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-易瑞沙與特羅凱的比較培訓(xùn)課件

1、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 histology200920082007199819951990s1970s1950sMST (months)BSCCis monotherapyPt/VP-16Pt/DocPt/PacPt/GemPt/NVB10.9

2、(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. 13.6 v. 27.2, HR=0.48Mutations 15.6 v. 29.2, HR=0.48ex19Chemother

3、apyTargeted TherapyCM Tsai 2009三十年來(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-447Anti-HER1,HER2,HER4 TKIsGefitinib, Erlotinib, BIBW-2992, PKI-166, GW-572016, CI-1033, AEE788RAS farnesyl

4、transferase inhibitorsMMS214662, R115777, SCH66336RAF inhibitorsSorafenib, L-779450MEK inhibitorsCI-1040, U-0126mTOR inhibitorsTemsirolimus, RAD001IIIIIIATPSOSSmall molecule tyrosine kinase inhibitors表皮生長(zhǎng)因子受體訊息傳遞的生物標(biāo)記與抑制劑 Tumour cellPI3KMAPKTumour cell肺腺癌的表皮生長(zhǎng)因子受體突變 Response Rate vs. Clinical Backgr

5、oundClinical Background vs. EGFR MutationsEGFR mutation (%)RR (%)AsianNon-AsianFemaleMaleNeverEverAdenoNon-AdenoAsianNon-AsianFemaleMaleNeverEverAdenoNon-AdenoMitsudomi, IJCO, 2006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T854AE88

6、4KL747SD761Y敏感性突變Sharm 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 55 125 288 283 104 102 563 1126 243 488 TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL

7、BR21 2127BSCGefitinib5.15.632488HR= 0.89P= 0.0870.70 0.00127601040428 100 55 125 288 283 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 C

8、omparison of Docetaxel, Pemetrexed & EGFR-TKIsGefitinib 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

9、J Med 2005;353:123322Thatcher N, et al. Lancet 2005;366:152737BR.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 sele

10、ction for early relapse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 55 125 288 283 104 102 563 1126 243 488 TAX317 T

11、AX320 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-387,7850.051 SU-114640.450 ZD64741.

12、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 Screen 47 known kinase inhibitIncidence of AEs (%)*Erlotinib (n=485)Gefitinib (n=1,126)AllGrade 3+AllGrade 3+Rash769372Diarrhea556273Nausea403171Anorexia699172Vomiting253141Dry skin1201

13、10易瑞沙與特羅凱：副作用表列 Incidence of AEs (%)*Erlotinib易瑞沙與特羅凱做為晚期非小細(xì)胞肺癌后線(xiàn)治療的比較 逆溯性配對(duì)研究Sungkyunkwan University, School of MedicineSamsung Medical CenterMyung-Ju Ahn, M.D.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

14、years100100NA 60 years7474SexMale111111NAFemale6363ECOG0-1116116NA 25858Histology Adenocarcinoma125125NANon-adenoca.4949No of prior chemo2145145NA 2 2/18 2nd stage: additional 25 pts方 法 RANDOMIZATIONGefitinib250mg/d Q4wKsErlotinib150mg/d Q4wksREEVALUAT IONREEVALUAT IONUntilDisease progression orInto

15、lerable toxicities4 weeks8 weeksAt least 2 of 3 Adenoca. Female Never smokerorEGFR mutant研究圖示方 法 RANDOMIGefitinibErl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)

16、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 (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 t

17、reatmentNeoadjuvant CCRTAdjuvant CCRTAdjuvant ChemoDefinitive CCRTPlatinum Chemo2 (2.1)3 (3.1)5 (5.2)3 (3.1)93 (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 muta

18、tionWild 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,

19、 0.5-20), total 274 cyclesGefitinib Erlotinib P valueN (n=48)%N (n=48)%CR12.112.10.942PR2245.81837.5SD1225.01327.1PD1225.01531.3NE12.112.1ORR2347.9 (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) Numbers of treatment cycles : 整體與無(wú)惡化存活曲線(xiàn)Median follow-up duration: 11

20、.5 months (range, 6.7-20.8)Median (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整體與無(wú)惡化存活曲線(xiàn)Median follow-up dur毒性副作用 GefitinibErlotinib Toxicity gradeToxicity grade123Total123Total

21、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)-3 (6.

22、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- Except 3 mo

23、rtalities from pneumonia. (2 of gefitinib and 1 of erlotinib)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 表皮生長(zhǎng)因子受體突變患者的論文搜集策略摘要 Reports identified from broad literature search (n=564)Studies retained fo

24、r 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 for pts with mutations (n=96) EGFR-TKIs given sequentially or as maintenance or adjuvant therapy (n=1

25、0) Data duplicated in another publication (n=15)Studies included (n=54)論文搜集策略摘要 Reports identified fr資料搜集策略摘要ErlotinibGefitinibChemotherapyPts treated in any line; n3651,069375Pts treatedin first-line setting57%57%95%Total number of patients = 1,809(65% treated in first-line setting)資料搜集策略摘要Erlotini

26、bGefitinibChem個(gè)別研究之疾病無(wú)惡化期 90% accuracy intervals (any line of therapy)ErlotinibGefitinibChemotherapy個(gè)別研究之疾病無(wú)惡化期 90% accuracy inte Pooled median PFS(95% accuracy interval) 13.2 (12.014.7)9.8 (9.210.4)5.9 (5.36.5)Permutation test for estimated pooled median PFS (1,000 iterations)EGFR TKI vs chemothera

27、py p=0.000 (two-sided)Erlotinib N = 365 (2/12)Gefitinib N = 1069 (19/39)Chemotherapy N = 375Pooled studies表皮生長(zhǎng)因子受體突變陽(yáng)性各種治療療效 Pooled median PFS(95% accuraSATURN 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/d

28、oc vs others)Smoking history (current vs former vs never)Region1:1Chemonave 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; carbo

29、platin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxelEGFR = 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,

30、 OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL)SATURN 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全 部 肺腺癌 WJTOG 0203 - OS非鱗狀細(xì)胞癌 SATURN - OS全 部 非鱗狀細(xì)胞癌 S

31、ATURN - OS全 部 WJTOG0203: 整體存活依臨床特質(zhì)之亞群分析WJTOG0203: 整體存活依臨床特質(zhì)之亞群分析0.40.60.81.01.2FavourserlotinibFavoursplaceboHRMaleFemaleCaucasianAsianAdenocarcinomaSquamous-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)

32、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0.40.60.81.01.2FavourserlotinSATURN: 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)Plac

33、ebo (n=193)PFS probabilityLog-rank p=0.0185HR=0.78 (0.630.96)1.00.80.60.40.20Time (weeks)Erlotinib (n=199)Placebo (n=189)0 8 16 24 32 40 48 56 64 72 80 88 96EGFR 野生型 SATURN: 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 an