NCCN NSCLC指南解讀和治療模式

1、NCCN NSCLC指南解讀和治療模式2009 NCCN指南在術(shù)后NSCLC輔助治療方面的更改2008版2009版術(shù)后化療方案長春瑞濱+順鉑，VP16+順鉑，VDS+順鉑；其余可接受方案包括：健擇+順鉑、多西他賽+順鉑未有變化術(shù)后化療方案（對于有合并癥、不能耐受順鉑的患者）健擇+卡鉑、紫杉醇+卡鉑、多西他賽+卡鉑、多西他賽+健擇紫杉醇+卡鉑近年非小細胞肺癌輔助化療的臨床隨機對照研究研究分期MSTP5-年生存率HRIALT1（鉑類為基礎(chǔ)的化療 vs 觀察）I，II，III50.8 月vs 44.4 月0.0344.5%40.4%HR: 0.86 ；95% CI: 0.76 - 0.98JBR10

2、2（長春瑞濱+順鉑 vs觀察）IB，II94月vs 73 月0.0469%54%HR: 0.69 ；95% CI: 0.52 - 0.91CALGB 96333（紫杉醇+卡鉑 vs觀察）IB95月vs 78 月0.3759%57%HR: 0.80；95% CI: 0.60 1.07ANITA4（長春瑞濱+順鉑 vs觀察）IB，II，IIIA65.7月vs 43.7月0.01751.2%42.6%HR: 0.80 ；95% CI: 0.66 - 0.961. New Engl J Med 2004; 350:351-602. N Engl J Med 2005; 352:2589-973. Pr

3、oc ASCO 2006; 24:3654. Lancet Oncology 2006;7:719-27目前取得陽性結(jié)果的有關(guān)輔助化療隨機臨床試驗較多采用長春瑞濱+順鉑方案，而健擇+順鉑、多西他賽+順鉑用于術(shù)后輔助化療的臨床研究不多見。雖然循證醫(yī)學(xué)的證據(jù)提示這三個方案均可用于晚期NSCLC的一線治療，但是在術(shù)后輔助化療中的作用是否一致還缺乏強有力的證據(jù)，這點在大腸癌的輔助治療中有過先例。我們還需要更多的循證醫(yī)學(xué)根據(jù)來證明這一點。2009NCCN指南在局部晚期NSCLC的治療方面的更改2008版2009版順鉑+VP16同步放化療后后加多西他賽鞏固化療3類共識基本不變2009 NCCN指南在晚期N

4、SCLC一線治療方面的更改2008版2009版一線治療：PS0-1分的患者標(biāo)準(zhǔn)含鉑兩藥方案或貝伐單抗+化療，對于有EGFR突變或擴增，不吸煙的患者，可以考慮Tarceva + 化療增加的內(nèi)容：“西妥昔單抗順鉑長春瑞濱”或“培美曲塞+順鉑”一線治療：PS2分的患者推薦化療除化療外，“西妥昔單抗順鉑長春瑞濱”可以作為一個選擇維持治療無力比泰+順鉑對于非鱗癌的患者可以作為治療的一種選擇一線治療：有 KRAS突變的患者無不建議厄羅替尼治療Flex 西妥西單抗聯(lián)合順鉑/長春瑞濱(CV)與單用CV一線治療晚期非小細胞肺癌的隨機,多中心的III期臨床研究NSCLC濕性b/表達EGFR化療 +C-225化療C

5、-225 直到PD 或不能耐受毒性化療C-225順鉑 80mg/m2 D1初始劑量400mg/m2 D1NVB 25(30)mg/m2 D1,8然后250mg/m2 weeklyEvery 3 weeks, up to 6 cyclesASCO 2008MonthsOverall survival (%)Median OS1-year survivalCT + cetuximab(n=557)11.3 mo47%CT(n=568)10.1 mo42%HR=0.87 (95% CI; 0.761.0) p=0.04Pirker R, et al. Lancet 2009;373: 152531F

6、LEX: 總體生存期CT, chemotherapy; HR, hazard ratio; OS, overall survivalcetuximab聯(lián)合一線化療治療NSCLC可能的預(yù)測指標(biāo)標(biāo)記物背景KRASKRAS 是cetuximab治療結(jié)腸癌時預(yù)測療效的有效指標(biāo)1,2 EGFR 基因拷貝數(shù)(FISH)對于結(jié)腸癌與肺癌來說，基因拷貝數(shù)越高，療效越好3,41Van Cutsem E, et al. N Engl J Med 2009;360:1408-14172Bokemeyer C, et al. J Clin Oncol 2008;27:663-6713Cappuzzo F, et al

