DCR (%)96820.00

28、2PD (%)417中位PFS (月)13.14.60.00011.00.80.60.40.2005101520時(shí)間時(shí)間 (月月)PFS概率概率4.613.1厄洛替尼厄洛替尼 (n=82)吉西他濱卡鉑吉西他濱卡鉑 (n=72)HR=0.16 (0.10-0.26)Log-rank p0.0001OPTIMAL：PFS的亞組分析的亞組分析OverallNo prior treatmentStage IV Stage IIIBFemaleMaleAge 65Age 65PS 01PS 2Never smokerCurrent/former smokerAdenocarcinomaNon-adeno

29、carcinomaExon 19 deletionsL858R00.51.01.50.16 (0.100.26)1540.22 (0.140.35)0.18 (0.110.28)138 0.27 (0.061.16)160.13 (0.070.24)910.26 (0.140.50)630.17 (0.070.43)380.19 (0.110.31)1160.16 (0.100.26)1440.21 (0.041.28)100.14 (0.080.25)1090.21 (0.090.49)450.17 (0.110.28)1340.22 (0.060.73)200.13 (0.070.25)8

30、20.26 (0.140.49)72HR (95% Cl)nHRFavours erlotinibFavours gem/carboAuthorStudyN (EGFR mut +)RR (TKI vs Chemo)PFS(mo)HR, (95%CI)Mok et alIPASS26171.2% vs 47.3%9.50.48 (0.36, 0.64)Mitsudomi WJTOG 340519862.1% vs 32.2%9.20.49 (0.34, 0.71)Kobayashi NEJGSG00217774.5% vs 29%10.50.36 (0.25, 0.51)Zhoa et alO

31、PTIMAL15083 % vs 36%13.10.16 (0.100.26)RosellEURTAC178ASCO 2011隨機(jī)研究支持隨機(jī)研究支持TKI一線治療一線治療EGFR突變?nèi)巳和蛔內(nèi)巳篍GFR狀態(tài)未知的患者如何選擇狀態(tài)未知的患者如何選擇: TORCH厄厄洛替尼洛替尼150mg/d,至至PD順鉑80mg/m2 D1吉西他濱1200mg/m2D1/8, q3w, 6個(gè)周期順順鉑鉑+吉西他濱吉西他濱順鉑順鉑80mg/m2 D1吉西他濱吉西他濱1200mg/m2D1/8, q3w, 6個(gè)個(gè)周期周期厄洛替尼150mg/d 細(xì)胞學(xué)或組織學(xué)確診的IIIB*與IV期NSCLC ECOG PS 0-

32、1 分層因素 組織學(xué) 吸煙狀態(tài) 性別 國(guó)家 年齡 種族 既往未用化療(既往輔助化療可入組，但需不含吉西他濱方案且一年后復(fù)發(fā))RPDPD*鎖骨上淋巴結(jié)轉(zhuǎn)移或胸腔積液首要研究終點(diǎn): OS (非劣效性)TORCH: 未經(jīng)選擇的患者一線使用未經(jīng)選擇的患者一線使用TKI有害有害Patients at risk Standard38022610834111 Experimental 38019788341642PatientsEventsMedian OSMonths (95% CI)Standard 38018912.0 (10.3 14.8)Experimental3802268.5 (7.2 10.

33、5)Hazard Ratio 1.36 (95%CI 1.12 1.65)Log-rank test p = 0.002 IPASS及及First-SIGNAL研究研究EGFR突變陰性的患者，一線需選化療突變陰性的患者，一線需選化療Mok et al, N Engl J Med 2009; 361(3): 947-57.WCLC 2009 Lee et al., Abstract # PRS.4一線進(jìn)展以后的選擇一線進(jìn)展以后的選擇: 新的治療模式新的治療模式DiagnosisCR/PR/SDFirst-line treatmentPlatinum doublet chemotherapy(46

34、 cycles)Watch and waitPDSecond and further lines of treatmentPDIncreased time to PDDiagnosisCR/PR/SDPDPDMaintenance therapyNew approachHistorical approach為什么要維持為什么要維持?0255075100Fidias et al. 200910Scagliotti et al. 20089Pirker et al. 20088Ciuleanu et al. 20087Park et al. 20076Barata et al. 20075von

