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-易瑞沙与特罗凯的比较培训课件

1、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 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-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表皮生长因子受体讯息传递的生物标记与抑制剂 Tumour cellPI3KMAPKTumour cell肺腺癌的表皮生长因子受体突变 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T854AE88

6、4KL747SD761Y敏感性突变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非小细胞肺癌的救援性治疗 C

8、omparison of Docetaxel, Pemetrexed & EGFR-TKIsGefitinib 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

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

10、ction for early relapse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 55 125 288 283 104 102 563 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抗药性药物之研究 Screen 47 known kinase inhibitIncidence of AEs (%)*Erlotinib (n=485)Gefitinib (n=1,126)AllGrade 3+AllGrade 3+Rash769372Diarrhea556273Nausea403171Anorexia699172Vomiting253141Dry skin1201

13、10易瑞沙与特罗凯：副作用表列 Incidence 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.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

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研究图示方 法 RANDOMIGefitinibErl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)

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,

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肿瘤反应 Numbers of treatment cycles : 整体与无恶化存活曲线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整体与无恶化存活曲线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 表皮生长因子受体突变患者的论文搜集策略摘要 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)论文搜集策略摘要 Reports identified fr资料搜集策略摘要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)资料搜集策略摘要Erlotini

26、bGefitinibChem个别研究之疾病无恶化期 90% accuracy intervals (any line of therapy)ErlotinibGefitinibChemotherapy个别研究之疾病无恶化期 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表皮生长因子受体突变阳性各种治疗疗效 Pooled median PFS(95% accuraSATURN 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/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全 部 肺腺癌 WJTOG 0203 - OS非鳞状细胞癌 SATURN - OS全 部 非鳞状细胞癌 S

31、ATURN - OS全 部 WJTOG0203: 整体存活依临床特质之亚群分析WJTOG0203: 整体存活依临床特质之亚群分析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: 整体存活依临床特质之亚群分析0.40.60.81.01.2FavourserlotinSATURN: 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)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 an