7、. Ann Oncol 2008;19:717-723 4Hirsch FR, et al. J Clin Oncol 2008;26:3351-3357 KRAS 評價野生型突變型Total39532081%7519%CT + cetuximab19916181%3819%CT19615981%3719%CT, chemotherapy35% 的ITT 治療人群可評價 KRAS 突變情況KRAS 突變分析MonthsOverall survival (%)KRAS wild typeCT + cetuximab(n=161)CT(n=159)KRAS mutantCT + cetuximab

8、(n=38)CT(n=37)CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survivalKRAS 突變分析: OS突變情況治療情況CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survivalKRAS statusCT + cetuximabCTHR (95% CI)p-valueMedian OSWild type 11.4 mo10.3 mo0.96 (0.751.23)0.75Mutant

9、8.9 mo11.1 mo1.00 (0.601.66)1.00ArmKRASWild typeKRAS MutantHR (95% CI)p-valueMedianOSCT + cetuximab11.4 mo8.9 mo1.06 (0.721.56)0.77CT10.3 mo11.1 mo1.02 (0.681.54)0.91KRAS 突變分析: OSKRAS 突變分析: PFS 與 RRKRAS statusCT + cetuximabCTHR (95% CI)P-valueMedian PFSWild type4.4 mo4.8 mo0.97 (0.761.24)0.80Mutant5

10、.5 mo2.9 mo0.84 (0.501.40)0.50RRWild type37.3%28.3%-0.09Mutant36.8%21.6%-0.15ArmKRASWild typeKRAS MutantHR (95% CI)P-valueMedian PFSCT + cetuximab4.4 mo5.5 mo0.78 (0.521.16)0.21CT4.8 mo2.9 mo1.01 (0.671.53)0.96RRCT + cetuximab37.3%36.8%-0.96CT28.3%21.6%-0.41突變情況治療情況CI, confidence interval; CT, chemo

11、therapy; HR, hazard ratio; OS, overall survivalEGFR 基因拷貝數(shù): FISH 分析CT, chemotherapy FISH evaluable FISH -FISH +Total27917763%10237%CT + cetuximab1318263%4937%CT1489564%5336%25% 的ITT 人群進行FISH 分析CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survivalMonthsOverall survival (%)F

12、ISH +CT + cetuximab (n=49)CT (n=53)FISH CT + cetuximab (n=82)CT (n=95)FISH 分析 : OSFISH 情況治療情況CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survivalFISH statusCT + cetuximabCTHR (95% CI)p-valueMedian OSFISH -10.6 mo10.0 mo0.91 (0.651.26)0.56FISH +11.6 mo9.9 mo0.85 (0.561.29

13、)0.44ArmFISH -FISH +HR (95% CI)p-valueMedian OSCT + cetuximab10.6 mo11.6 mo1.09 (0.741.61)0.66CT10.0 mo9.9 mo1.10 (0.761.58)0.62FISH 分析 : OSFISH 分析: PFS 與 RRFISH statusCT + cetuximabCTHR (95% CI)P-valueMedian PFSFISH -4.2 mo5.2 mo1.05 (0.751.47)0.77FISH +4.2 mo4.4 mo0.80 (0.521.25)0.33RRFISH -32.9%3

14、4.7%-0.80FISH +36.7%26.4%-0.26ArmFISH -FISH +HR (95% CI)P-valueMedian PFSCT + cetuximab4.2 mo4.2 mo1.08 (0.741.59)0.69CT5.2 mo4.4 mo1.54 (1.032.29)0.03RRCT + cetuximab32.9%36.7%-0.66CT34.7%26.4%-0.30FISH 情況治療情況CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survival臨床標(biāo)記物: 第一

15、周期出現(xiàn)皮疹分析Acne-like rash defined by MedDRA guidelines, grading according to NCI-CTC toxicity guidelines定義：痤瘡樣皮疹，在第1-21天出現(xiàn)第21天時所有患者存活單化療組很少見出現(xiàn)皮疹(11 例) 第一周期出現(xiàn)皮疹: 化療 + cetuximab 發(fā)生率以及嚴(yán)重程度皮疹無皮疹A(yù)ny grade (1-3)vsGrade 0n=290 (56%)n=228 (44%)518 (557) 例患者納入分析第一周期皮疹患者數(shù)(%)Grade 0228 (44%)Grade 1170 (33%)Grade

