晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较培训课件

1、晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙三十年来晚期非小细胞肺癌的治疗成果I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30for patients independent of histology200920082007199819951990s1970s1950s

2、MST (months)BSCCis monotherapyPt/VP-16Pt/DocPt/PacPt/GemPt/NVB10.9 (GC) v. 12.6, HR=0.84 JMDB Adeno.Cis/PemNon-squamousPac/Cb/Avastin10.3 v. 12.3, HR=0.79 20.4 v. 17.6NVB/Cis/Erbitux10.1 v. 11.3, HR=0.87113.1 v. 13.6, HR=0.9317.4 v. 28.2, HR=0.46Gem/Cis/AvastinEGFR-TKIs12.5 v. 18.1, HR=0.66All Adeno

3、. 13.6 v. 27.2, HR=0.48Mutations 15.6 v. 29.2, HR=0.48ex19ChemotherapyTargeted TherapyCM Tsai 2009晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较2三十年来晚期非小细胞肺癌的治疗成果I I Tumour cellproliferationPI3KMAPKTumour cellsurvivalAktmTORSTAT 3/5Grb-2RasRafMEKATPAnti-EGFR AbsCetuximab, Panitumumab, Matuzumab, h-R3, MDX-44

4、7Anti-HER1,HER2,HER4 TKIsGefitinib, Erlotinib, BIBW-2992, PKI-166, GW-572016, CI-1033, AEE788RAS farnesyltransferase inhibitorsMMS214662, R115777, SCH66336RAF inhibitorsSorafenib, L-779450MEK inhibitorsCI-1040, U-0126mTOR inhibitorsTemsirolimus, RAD001IIIIIIATPSOSSmall molecule tyrosine kinase inhib

5、itors表皮生长因子受体讯息传递的生物标记与抑制剂 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较3Tumour cellPI3KMAPKTumour cell肺腺癌的表皮生长因子受体突变 Response Rate vs. Clinical BackgroundClinical Background vs. EGFR MutationsEGFR mutation (%)RR (%)AsianNon-AsianFemaleMaleNeverEverAdenoNon-AdenoAsianNon-AsianFemaleMaleNeverEverAdenoNon-Ade

6、noMitsudomi, IJCO, 2006晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较4肺腺癌的表皮生长因子受体突变 Response Rate vT854AE884KL747SD761Y敏感性突变Sharma, et al.Nat Rev Cancer 2007生长因子受体易瑞沙与特罗凯的敏感性突变抗药性突变晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较5T854AE884KL747SD761Y敏感性突变Sharm 100 55 125 288 283 104 102 TAX317 TAX320 JMEI IDEAL1 IDEAL

7、2 29Gefitinib7.66.566.858.611.818.4Gefitinib35 100 55 125 288 283 104 102 TAX317 TAX320 JMEI IDEAL1 IDEAL2 2231BSCErlotinib4.76.728538.9 100 55 125 288 283 104 102 563 1126 243 488 TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21 2127BSCGefitinib5.15.632488HR= 0.89P= 0.0870.70 0.00127601040428 100 55 125

8、288 283 TAX317 TAX320 JMEI 1930293230BSCDocetaxelDocetaxelPemetrexed4.67.975.78.31-yr Survival (%) MS (m) DCR (%)0481201020304047.363.446.653.154.1015304560759.18.86.75.8Docetaxel 70 80 14 4711760271040428非小细胞肺癌的救援性治疗 Comparison of Docetaxel, Pemetrexed & EGFR-TKIsGefitinib晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治

9、疗易瑞沙和特罗凯的比较6 100 55 12BR.21 versus ISEL 以安慰剂为对照组的研究Favours EGFR TKIFavours placeboHR0.400.600.801.001.20特罗凯 Erlotinib (BR.21)130% reduction in risk of deathp=0.001易瑞沙 Gefitinib (ISEL)211% reduction in risk of deathNot significant1Shepherd FA, et al. N Engl J Med 2005;353:123322Thatcher N, et al. Lan

