NCCN NSCLC指南解读和治疗模式

1、NCCN NSCLC指南解读和治疗模式2009 NCCN指南在术后NSCLC辅助治疗方面的更改2008版2009版术后化疗方案长春瑞滨+顺铂，VP16+顺铂，VDS+顺铂；其余可接受方案包括：健择+顺铂、多西他赛+顺铂未有变化术后化疗方案（对于有合并症、不能耐受顺铂的患者）健择+卡铂、紫杉醇+卡铂、多西他赛+卡铂、多西他赛+健择紫杉醇+卡铂近年非小细胞肺癌辅助化疗的临床随机对照研究研究分期MSTP5-年生存率HRIALT1（铂类为基础的化疗 vs 观察）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（长春瑞滨+顺铂 vs观察）IB，II94月vs 73 月0.0469%54%HR: 0.69 ；95% CI: 0.52 - 0.91CALGB 96333（紫杉醇+卡铂 vs观察）IB95月vs 78 月0.3759%57%HR: 0.80；95% CI: 0.60 1.07ANITA4（长春瑞滨+顺铂 vs观察）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目前取得阳性结果的有关辅助化疗随机临床试验较多采用长春瑞滨+顺铂方案，而健择+顺铂、多西他赛+顺铂用于术后辅助化疗的临床研究不多见。虽然循证医学的证据提示这三个方案均可用于晚期NSCLC的一线治疗，但是在术后辅助化疗中的作用是否一致还缺乏强有力的证据，这点在大肠癌的辅助治疗中有过先例。我们还需要更多的循证医学根据来证明这一点。2009NCCN指南在局部晚期NSCLC的治疗方面的更改2008版2009版顺铂+VP16同步放化疗后后加多西他赛巩固化疗3类共识基本不变2009 NCCN指南在晚期N

4、SCLC一线治疗方面的更改2008版2009版一线治疗：PS0-1分的患者标准含铂两药方案或贝伐单抗+化疗，对于有EGFR突变或扩增，不吸烟的患者，可以考虑Tarceva + 化疗增加的内容：“西妥昔单抗顺铂长春瑞滨”或“培美曲塞+顺铂”一线治疗：PS2分的患者推荐化疗除化疗外，“西妥昔单抗顺铂长春瑞滨”可以作为一个选择维持治疗无力比泰+顺铂对于非鳞癌的患者可以作为治疗的一种选择一线治疗：有 KRAS突变的患者无不建议厄罗替尼治疗Flex 西妥西单抗联合顺铂/长春瑞滨(CV)与单用CV一线治疗晚期非小细胞肺癌的随机,多中心的III期临床研究NSCLC湿性b/表达EGFR化疗 +C-225化疗C

5、-225 直到PD 或不能耐受毒性化疗C-225顺铂 80mg/m2 D1初始剂量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: 总体生存期CT, chemotherapy; HR, hazard ratio; OS, overall survivalcetuximab联合一线化疗治疗NSCLC可能的预测指标标记物背景KRASKRAS 是cetuximab治疗结肠癌时预测疗效的有效指标1,2 EGFR 基因拷贝数(FISH)对于结肠癌与肺癌来说，基因拷贝数越高，疗效越好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 评价野生型突变型Total39532081%7519%CT + cetuximab19916181%3819%CT19615981%3719%CT, chemotherapy35% 的ITT 治疗人群可评价 KRAS 突变情况KRAS 突变分析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 突变分析: OS突变情况治疗情况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 突变分析: OSKRAS 突变分析: PFS 与 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突变情况治疗情况CI, confidence interval; CT, chemo

11、therapy; HR, hazard ratio; OS, overall survivalEGFR 基因拷贝数: FISH 分析CT, chemotherapy FISH evaluable FISH -FISH +Total27917763%10237%CT + cetuximab1318263%4937%CT1489564%5336%25% 的ITT 人群进行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 情况治疗情况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 与 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 情况治疗情况CI, confidence interval; CT, chemotherapy; HR, hazard ratio; OS, overall survival临床标记物: 第一

15、周期出现皮疹分析Acne-like rash defined by MedDRA guidelines, grading according to NCI-CTC toxicity guidelines定义：痤疮样皮疹，在第1-21天出现第21天时所有患者存活单化疗组很少见出现皮疹(11 例) 第一周期出现皮疹: 化疗 + cetuximab 发生率以及严重程度皮疹无皮疹Any grade (1-3)vsGrade 0n=290 (56%)n=228 (44%)518 (557) 例患者纳入分析第一周期皮疹患者数(%)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)第一周期皮疹与生存: 化疗 + cetuximab患者的一般情况特征Any grade (n=290)%Grade 0 (n=228)%性别女男28723664ECOG PS0/1287138119吸烟情况不吸烟吸烟21792377病理类型腺鳞其他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)第一周期皮疹与生存患者数中位生存期Grade 1-329015.0Gr