16、2 92 (18%)Grade 3 28 (5%)Grade 4 0 Gatzemeier et al. JTO 2008;3(Suppl. 4):S265 (Abstract 8)第一周期皮疹與生存: 化療 + cetuximab患者的一般情況特征Any grade (n=290)%Grade 0 (n=228)%性別女男28723664ECOG PS0/1287138119吸煙情況不吸煙吸煙21792377病理類型腺鱗其他473023453817分期IIIBIV793694CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Gro

17、up Performance Status Gatzemeier et al. JTO 2008;3(Suppl. 4):S265 (Abstract 8)10.3 months(n=540)CTMonthsOverall survival (%)15.0 months monthsGatzemeier et al. JTO 2008;3(Suppl. 4):S265 (Abstract 8)HR=Any grade: CT + cetuximab (n=290)Grade 0: CT + cetuximab (n=228)第一周期皮疹與生存患者數(shù)中位生存期Grade 1-329015.0Gr

18、ade 2-312014.7小結(jié)FLEX研究表明，不管何種病理類型， cetuximab聯(lián)合一線化療均可帶來生存獲益目前的資料表明不管KRAS 突變或者EGFR基因拷貝數(shù)(FISH) 聯(lián)合cetuximab可以帶來生存獲益第一治療周期出現(xiàn)的皮疹是預(yù)測生存期延長(中位生存期為15個月)的臨床標(biāo)記物，但療效與皮疹嚴(yán)重程度無關(guān)培美曲塞的III期隨機臨床研究-對于非鱗癌有優(yōu)勢JMDB:力比泰/順鉑 Vs.吉西他濱/順鉑一線治療NSCLC的研究設(shè)計隨機、III期、非劣效性設(shè)計試驗隨機因素ECOG PS 分期 腦轉(zhuǎn)移史 性別病理學(xué)類型(組織學(xué) Vs. 細胞學(xué))兩組均接受葉酸、維生素B12以及地塞米松Sca

19、gliotti GV, et al. J Clin Oncol. 2008 (28). 隨機分組力比泰(n=862)500 mg/m2 IV 每3周+ 順鉑75 mg/m2 第1天吉西他濱(n=863)1250 mg/m2 第1/8天+順鉑75 mg/m2 第1天主要研究終點：總生存期（） -特定的組織學(xué)亞型分析次要研究重點：PFS與緩解率 -報道了毒性分析的比較無疾病進展時間總的生存時間腺癌與大細胞癌患者的PFS腺癌與大細胞癌患者的OSJMDB研究：組織學(xué)類型與結(jié)果MST，月中位PFS，月緩解率，%力比泰順鉑吉西他濱順鉑Adj. p-value HR (95%CI)力比泰順鉑吉西他濱順鉑Ad

20、j. p-value HR (95%CI)力比泰順鉑吉西他濱順鉑Adj. p-value 腺癌 n=84712.610.9p=0.0330.84 (0.71, 0.99)5.55.0p=0.1250.90 (0.78, 1.03)31.924.50.024大細胞癌 n=15310.46.7p=0.0270.67 (0.48, 0.96)4.54.2p=0.4990.89 (0.65, 1.24)31.330.90.954其他*n=2528.69.2p=0.5861.08 (0.81, 1.45)4.55.6p=0.0641.28 (0.99, 1.67)33.024.20.156鱗癌 n=47

21、39.410.8p=0.0501.23 (1.00, 1.51)4.45.5p=0.0021.36 (1.12, 1.65)26.936.70.033Scagliotti GV, et al. J Clin Oncol. 2008 (in press). *指未明確為腺癌、鱗癌或大細胞癌的患者JMDB研究：基線特征與總生存期所有患者 (N=1722)年齡65歲(n=1116)年齡65歲(n=606)女性 (n=514)男性(n=1208)高加索裔(n=1346)東南亞裔 (n=220)其他種族 (n=156)吸煙(n=1265)不吸煙 (n=250)ECOG PS 0 (n=612)ECOG

