晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較培訓(xùn)課件

1、晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙三十年來(lái)晚期非小細(xì)胞肺癌的治療成果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晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較2三十年來(lái)晚期非小細(xì)胞肺癌的治療成果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表皮生長(zhǎng)因子受體訊息傳遞的生物標(biāo)記與抑制劑 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較3Tumour cellPI3KMAPKTumour cell肺腺癌的表皮生長(zhǎng)因子受體突變 Response Rate vs. Clinical BackgroundClinical Background vs. EGFR MutationsEGFR mutation (%)RR (%)AsianNon-AsianFemaleMaleNeverEverAdenoNon-AdenoAsianNon-AsianFemaleMaleNeverEverAdenoNon-Ade

6、noMitsudomi, IJCO, 2006晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較4肺腺癌的表皮生長(zhǎng)因子受體突變 Response Rate vT854AE884KL747SD761Y敏感性突變Sharma, et al.Nat Rev Cancer 2007生長(zhǎng)因子受體易瑞沙與特羅凱的敏感性突變抗藥性突變晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較5T854AE884KL747SD761Y敏感性突變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非小細(xì)胞肺癌的救援性治療 Comparison of Docetaxel, Pemetrexed & EGFR-TKIsGefitinib晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治

9、療易瑞沙和特羅凱的比較6 100 55 12BR.21 versus ISEL 以安慰劑為對(duì)照組的研究Favours EGFR TKIFavours placeboHR0.400.600.801.001.20特羅凱 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晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較7BR.21 versus ISEL 以安慰劑為對(duì)照組的研究何以易瑞沙失敗 ? BR21 vs ISEL病人選擇與納入條件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晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較8何以易瑞沙失敗 ? BR21 vs ISEL病人選擇與納入 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抗藥性藥物之研究 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較23Screen 47 known kinase inhibitIncidence of AEs (%)*Erlotinib (n=485)Gefitinib (n=1,126)AllGrade 3+AllGrade 3+Rash

14、769372Diarrhea556273Nausea403171Anorexia699172Vomiting253141Dry skin120110易瑞沙與特羅凱：副作用表列 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較24Incidence of AEs (%)*Erlotinib易瑞沙與特羅凱做為晚期非小細(xì)胞肺癌后線治療的比較 逆溯性配對(duì)研究Sungkyunkwan University, School of MedicineSamsung Medical CenterMyung-Ju Ahn, M.D.晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易

15、瑞沙和特羅凱的比較25易瑞沙與特羅凱做為晚期非小細(xì)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晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較29研究圖示方 法 RANDOMIGefitin

17、ibErl病患基本資料 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晚期非小細(xì)

20、胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較30病患基本資料 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腫瘤反應(yīng) 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較31Numbers of treatment cycles : 整體與無(wú)惡化存活曲線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晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較32整體與無(wú)惡化存活曲線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)晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較33毒性副作用 GefitinibErlotinib 表皮生長(zhǎng)因子受體突變患者的臨床后果非小細(xì)胞肺癌患者接受表皮生長(zhǎng)因子受體酪氨酸抑制劑或化療的集體分析L Paz-Ares, et al. ESMO/ECCO Berlin 2009J Cell Mol Med 2010 14:51-69 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較34表皮生長(zhǎng)因子受體突變患者

26、的晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪論文搜集策略摘要 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)晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較35論文搜集策略摘要 Reports identified fr資料搜集策略摘要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)晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較36資料搜集策略摘要ErlotinibGefitinibChem個(gè)別研究之疾病無(wú)惡化期 90% accuracy intervals (any line of therapy)ErlotinibGefitinibChemotherapy晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制

29、劑的最佳治療易瑞沙和特羅凱的比較37個(gè)別研究之疾病無(wú)惡化期 90% accuracy inte晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較培訓(xùn)課件SATURN 研究設(shè)計(jì) 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)晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較39SATURN 研究設(shè)計(jì) Stratification fa晚期非小細(xì)胞肺癌含鉑兩藥方案后以易瑞沙治療或持續(xù)化療之隨機(jī)第三相研究: WJTOG試驗(yàn)結(jié)果 LBA#8012晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較40晚期非小細(xì)胞肺癌含鉑兩藥方案后以易瑞沙治療或持續(xù)化療之隨機(jī)第全 部 肺腺癌 WJTOG 0203 - OS晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較41全

33、 部 肺腺癌 WJTOG 0203 - OS晚期非小細(xì)胞肺非鱗狀細(xì)胞癌 SATURN - OS全 部 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較42非鱗狀細(xì)胞癌 SATURN - OS全 部 晚期非小細(xì)胞肺癌WJTOG0203: 整體存活依臨床特質(zhì)之亞群分析晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較43WJTOG0203: 整體存活依臨床特質(zhì)之亞群分析晚期非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: 整體存活依臨床特質(zhì)之亞群分析晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱

35、的比較440.40.60.81.01.2FavourserlotinSATURN: 疾病無(wú)惡化期 (野生型 vs.鱗狀細(xì)胞癌 )Log-rank p=0.0148HR=0.76 (0.600.95)鱗狀細(xì)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 晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較45SATURN: 疾病無(wú)惡化期 (野生型 vs.鱗狀細(xì)胞癌 臺(tái)灣晚期非小細(xì)胞肺癌易瑞沙與特羅凱的比較 多中心逆溯型研究胸腔醫(yī)學(xué)會(huì) 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.晚期非小細(xì)胞肺癌表皮生長(zhǎng)因子受體酪氨酸抑制劑的最佳治療易瑞沙和特羅凱的比較46臺(tái)灣晚期非小細(xì)胞肺癌易瑞沙與特羅凱的比較胸腔醫(yī)學(xué)會(huì) 200一非小細(xì)胞肺癌具有表皮生長(zhǎng)因子受體突變*并合并腦膜轉(zhuǎn)移病例以高劑量易瑞沙治療的反應(yīng)與抗藥性 Pasi A. Janne and Bruce E. Johnson JCO 200612/200409/2004*Exon 19 deletio