18、ade 2-312014.7小结FLEX研究表明，不管何种病理类型， cetuximab联合一线化疗均可带来生存获益目前的资料表明不管KRAS 突变或者EGFR基因拷贝数(FISH) 联合cetuximab可以带来生存获益第一治疗周期出现的皮疹是预测生存期延长(中位生存期为15个月)的临床标记物，但疗效与皮疹严重程度无关培美曲塞的III期随机临床研究-对于非鳞癌有优势JMDB:力比泰/顺铂 Vs.吉西他滨/顺铂一线治疗NSCLC的研究设计随机、III期、非劣效性设计试验随机因素ECOG PS 分期 脑转移史 性别病理学类型(组织学 Vs. 细胞学)两组均接受叶酸、维生素B12以及地塞米松Sca

19、gliotti GV, et al. J Clin Oncol. 2008 (28). 随机分组力比泰(n=862)500 mg/m2 IV 每3周+ 顺铂75 mg/m2 第1天吉西他滨(n=863)1250 mg/m2 第1/8天+顺铂75 mg/m2 第1天主要研究终点：总生存期（） -特定的组织学亚型分析次要研究重点：PFS与缓解率 -报道了毒性分析的比较无疾病进展时间总的生存时间腺癌与大细胞癌患者的PFS腺癌与大细胞癌患者的OSJMDB研究：组织学类型与结果MST，月中位PFS，月缓解率，%力比泰顺铂吉西他滨顺铂Adj. p-value HR (95%CI)力比泰顺铂吉西他滨顺铂Ad

20、j. p-value HR (95%CI)力比泰顺铂吉西他滨顺铂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大细胞癌 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鳞癌 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). *指未明确为腺癌、鳞癌或大细胞癌的患者JMDB研究：基线特征与总生存期所有患者 (N=1722)年龄65岁(n=1116)年龄65岁(n=606)女性 (n=514)男性(n=1208)高加索裔(n=1346)东南亚裔 (n=220)其他种族 (n=156)吸烟(n=1265)不吸烟 (n=250)ECOG PS 0 (n=612)ECOG

22、PS 1(n=1110)组织学确诊(n=1145)细胞学确诊(n=577)IIIB期(n=414)IV期(n=1308)腺癌(n=846)大细胞癌(n=153)鳞癌(n=473)其他组织学类型(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). 结论该研究完成首要研究目的，顺铂/力比泰不劣于健择/顺铂（）2组方案的次要研究目的结果类似亚组分析提示：腺癌与大细胞癌组中，接受顺铂/力比泰治疗的患者生存情况较优（）鳞癌组中，接受顺铂/健择治疗的患者生存情况较优（）延缓进展时间确诊CR/PR/SDPDPD维持治疗新模式确诊CR/PR/SD一线治疗含铂两药化疗 (46 周期)观察并等待PD二线或后续治疗PD维持治疗：NSCLC新的治疗模式维持治疗的理想特征有效延缓疾病进展无威胁生命的不良反应使患者从既往化疗中恢复无影响生活质量的不良反应耐受良好积极的

24、治疗/风险比不影响生活质量使患者如正常人般生活尝试一：继续一线两药化疗药物直到4-6个周期中位周期数(范围)MST，月(范围)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周期后延长化疗将导致毒性累积，但没有确切的疗效(生存)优势尝试二：一线两药化疗药物中某一化疗药物维持治疗T. E. Stinchcombe, and Mark A. Socinski, JTO 2009显著延长PFS但OS的延长没有统计学意义增加了不良反应并影响了生活质量尝试三：二线治疗的化疗药物提前应用多西他赛显著延长PFS但OS的延长达边缘统计学意义，而培美曲赛仅对非鳞癌有意义T. E. Stinchcombe, and Mark A. Socins

26、ki, JTO 2009IIIB/IV期 NSCLCECOG PS 0-1既往4周期健择, 泰索帝, 活泰素 + 顺铂或卡铂, 缓解率为 CR, PR, 或SD随机分层因素: 性别PS分期最佳缓解不含铂药物脑转移*两组均给予B12, 叶酸, 地塞米松双盲, 安慰剂对照, 多中心, III期临床研究首要研究终点= PFS2:1 随机培美曲塞500 mg/m2 (d1,q21d) +最佳支持治疗 (N=441)*安慰剂 (d1, q21d) + 最佳支持治疗 (N=222)*力比泰联合BSC对照安慰剂联合BSC维持治疗的III期临床研究培美曲塞 4.0 月安慰剂 2.0 月无疾病进展生存期(PFS

27、)Progression-free ProbabilityTime (months) HR=0.60 (95% CI: 0.490.73) P 总生存期(意向性治疗人群) 培美曲塞13.4 月安慰剂 10.6 月Survival ProbabilityTime (months) HR=0.79 (95% CI: 0.650.95) P =0.012不同组织学类型的生存期培美曲塞 15.5 月培美曲塞 9.9 月安慰剂10.3 月安慰剂10.8 月非鳞癌 (n=481)鳞癌 (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) 不同组织学类型的PFS培美曲塞 4.4 月培美曲塞2.4 月安慰剂1.8 月安慰剂 2.5 月非鳞癌鳞癌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 这是第一项随机，双盲，安慰剂对照的III期临床研究提示培美曲塞维持治疗可以为晚期NSCLC患者带来生存获益晚期非鳞型NSCLC患者接受培美曲塞疗效较好培美曲塞作为