22、PS 1(n=1110)組織學(xué)確診(n=1145)細胞學(xué)確診(n=577)IIIB期(n=414)IV期(n=1308)腺癌(n=846)大細胞癌(n=153)鱗癌(n=473)其他組織學(xué)類型(n=250)Overall Survival Hazard Ratio with 95% CIHazard Ratio 1.081.230.670.840.950.890.990.920.950.911.000.931.340.880.930.980.840.880.970.940.40.60.81.01.21.41.61.82.02.2Favors Cis/PemFavors Cis/GemScagl

23、iotti GV, et al. J Clin Oncol. 2008 (in press). 結(jié)論該研究完成首要研究目的，順鉑/力比泰不劣于健擇/順鉑（）2組方案的次要研究目的結(jié)果類似亞組分析提示：腺癌與大細胞癌組中，接受順鉑/力比泰治療的患者生存情況較優(yōu)（）鱗癌組中，接受順鉑/健擇治療的患者生存情況較優(yōu)（）延緩進展時間確診CR/PR/SDPDPD維持治療新模式確診CR/PR/SD一線治療含鉑兩藥化療 (46 周期)觀察并等待PD二線或后續(xù)治療PD維持治療：NSCLC新的治療模式維持治療的理想特征有效延緩疾病進展無威脅生命的不良反應(yīng)使患者從既往化療中恢復(fù)無影響生活質(zhì)量的不良反應(yīng)耐受良好積極的

24、治療/風(fēng)險比不影響生活質(zhì)量使患者如正常人般生活嘗試一：繼續(xù)一線兩藥化療藥物直到4-6個周期中位周期數(shù)(范圍)MST，月(范圍)Socinski et al, Arm A (standard)4 (06)6.6 (5.49.0)Socinski et al, Arm B (extended)4 (019)8.5 (6.310.3)Park et al, Arm A (2 + 4 cycles)6 (26)14.9 (13.016.8)Park et al, Arm B (2 + 2 cycles)4 (24)15.9 (12.419.4)Socinski MA, et al. J Clin On

25、col 2002;20:13351343.Park JO, et al. J Clin Oncol 2007;25:52335239. 3-4周期后延長化療將導(dǎo)致毒性累積，但沒有確切的療效(生存)優(yōu)勢嘗試二：一線兩藥化療藥物中某一化療藥物維持治療T. E. Stinchcombe, and Mark A. Socinski, JTO 2009顯著延長PFS但OS的延長沒有統(tǒng)計學(xué)意義增加了不良反應(yīng)并影響了生活質(zhì)量嘗試三：二線治療的化療藥物提前應(yīng)用多西他賽顯著延長PFS但OS的延長達邊緣統(tǒng)計學(xué)意義，而培美曲賽僅對非鱗癌有意義T. E. Stinchcombe, and Mark A. Socins

26、ki, JTO 2009IIIB/IV期 NSCLCECOG PS 0-1既往4周期健擇, 泰索帝, 活泰素 + 順鉑或卡鉑, 緩解率為 CR, PR, 或SD隨機分層因素: 性別PS分期最佳緩解不含鉑藥物腦轉(zhuǎn)移*兩組均給予B12, 葉酸, 地塞米松雙盲, 安慰劑對照, 多中心, III期臨床研究首要研究終點= PFS2:1 隨機培美曲塞500 mg/m2 (d1,q21d) +最佳支持治療 (N=441)*安慰劑 (d1, q21d) + 最佳支持治療 (N=222)*力比泰聯(lián)合BSC對照安慰劑聯(lián)合BSC維持治療的III期臨床研究培美曲塞 4.0 月安慰劑 2.0 月無疾病進展生存期(PFS

27、)Progression-free ProbabilityTime (months) HR=0.60 (95% CI: 0.490.73) P 總生存期(意向性治療人群) 培美曲塞13.4 月安慰劑 10.6 月Survival ProbabilityTime (months) HR=0.79 (95% CI: 0.650.95) P =0.012不同組織學(xué)類型的生存期培美曲塞 15.5 月培美曲塞 9.9 月安慰劑10.3 月安慰劑10.8 月非鱗癌 (n=481)鱗癌 (n=182)HR=0.70 (95% CI: 0.56-0.88) P HR=1.07 (95% CI: 0.490.7