10、cet 2005;366:152737晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较7BR.21 versus ISEL 以安慰剂为对照组的研究何以易瑞沙失败 ? BR21 vs ISEL病人选择与纳入条件Criteria for inclusion in ISEL and BR21 clinical trialsISEL: development of progressive disease within 90 days of the preceding round of chemotherapy (early relapse)BR21: no selection

11、 for early relapse晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较8何以易瑞沙失败 ? BR21 vs ISEL病人选择与纳入 100 55 125 288 283 104 102 TAX317 TAX320 JMEI IDEAL1 IDEAL2 29Gefitinib7.66.566.858.611.818.4Gefitinib35 100 55 125 288 283 104 102 TAX317 TAX320 JMEI IDEAL1 IDEAL2 2231BSCErlotinib4.76.728538.9 100 55 125 288 283

12、104 102 563 1126 243 488 TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21 2127BSCGefitinib5.15.632488HR= 0.89P= 0.0870.70 85% inhibition at 2 MIdentification 3 compoundsCL-387,785; EKB-569; CI-1033Determine IC50Measure EGFRAutophos inhibitionAmbit BiosciencesCompound IC50 (M)CI-10330.023EKB-569 0.033CL-38

13、7,7850.051 SU-114640.450 ZD64741.900 GW5720163.500 Gefitinib6.600 PKI-1667.700 Erlotinib10.000Inhibition of H1975 cell proliferation克服T790M抗药性药物之研究 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较23Screen 47 known kinase inhibitIncidence of AEs (%)*Erlotinib (n=485)Gefitinib (n=1,126)AllGrade 3+AllGrade 3+Rash

14、769372Diarrhea556273Nausea403171Anorexia699172Vomiting253141Dry skin120110易瑞沙与特罗凯：副作用表列 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较24Incidence of AEs (%)*Erlotinib易瑞沙与特罗凯做为晚期非小细胞肺癌后线治疗的比较 逆溯性配对研究Sungkyunkwan University, School of MedicineSamsung Medical CenterMyung-Ju Ahn, M.D.晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易

15、瑞沙和特罗凯的比较25易瑞沙与特罗凯做为晚期非小细胞肺癌Sungkyunkwan CharacteristicsGefitinib (N=174)Erlotinib (N=174)P-valueAgeMedian (Range)58.0 (25.0-87.0)59.0 (20.0-82.0) 60 years100100NA 60 years7474SexMale111111NAFemale6363ECOG0-1116116NA 25858Histology Adenocarcinoma125125NANon-adenoca.4949No of prior chemo2145145NA 2 2

16、/18 2nd stage: additional 25 pts方 法 RANDOMIZATIONGefitinib250mg/d Q4wKsErlotinib150mg/d Q4wksREEVALUAT IONREEVALUAT IONUntilDisease progression orIntolerable toxicities4 weeks8 weeksAt least 2 of 3 Adenoca. Female Never smokerorEGFR mutant晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较29研究图示方 法 RANDOMIGefitin

17、ibErl病患基本资料 Characteristics All (n=96, %)Gefitinib(n=48, %)Erlotinib(n=48, %)P valueAge (yrs)MedianRange 5932-836037-835632-810.161Sex MaleFemale 14 (14.6)82 (85.4)7 (14.6)41 (85.4)7 (14.6)41 (85.4)1.000ECOG PS1282 (85.4)14 (14.6)41 (85.4)7 (14.6)41 (85.4)7 (14.6)1.000Stage IIIBIVRecurred12 (12.5)69

18、 (71.9)13 (13.5)7 (14.6)35 (72.9)6 (12.5)5 (10.4)34 (70.8)7 (14.6)0.489HistologyAdenocarcinomaSquamousOthers87 (90.6)6 (6.3)3 (3.1)44 (91.7)3 (6.3)1 (2.1)43 (89.6)3 (6.3)2 (4.1)0.798Prior treatmentNeoadjuvant CCRTAdjuvant CCRTAdjuvant ChemoDefinitive CCRTPlatinum Chemo2 (2.1)3 (3.1)5 (5.2)3 (3.1)93