35、Plessen et al. 20064Brodowicz et al. 20063Belani et al. 20032Socinski et al. 20021接受二線治療的患者比例 (%)3或4周期紫杉醇、長(zhǎng)春瑞濱、吉西他濱或多西他賽治療后，PFS顯著延長(zhǎng)，但OS無(wú)顯著獲益Soon et al. ASCO 2008 abst 8013; Soon et al J Clin Oncol 20091J Clin Oncol 2002; 2J Clin Oncol 2003; 3Lung Cancer 2006; 4Br J Cancer 2006; 5J Thoracic Oncol 200

36、7; Abs. P2-235;6J Clin Oncol 2007;7J Clin Oncol 2008 Abs. 8011; 8J Clin Oncol 2008; Abs. 3; 9J Clin Oncol 2008; 10J Clin Oncol 2009約50%的患者一線治療進(jìn)展后不接受二線治療化療藥物維持化療藥物維持: JMEN / 培美曲塞培美曲塞ProbabilityTime (months)PFS(n=581)OS(n=663)Time (months)036912151821242730036912151821241.00.80.60.40.201.00.80.60.40.2

37、0Pemetrexed (n=153)Placebo (n=156)HR=0.60 (0.490.73)p0.00001HR=0.79 (0.650.95)p=0.012Ciuleanu T, et al. Lancet 374: 1432-40, 2009JMEN: 培美曲塞不同組織學(xué)類(lèi)型的差異培美曲塞不同組織學(xué)類(lèi)型的差異PemPlaceboPost-therapy52% (Pem, 15)67% (Pem, 19%)HR (95%CI) & P-valueProgression-free Survival (PFS)4.0m2.0m0.60(0.49-0.73); p0.0001N

38、on-Sq4.4m1.8m0.47(0.37-0.60); p0.00001Sq2.4m2.5m 1.03(0.71-1.49); p=0.896Overall Survival (OS)13.4m10.6m0.79(0.65-0.95); p=0.012Non-Sq15.5m 10.3m 0.70(0.56-0.88); p=0.002Sq9.9m 10.8m 1.07(0.49-1.50); p=0.678Ciuleanu T, et al. Lancet 374: 1432-40, 2009靶向藥物維持靶向藥物維持: SATURN / 厄羅替尼厄羅替尼Cappuzzo et al. La

39、ncet Oncology 2010ProbabilityTime (weeks)PFSOS0816 24 32 40 48 56 64 72 80 88 96Time (weeks)0816 24 32 40 48 56 64 72 80 88 96Erlotinib (n=438) Placebo (n=451)Erlotinib (n=437) Placebo (n=447)HR=0.71 (0.620.82)Log-rank p0.0001HR=0.81 (0.700.95)Log-rank p=0.00881.00.80.60.40.201.00.80.60.40.20SATURN:

40、 EGFR突變狀態(tài)分析突變狀態(tài)分析Cappuzzo F, et al. ASCO 2009. Abstract 8001. Brugger W, et al. ASCO 2009. Abstract 8020.WksPatients Without Progression (%)WksPatients Without Progression (%)PFS: Wild-Type EGFRPFS: Mutated EGFRHR: 0.78P = .0185HR: 0.10P .000102040608010008162432404856640204060801000816243240485664E

41、rlotinib (n = 22) Placebo (n = 27) Erlotinib (n = 199) Placebo (n = 189) ReferencenTherapyPrimary end-pointPFS (HR)OS (HR)Fidias1309DocetaxelOSNRNRCiuleanu2663PemetrexedPFS0.600.79Belani3255GemcitabineOS1.090.97Cappuzzo4889ErlotinibPFS0.710.81Miller5768Erlotinib + bevacizumabPFS0.720.92Prol6464Erlot

42、inib vs gemcitabinePFS0.820.550.910.86Takeda7604GefitinibOS0.680.86是否需要維持治療是否需要維持治療? - 近期近期III期臨床試驗(yàn)期臨床試驗(yàn) - 1. Fidias, et al. JCO 2004; 2. Ciuleanu, et al. Lancet Oncol 2009; 3. Belani et al. ASCO 20104. Cappuzzo, et al. Lancet Oncol 2010; 5. Miller, et al. ASCO 20096. Prol, et al. ASCO 2010; 7. Take

43、da, et al. JCO 2010NR = not reported化療藥物作為維持治療的薈萃分析化療藥物作為維持治療的薈萃分析維持化療在一定程度上延長(zhǎng)了生存期維持化療在一定程度上延長(zhǎng)了生存期(HR 0.92；95% CI，0.86-0.99；P =0.03)同樣維持化療明顯延長(zhǎng)同樣維持化療明顯延長(zhǎng)PFS(HR 0.75；95% CI，0.69-0.81；P=0.00001)Soon YY et al, J Clin Oncol 2009; 27(20): 3277-83NSCLC的二、三線治療的二、三線治療細(xì)胞毒藥物的細(xì)胞毒藥物的III期臨床研究期臨床研究作者分組生存期無(wú)進(jìn)展生存期總生存