28、3) P Survival ProbabilityTime (months) Time (months) 不同組織學(xué)類型的PFS培美曲塞 4.4 月培美曲塞2.4 月安慰劑1.8 月安慰劑 2.5 月非鱗癌鱗癌Time (months) Time (months) Progression-free ProbabilityHR=0.47 (95% CI: 0.37-0.6) P HR=1.03 (95% CI: 0.77-1.5) P 這是第一項隨機，雙盲，安慰劑對照的III期臨床研究提示培美曲塞維持治療可以為晚期NSCLC患者帶來生存獲益晚期非鱗型NSCLC患者接受培美曲塞療效較好培美曲塞作為

29、維持治療耐受性較好，累積毒性不大小結(jié)TITAN oroff study(n=889)既往未化療的IIIB/IV NSCLCn=1,949CR, PR, SD1:14周期一線含鉑兩藥標(biāo)準(zhǔn)化療*PD安慰劑PDOff study特羅凱150mg/dPDOff study腫瘤樣本(強制性)根據(jù)EGFR免疫組化蛋白表達分層F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) *含鉑方案可以為以下任何之一：紫杉醇，吉西他賓，多西他賽+順鉑或卡鉑；長春瑞賓+順鉑主要終點: PFS in all patients PFS in EGF

30、R IHC+SATURN: 不可手術(shù)的 NSCLC患者中序貫使用Tarceva的III 期臨床研究主要終點PFS*: 所有患者 (ITT)PFS probability0081624324048566472808896Time (weeks)HR=0.71 (0.620.82)Erlotinib (n=437)Placebo (n=447)ErlotinibPlaceboPFS at 12 wks (%)5340PFS at 24 wks (%)3117*PFS從隨機化開始接受維持治療計算；每6周評估一次F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009

31、(suppl; abstr 8001) 特羅凱n=437安慰劑n=44712周, %534024周, %311736周, %171048周, %13 5Median PFS (wks)12.311.1Mean PFS (wks)22.416.0PFS與隨訪時間 (ITT)F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) 聯(lián)合主要終點PFS*: IHC+患者0081624324048566472808896Time (weeks)HR=0.69 (0.580.82)Erlotinib (n=307)Placebo (

32、n=311)ErlotinibPlaceboPFS at 12 wks (%)5440PFS at 24 wks (%)3218*PFS從隨機化開始接受維持治療計算；每6周評估一次F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) PFS probabilityPFS和EGFR狀態(tài)的關(guān)系Erlotinib (n=199)Placebo (n=189)PFS probabilityLog-rank p0.0001 HR=0.10 (0.040.25)0Time (weeks)Erlotinib (n=22)Placeb

33、o (n=27)HR=0.78 (0.630.96)0Time (weeks)08162432404856647280 88 9608162432404856647280 88 96EGFR mutation+EGFR wild-typeW. Brugger . et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8020) OS: 所有患者(ITT)0369121518212427303336Time (months)OS probability 0Erlotinib (n=438) Placebo (n=451)HR=0.81 (0.700.95)F

34、. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) SATURN：結(jié)論特羅凱維持治療比較安慰劑組：所有患者群都顯示臨床獲益，無論組織學(xué)類型，種族或吸煙狀態(tài)達到了主要終點和聯(lián)合主要終點，降低了29%疾病進展風(fēng)險（P18歲IPASS (Iressa Pan-Asian Study) n=608紫杉醇 +卡鉑隨機化吉非替尼 n=609- 無吸煙者： 100/年支- 少量吸煙者： 10 包/年并且戒煙15年以上 由AstraZeneca資助的亞洲合作研究入組病例目標(biāo) N=1212(日本:200, 中國:300, 其他:712)

35、主要終點; PFS非劣效性 優(yōu)越性無進展生存期（PFS）609453 (74.4%)608497 (81.7%)NEventsHR (95% CI) = (0.65GefitinibGefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFSPrimary Cox analysis with covariates; HR 1 implies a lower risk of progression on gefitinib; ITT populationPFS, progression-

36、free survival; ITT, intent-to-treat; HR, hazard ratio; CI, confidence interval; C/P, carboplatin/paclitaxelCarboplatin /paclitaxelC/PGefitinibMedian PFS (months)4 months progression-free6 months progression-free12 months progression-free5.761%48%25%5.874%48%7%6092127624506081182231036341204812162024