19、(96.9)1 (2.1)2 (4.2)2 (4.2)2 (4.2)45 (93.8)1 (2.1)1 (2.1)3 (6.3)1 (2.1)48 (100)0.078SmokingEver-smokerNever-smoker6 (6.2)90 (93.7)4 (8.3)44 (91.7)2 (4.2)46 (95.8)0.512EGFR mutationEGFR mutationWild typeNot tested17 (17.7)23 (24.0)56 (58.3)9 (18.8)8 (16.7)31 (64.6)8 (16.7)15 (31.3)25 (52.1)0.243晚期非小细

20、胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较30病患基本资料 Characteristics All GefNumbers of treatment cycles : median 5 (range, 0.5-20), total 605 cyclesGefitinib group: median 6 (range, 0.5-19), total 331 cyclesErlotinib group: median 4 (range, 0.5-20), total 274 cyclesGefitinib Erlotinib P valueN (n=48)%N (n=48)%C

21、R12.112.10.942PR2245.81837.5SD1225.01327.1PD1225.01531.3NE12.112.1ORR2347.9 (33.8-62.0)1939.6 (25.8-53.4)0.411DCR3572.9 (60.3-85.4)3266.7 (53.4-80.0)0.505肿瘤反应 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较31Numbers of treatment cycles : 整体与无恶化存活曲线Median follow-up duration: 11.5 months (range, 6.7-20.8)Median

22、 (95% CI)20.4 months (8.8-32.0)4.8 months (2.7-6.9)GefitinibErlotinibPFS by Treatment P=0.167Median PFS (95% CI)4.9 months (1.5-8.3)3.1 months (0.0-6.4)OS and PFSOSPFS晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较32整体与无恶化存活曲线Median follow-up dur毒性副作用 GefitinibErlotinib Toxicity gradeToxicity grade123Total123

23、Total P valueSkin rash25 (52.1)4 (8.3)1 (2.1)30 (62.5)14 (29.2)16 (33.3)5 (10.4)35 (72.9)0.003Dry skin8 (16.7)0 (0)-8 (16.7)9 (18.8)1 (2.1)-10 (20.9)0.733Paronychia4 (8.3)1 (2.1)-5 (10.4)4 (8.3)0 (0)-4 (8.3)0.767Diarrhea8 (16.7)8 (16.7)-16 (33.4)14 (29.2)3 (6.3)-17 (35.5)0.238Mucositis1 (2.1)2 (4.2)

24、-3 (6.3)4 (8.3)1 (2.1)-5 (10.4)0.300Fatigue0 (0)0 (0)-0 (0)5 (10.4)3 (3.1)-8 (16.7)0.027Anorexia7 (14.6)0 (0)-7 (14.6)4 (8.3)1 (2.1)-5 (10.4)0.587Alopecia3 (6.3)-3 (6.3)1 (2.1)-1 (2.1)0.463Neuropathy2 (4.2)2 (4.2)-4 (8.4)3 (6.3)0 (0)-3 (6.3)0.414Infection-1 (2.1)1 (2.1)-1 (2.1)1 (2.1)1.000ILD- Excep

25、t 3 mortalities from pneumonia. (2 of gefitinib and 1 of erlotinib)晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较33毒性副作用 GefitinibErlotinib 表皮生长因子受体突变患者的临床后果非小细胞肺癌患者接受表皮生长因子受体酪氨酸抑制剂或化疗的集体分析L Paz-Ares, et al. ESMO/ECCO Berlin 2009J Cell Mol Med 2010 14:51-69 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较34表皮生长因子受体突变患者

26、的晚期非小细胞肺癌表皮生长因子受体酪论文搜集策略摘要 Reports identified from broad literature search (n=564)Studies retained for full paper review (n=175)Studies identified from ASCO 20089 search (+n=42)Excluded based on abstract or title: no clinical data related to question (- n=431)Excluded (n=121) PFS/TTP/n not reported

27、for pts with mutations (n=96) EGFR-TKIs given sequentially or as maintenance or adjuvant therapy (n=10) Data duplicated in another publication (n=15)Studies included (n=54)晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较35论文搜集策略摘要 Reports identified fr资料搜集策略摘要ErlotinibGefitinibChemotherapyPts treated in any li