44、期Shepherd最佳支持治療1.5m4.6m(TAX317) 1多西他賽 (75mg/m2100mg/m2)2.4m7.0m (7.5/5.9)Fossella(TAX329) 2長(zhǎng)春瑞濱或異環(huán)磷酰胺1.8m5.6m多西他賽 (75mg/m2)2.0m5.7m多西他賽 (75mg/m2)1.9m5.5mHanna 3多西他賽 (100mg/m2)多西他賽 (75mg/m2)2.9m7.9m培美曲塞 (100mg/m2)2.9m8.3mRamlau 4多西他賽 (75mg/m2)3.0m7.1m拓?fù)涮婵?(口服)2.6m6.4mBonomi 5多西他賽 (75mg/m2)-6.9m聚谷氨酸紫杉

45、醇-6.9mKrzakowski 6多西他賽 (75mg/m2)2.3m7.2m長(zhǎng)春氟寧2.3m6.7m1 JCO 18:2085-103,2000; 2 JCO 18:2354-62,2000; 3 JCO 22:1589-97,2004; 4 JCO 24:2800-7,2006; 5 Lung Cancer 49: s35, 2005; 6 ASCO2007(#7511)NSCLC的二、三線治療的二、三線治療JMEI: 二線化療二線化療 培美曲塞培美曲塞 vs. 多西他賽多西他賽Hanna N, et al. JCO 22: 1589-97, 2004 & Scagliotti

46、G, Oncologist 14: 253-63, 2009III或IV期NSCLCl 既往僅接受一種方案化療l 既往化療不含培美曲塞或多西他賽l ECOG PS 0-2l 足夠的器官功能l 無(wú)大于3度外周血中性粒細(xì)胞減少 (總生存期，主要終點(diǎn)非劣效)隨機(jī)化培美曲塞 500 mg/m2 D1N=283多西他賽 75 mg/m2 D1N=288q3w培美曲塞多西他賽HR (95%CI) & P-value緩解率 (ORR)9.1%8.8%NS非鱗癌11.5%9.0%鱗癌2.8%8.1%無(wú)進(jìn)展生存期 (PFS)2.9m2.9m0.97 (0.82-1.16); p=0.759非鱗癌3.1m

47、3.0m0.82 (0.66-1.02); p=0.076鱗癌2.3m2.7m1.40 (1.01-1.96); p=0.046總體生存期 (OS)8.3m7.9m0.99 (0.80-1.20); p=0.226非鱗癌9.3m8.0m0.78 (0.61-1.00); p=0.048鱗癌6.2m7.4m1.56 (1.08-2.26); p=0.018NSCLC的二、三線治療的二、三線治療 (EGFR-TKIs)III期臨床研究：期臨床研究：EGFR-TKI (EGFR未選擇人群未選擇人群)吉非替尼厄洛替尼試驗(yàn)主要終點(diǎn)試驗(yàn)主要終點(diǎn)vs 安慰劑 ISEL1總體生存期(陰性)(*無(wú)進(jìn)展生存期，延

48、長(zhǎng))BR212總生存期(陽(yáng)性)vs 多西他賽V15-323總體生存期(非劣性，陰性)(*無(wú)進(jìn)展生存期，非劣于)INTEREST4 總體生存期(非劣效，陽(yáng)性)ISTANA5無(wú)進(jìn)展生存期(陽(yáng)性)1 Lancet 366: 1527-37, 2005; 2 NEJM 353: 123-32, 2005; 3 J Clin Oncol 26: 4244-52, 2008; 4 Lancet 372: 1809-18, 2008;5 J Clin Oncol 26: 430s (ASCO#8025), 2008BR. 21: 厄羅替尼厄羅替尼 vs. 安慰劑安慰劑Survival distributio

49、n function(months)ErlotinibPlacebo1.000.750.500.25005101520253031%21%(Shepherd FA, et al. NEJM 353; 123-132, 2005)Erlotinib(n=488)Ad, 50%Placebo(n=243)Ad, 49%HR & p-valueORR8.2%1.0%P0.001PFS2.2m1.8m0.61(0.51-0.74); P0.001OS6.7m4.7m0.70(0.58-0.85); P0.0016.7m4.7mISEL: 吉非替尼吉非替尼 vs. 安慰劑安慰劑 024810121416(months)At risk:169213478774852521043