37、MonthsProbabilityof PFSPatients at risk :Mok et al 2008生物標(biāo)記物分析的分配比例1038同意提供標(biāo)本(85%)683提供標(biāo)本(56%)評價:EGFR 突變: 437 (36%)EGFR 基因拷貝數(shù): 406 (33%)EGFR 表達: 365 (30%)1217 隨機的患者 (100%)標(biāo)本不可用，標(biāo)本量不夠，僅僅細胞學(xué)診斷，樣本在他處獲取樣本分析的患者可以代表整體患者人群一般狀況 65 yrs 女性 PS 0/1 不吸煙 局部晚期療效 HR (95% CI) for PFS OR (95% CI) for ORR74.6%76.7%92.

38、0%92.7%19.0%已知EGFR 突變結(jié)果(N=437)0.85 (0.69, 1.06)1.21 (0.83, 1.78)71.8%78.1%91.5%91.5%18.4%已知EGFR 表達結(jié)果(N=365)0.79 (0.62, 0.99)1.43 (0.94, 2.18)74.6%77.1%92.4%92.4%19.0%已知EGFR-基因拷貝數(shù)結(jié)果(N=406)0.83 (0.66, 1.03)1.31 (0.88, 1.95)73.9%79.3%89.6%93.7%24.2%Overall (N=1217)0.74 (0.65, 0.85)1.59 (1.25, 2.01)HR 1

39、 implies greater chance of response on gefitinibOR, odds ratio; ORR, objective response rateN (% of total known)Carboplatin / paclitaxel129 (60%)85 (40%)125 (62%)76 (38%)134 (74%)46 (26%)Overall261 (60%)176 (40%)249 (61%)157 (39%)266 (73%)99 (27%)Gefitinib132 (59%)91 (41%)124 (60%)81 (40%)132 (71%)5

40、3 (29%)陽性陰性高低陽性陰性標(biāo)記物EGFR 突變EGFR-基因拷貝數(shù)EGFR 表達 生物標(biāo)記物可利用的患者情況生物標(biāo)記物重疊分析3項生物學(xué)指標(biāo)N=3293 項指標(biāo)均陰性 N=31EGFR 蛋白表達陽性N=242EGFR 突變陽性N=209高EGFR-基因拷貝數(shù)=198 3項指標(biāo)均陽性N=132255113281534 85 (14.0) 129 (21.2) 74 57.4 47 36.4 6 4.7 7 5.4 394 (64.8) 91 (14.9) 132 (21.7) 66 50.0 64 48.8 5 3.8 3 2.3386 (63.4)EGFR 突變陰性a 陽性b Exon

41、 19 deletions Exon 21 L858R Exon 20 T790M Otherc未知dN (% 所有患者)% EGFR 突變陽性Gefitinib(n=609)Carboplatin/paclitaxel(n=608)aNo mutation detectedbEleven patients had multiple mutations and are counted more than oncecIncludes 3 patients with exon 18 G719X, 5 with exon 20 S768I, and 2 with exon 21 L861Qd Pat

42、ients without a tumour sample evaluable for EGFR mutation analysis, and samples which were not successfully analysed for EGFR mutation status were classified as unknown.EGFR突變情況EGFR突變情況與PFSCox analysis with covariates; HR 1 implies a lower risk of progression on gefitinib; ITT populationEGFR 突變陽性EGF

43、R突變陽性陰性HR (95% CI) = (0.36No. events gefitinib, 97 (73.5%)No. events C/P, 111 (86.0%)Median PFS G, 9.5 monthsMedian PFS C/P, 6.3 monthsHR (95% CI) = No. events gefitinib , 88 (96.7%)No. events C/P, 70 (82.4%)Median PFS G, 1.5 monthsMedian PFS C/P, 5.5 months1327131113012937721010810304812162024Gefit

44、inibC/PProbability of progression-free survivalPatients at risk :914210085141000215804812162024Probability of progression-free survivalGefitinib (n=91)Carboplatin/paclitaxel (n=85)MonthsMonthsMok et al 2008Gefitinib (n=132)Carboplatin/paclitaxel (n=129)EGFR突變情況未知患者的PFS,%)C/P, 316 (80.2%)Median PFS g