29、维持治疗耐受性较好，累积毒性不大小结TITAN oroff study(n=889)既往未化疗的IIIB/IV NSCLCn=1,949CR, PR, SD1:14周期一线含铂两药标准化疗*PD安慰剂PDOff study特罗凯150mg/dPDOff study肿瘤样本(强制性)根据EGFR免疫组化蛋白表达分层F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) *含铂方案可以为以下任何之一：紫杉醇，吉西他宾，多西他赛+顺铂或卡铂；长春瑞宾+顺铂主要终点: PFS in all patients PFS in EGF

30、R IHC+SATURN: 不可手术的 NSCLC患者中序贯使用Tarceva的III 期临床研究主要终点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从随机化开始接受维持治疗计算；每6周评估一次F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009

31、(suppl; abstr 8001) 特罗凯n=437安慰剂n=44712周, %534024周, %311736周, %171048周, %13 5Median PFS (wks)12.311.1Mean PFS (wks)22.416.0PFS与随访时间 (ITT)F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) 联合主要终点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从随机化开始接受维持治疗计算；每6周评估一次F. Cappuzzo. et al, J Clin Oncol 27:7s, 2009 (suppl; abstr 8001) PFS probabilityPFS和EGFR状态的关系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：结论特罗凯维持治疗比较安慰剂组：所有患者群都显示临床获益，无论组织学类型，种族或吸烟状态达到了主要终点和联合主要终点，降低了29%疾病进展风险（P18岁IPASS (Iressa Pan-Asian Study) n=608紫杉醇 +卡铂随机化吉非替尼 n=609- 无吸烟者： 100/年支- 少量吸烟者： 10 包/年并且戒烟15年以上 由AstraZeneca资助的亚洲合作研究入组病例目标 N=1212(日本:200, 中国:300, 其他:712)

35、主要终点; PFS非劣效性 优越性无进展生存期（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生物标记物分析的分配比例1038同意提供标本(85%)683提供标本(56%)评价:EGFR 突变: 437 (36%)EGFR 基因拷贝数: 406 (33%)EGFR 表达: 365 (30%)1217 随机的患者 (100%)标本不可用，标本量不够，仅仅细胞学诊断，样本在他处获取样本分析的患者可以代表整体患者人群一般状况 65 yrs 女性 PS 0/1 不吸烟 局部晚期疗效 HR (95% CI) for PFS OR (95% CI) for ORR74.6%76.7%92.

38、0%92.7%19.0%已知EGFR 突变结果(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 表达结果(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-基因拷贝数结果(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%)阳性阴性高低阳性阴性标记物EGFR 突变EGFR-基因拷贝数EGFR 表达 生物标记物可利用的患者情况生物标记物重叠分析3项生物学指标N=3293 项指标均阴性 N=31EGFR 蛋白表达阳性N=242EGFR 突变阳性N=209高EGFR-基因拷贝数=198 3项指标均阳性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 突变阴性a 阳性b Exon

41、 19 deletions Exon 21 L858R Exon 20 T790M Otherc未知dN (% 所有患者)% EGFR 突变阳性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突变情况EGFR突变情况与PFSCox analysis with covariates; HR 1 implies a lower risk of progression on gefitinib; ITT populationEGFR 突变阳性EGF

43、R突变阳性阴性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突变情况未知患者的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 突变

46、情况与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突变阳性EGFR突变阴性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基因拷贝数与PFS高EGFR-基因拷贝数低EGFR-基因拷贝数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基因高拷贝数患者的突变状态与PFSCox analysis with covariates; HR 1 implies a lower risk of progression on gefitinib;Post-hoc analysis in ITT population高EGFR-基因拷贝数,突变阳性高EGFR-基因拷贝数,突变阴性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蛋白表达与PFSEGFR 蛋白表达阳性EGFR蛋白表达阴性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生物标记物与PFSp0.0001 for EGFR mutationTreatment-by-subgroup interaction test p-value已知突变情况EGFR 突变阳性EGFR突变阴性0.51.02.04.0HR (gefitinib vs carboplatin/paclitaxel) and 95% CI0.25低EGFR-基因拷贝已知EGFR-基因拷贝情况高EGFR-基因拷贝p=0.0437 for EGFR-gene-copy numberFavors gefitinibFavors carboplatin/paclitaxelp=0.2135 forEGFR expressionEGFR蛋白表达阳性已知EGFR蛋白表达情况EGFR蛋白表达阴性ITT population; Cox analysis with covariates; HR 1 implies greater chance of response on gefit