28、ne; n3651,069375Pts treatedin first-line setting57%57%95%Total number of patients = 1,809(65% treated in first-line setting)晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较36资料搜集策略摘要ErlotinibGefitinibChem个别研究之疾病无恶化期 90% accuracy intervals (any line of therapy)ErlotinibGefitinibChemotherapy晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制

29、剂的最佳治疗易瑞沙和特罗凯的比较37个别研究之疾病无恶化期 90% accuracy inte晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较培训课件SATURN 研究設計 Stratification factors:EGFR IHC (positive vs negative vs indeterminate)Stage (IIIB vs IV)ECOG PS (0 vs 1)CT regimen (cis/gem vs carbo/doc vs others)Smoking history (current vs former vs never)Region1:

30、1Chemonave advanced NSCLCn=1,949Non-PDn=8894 cycles of 1st-line platinum-based doublet*PlaceboPDErlotinib150mg/dayPDMandatory tumour sampling*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxelE

31、GFR = epidermal growth factor receptor; IHC = immunohistochemistryCo-primary endpoints:PFS in all patientsPFS in patients with EGFR IHC+ tumoursSecondary endpoints:Overall survival (OS) in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time

32、 to symptom progression; quality of life (QoL)晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较39SATURN 研究設計 Stratification fa晚期非小细胞肺癌含铂两药方案后以易瑞沙治疗或持续化疗之随机第三相研究: WJTOG试验结果 LBA#8012晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较40晚期非小细胞肺癌含铂两药方案后以易瑞沙治疗或持续化疗之随机第全 部 肺腺癌 WJTOG 0203 - OS晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较41全

33、 部 肺腺癌 WJTOG 0203 - OS晚期非小细胞肺非鳞状细胞癌 SATURN - OS全 部 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较42非鳞状细胞癌 SATURN - OS全 部 晚期非小细胞肺癌WJTOG0203: 整体存活依临床特质之亚群分析晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较43WJTOG0203: 整体存活依临床特质之亚群分析晚期非0.40.60.81.01.2FavourserlotinibFavoursplaceboHRMaleFemaleCaucasianAsianAdenocarcinomaSqu

34、amous-cellNever smokerFormer smokerCurrent smokerHR (95% CI)n0.88 (0.741.05)6590.64 (0.460.91)2300.86 (0.731.01)7460.66 (0.421.05)1310.77 (0.610.97)4030.86 (0.681.10)3600.69 (0.451.05)1520.75 (0.561.00)2440.88 (0.721.08)493All0.81 (0.700.95)889SATURN: 整体存活依临床特质之亚群分析晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯

35、的比较440.40.60.81.01.2FavourserlotinSATURN: 疾病无恶化期 (野生型 vs.鳞状细胞癌 )Log-rank p=0.0148HR=0.76 (0.600.95)鳞状细胞癌 1.00.80.60.40.20Time (weeks)0 8 16 24 32 40 48 56 64 72 80 88Erlotinib (n=166)Placebo (n=193)PFS probabilityLog-rank p=0.0185HR=0.78 (0.630.96)1.00.80.60.40.20Time (weeks)Erlotinib (n=199)Placebo

36、 (n=189)0 8 16 24 32 40 48 56 64 72 80 88 96EGFR 野生型 晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较45SATURN: 疾病无恶化期 (野生型 vs.鳞状细胞癌 台湾晚期非小细胞肺癌易瑞沙与特罗凯的比较 多中心逆溯型研究胸腔醫學會 2009 北榮 范紋健Total:1122Female45%Never/light smoker53%Adenocarcinoma77%Stage IV79%Chemo-naive41%GefitinibErlotinib*PN715407ORR34.4%35.6%0.68DCR58.9%65.6%0.02PFS3.6 m4.6 m* Erlotinib group: more male, smoker and non-adeno.晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙和特罗凯的比较46台湾晚期非小细胞肺癌易瑞沙与特罗凯的比较胸腔醫學會 200一非小细胞肺癌具有表皮生长因子受体突变*并合并脑膜转移病例以高剂量易瑞沙治疗的反应与抗药性 Pasi A. Janne and Bruce E. Johnson JCO 200612/200409/2004*Exon 19 deletio