45、efitinib, 6.6 monthsMedian PFS C/P, 5.8 months386137431220394671410023425104812162024MonthsGefitinibC/PProbabilityof PFSPatients at risk :Gefitinib (n= 386)Carboplatin/paclitaxel (n=394)Cox analysis with covariates; HR 1 implies a lower risk of death on gefitinib; ITT populationMok et al 2008EGFR 突變

46、情況與OSProbability of overall survival2824201612840Months2824201612840Months00174173114126132GefitinibPatients at risk: Probability of overall survival01153867105123129C/P0051325446991004924557585HR (95% CI) = 0.78 (0.50, 1.20) No. events gefitinib, 38 (28.8%)No. events C/P, 43 (33.3%)Gefitinib (n=132

47、)Carboplatin/paclitaxel (n=129)HR (95% CI) = 1.38 (0.92, 2.09)No. events gefitinib, 52 (57.1%)No. events C/P, 42 (49.4%)Gefitinib (n=91)Carboplatin/paclitaxel (n=85)EGFR突變陽性EGFR突變陰性Cox analysis with covariates; HR 1 implies a lower risk of death on gefitinib ; ITT populationPost-hoc analysis of over

48、all survival (follow-up ongoing) by EGFR mutation status Mok et al 2008EGFR基因拷貝數(shù)與PFS高EGFR-基因拷貝數(shù)低EGFR-基因拷貝數(shù)HR (95% CI) = No. events gefitinib, 98 (79.0%)No. events C/P, 104 (83.2%)Gefitinib (n=124)Carboplatin/paclitaxel (n=125)Cox analysis with covariates; HR 1 implies a lower risk of progression on

49、gefitinib; ITT populationHR (95% CI) = 1.24No. events gefitinib, 69 (85.2%)No. events C/P, 68 (89.5%)Gefitinib (n=81)Carboplatin/paclitaxel (n=76)04812162024Probability of progression-free survival12453205101253251108795GefitinibC/PAt risk :04812162024Probability of progression-free survival81171062

50、0761831003458MonthsMonthsEGFR基因高拷貝數(shù)患者的突變狀態(tài)與PFSCox analysis with covariates; HR 1 implies a lower risk of progression on gefitinib;Post-hoc analysis in ITT population高EGFR-基因拷貝數(shù),突變陽性高EGFR-基因拷貝數(shù),突變陰性965120510942541108274GefitinibC/PAt risk :26100002950000319Probability of progression-free survival2404

51、8121620Probability of progression-free survival0.80.60.40.20.01.0240481216200.80.60.40.20.01.0HR (95% CI) = 0.48 (0.34, 0.67) No. events gefitinib, 70 (72.9%)No. events C/P, 79 (84.0%)Gefitinib (n=96)Carboplatin/paclitaxel (n=94)HR (95% CI) = 3.85 (2.09, 7.09) No. events gefitinib, 26 (100%)No. even

52、ts C/P, 24 (82.8%)Gefitinib (n=26)Carboplatin/paclitaxel (n=29)MonthsMonthsEGFR蛋白表達與PFSEGFR 蛋白表達陽性EGFR蛋白表達陰性HR (95% CI) = No. events gefitinib, 103 (78.0%)No. events C/P, 115 (85.8%)Gefitinib (n=132)Carboplatin/paclitaxel (n=134)Cox analysis with covariates; HR 1 implies a lower risk of progression

53、on gefitinib; ITT populationNo. events gefitinib, 48 (90.6%)No. events C/P, 43 (93.5%)Gefitinib (n=53)Carboplatin/paclitaxel (n=46)04812162024Probability of progression-free survivalMonths132482593013434521081108GefitinibC/PAt risk :04812162024Probability of progression-free survivalMonths5317620046

54、1320003232生物標(biāo)記物與PFSp0.0001 for EGFR mutationTreatment-by-subgroup interaction test p-value已知突變情況EGFR 突變陽性EGFR突變陰性0.51.02.04.0HR (gefitinib vs carboplatin/paclitaxel) and 95% CI0.25低EGFR-基因拷貝已知EGFR-基因拷貝情況高EGFR-基因拷貝p=0.0437 for EGFR-gene-copy numberFavors gefitinibFavors carboplatin/paclitaxelp=0.2135 forEGFR expressionEGFR蛋白表達陽性已知EGFR蛋白表達情況EGFR蛋白表達陰性ITT population; Cox analysis with covariates; HR 1 implies greater chance of response on gefit