1、非小细胞肺癌的标靶非小细胞肺癌的标靶治疗治疗主要癌症每十萬人口死亡數非小细胞肺癌的标靶治疗2Fry WA,et al.Cancer.1996;77:1953.非小细胞肺癌的标靶治疗3Early stageLocally advancedMetastasticSurgeryCT+surgeryCT+RTCCRTSurgery+CTCTTargetIa,IbIIa,IIbIIIaIIIb no cy+effusionIIIb cy+effusionIV curative intentpalliative intentmetastasectomy非小细胞肺癌的标靶治疗4Thorax.58(4):35
2、2-6,2003 Apr.非小细胞肺癌的标靶治疗5Thorax.58(4):352-6,2003 Apr.非小细胞肺癌的标靶治疗6Thorax.58(4):352-6,2003 Apr.ASCO.NSCLC treatment guideline,2003非小细胞肺癌的标靶治疗7Thorax.58(4):352-6,2003 Apr.非小细胞肺癌的标靶治疗8非小细胞肺癌的标靶治疗9非小细胞肺癌的标靶治疗10非小细胞肺癌的标靶治疗11EGFR expression in human tumours NSCLC40-80%Prostate40-80%Gastric33-74%Head and ne
3、ck90-100%Breast14-91%Colorectal25-77%Pancreatic30-50%Ovarian35-70%InvasionMetastasis Late-stage diseaseChemotherapy resistanceHormonal therapy resistancePoor outcomeTumours showinghigh EGFR expressionHigh expressiongenerally associatedwith非小细胞肺癌的标靶治疗12MetastasisProliferation/maturationSurvival/apopt
4、osisAngiogenesisMAPKMEKGene transcriptionCell-cycle progressionPI3-KRAS RAFSOSGRB2PTENAKTSTATKpYMG1SpYpYKEGFRG2HER1Baselga 2002非小细胞肺癌的标靶治疗13Gefitinib(Iressa,Gefitinib(Iressa,艾瑞莎艾瑞莎)Erlotinib(TarcevaErlotinib(Tarceva，得舒緩得舒緩)非小细胞肺癌的标靶治疗14非小细胞肺癌的标靶治疗15RandomisationIRESSA 250 mgonce dailyIRESSA 500 mgon
5、ce dailyReceived 1 or 2(IDEAL 1)or 2(IDEAL 2)previouschemotherapyregimensContinue IRESSA until diseaseprogression or unacceptable toxicityPrimary endpointsPatientsl Response rate(both trials)l Safety profile(IDEAL 1)l Symptom relief(IDEAL 2)J Clin Oncol 2003;21:223746.JAMA 2003;290:214958.非小细胞肺癌的标靶治
6、疗16IDEAL 1:tumour response rateIRESSA250 mg/day IRESSA500 mg/day 18.419.0Patients with CR or PR(%)CR,complete response;PR,partial response非小细胞肺癌的标靶治疗17IDEAL 1:disease control ratePatients with CR,PR or SD(%)54.451.4CR,complete response;PR,partial response;SD,stable diseaseIRESSA250 mg/day IRESSA500
7、mg/day 非小细胞肺癌的标靶治疗18IDEAL 1:tumour response rate Patients with CR or PR(%)Japanese(n=102)Non-Japanese(n=106)IRESSA 250 mg/day IRESSA 500 mg/day27.59.611.127.5非小细胞肺癌的标靶治疗19IDEAL 2:tumour response rateIRESSA250 mg/day IRESSA500 mg/day 11.88.8Patients with CR or PR(%)CR,complete response;PR,partial res
8、ponse非小细胞肺癌的标靶治疗20IDEAL 2:disease control ratePatients with CR,PR or SD(%)42.236.0IRESSA250 mg/day IRESSA500 mg/day CR,complete response;PR,partial response;SD,stable disease非小细胞肺癌的标靶治疗2101020304050607081216202428Time to improvement(days)%patientsIDEAL 1:Time to Symptom improvement(n=54)6915467Basel
9、ga J et al 2001Median=8 days非小细胞肺癌的标靶治疗22010203040123456789 10 11 12 13 14 15 16 17 18Median=2 weeksPercentTime to Improvement(Weeks)非小细胞肺癌的标靶治疗23J Clin Oncol 21:2237-2246,2003J Clin Oncol 22:1103-1109,2004非小细胞肺癌的标靶治疗24RashDiarrhoea PruritusDry skin Acne Nausea ALT increasedAST increasedGrade 126322
10、5241011109IRESSA 250 mg/dayIRESSA 500 mg/dayGrade 3/410000120Grade 1303432225161314Grade 3/477102163Values are%patientsALT,alanine aminotransferase;AST,aspartate aminotransferaseGrade 2198533112Grade 23317388756非小细胞肺癌的标靶治疗25RashDiarrhoea Dry skin AcneVomiting Nausea Grade 13941121997IRESSA 250 mg/da
11、yIRESSA 500 mg/dayGrade 3/4010011Grade 136452418511Grade 3/4350431Values are%patientsGrade 2461625Grade 2151731116非小细胞肺癌的标靶治疗26Pre-treatmentPost-treatment,10 days非小细胞肺癌的标靶治疗27非小细胞肺癌的标靶治疗28WJTOG report非小细胞肺癌的标靶治疗29J Chin Med Assoc April 2005 Vol 68 No 4非小细胞肺癌的标靶治疗30Journal of Thoracic Oncology Volume
12、 1,Number 6,July 2006非小细胞肺癌的标靶治疗31 J Clin Oncol 2004;22:777-84.J Clin Oncol 2004;22:785-94 非小细胞肺癌的标靶治疗32End pointsPrimary:lSurvivalSecondary:lTTFlORRlQoL,symptomslSafetyExploratory:lTumour biomarker analysis(eg EGFR)Gefitinib(250mg/day)+BSCPlacebo+BSCRandomisation(2:1 ratio)CT,chemotherapy;BSC,best
13、supportive care;TTF,time to treatment failure;ORR,objective response rate;QoL,quality of lifePatients with:lHistologically/cytologically confirmed NSCLClLocally advanced or metastatic diseasel1 or 2 prior CT regimenslIntolerant to most recent CT regimen or progression 90 days of last CT cycleLancet.
14、2005;366(9496):1527-37.非小细胞肺癌的标靶治疗33非小细胞肺癌的标靶治疗34SurvivalHR and 95%CI0.40.6 0.8 1.01.5AdenocarcinomaAll patientsFemalePS 0,11 prior lineRefractoryNever smokedNon-adenocarcinomaEver smokedIntolerant2 prior linesPS 2,3Male11.9%8.0%14.7%8.8%7.6%7.9%18.1%4.8%5.3%9.4%8.4%6.6%5.1%Gefitinib ORRFavours gefi
15、tinibFavours placeboLancet.2005;366(9496):1527-37.非小细胞肺癌的标靶治疗35Survival11.1%8.0%12.4%7.4%6.9%9.0%6.8%7.5%10.1%7.7%6.4%7.2%10.2%Prior docetaxelAll patientsAsian ethnicity65 yearsNo prior docetaxel 65 yearsNon-Asian ethnicityPrior CT response:PD/NEPrior CT response:CR/PRPrior CT response:SDTime since
16、Dx:12 monthsGefitinib ORRFavours gefitinibFavours placebo0.40.6 0.8 1.01.5HR and 95%CILancet.2005;366(9496):1527-37.非小细胞肺癌的标靶治疗36非小细胞肺癌的标靶治疗37非小细胞肺癌的标靶治疗38N Engl J Med 2005;353:12332.非小细胞肺癌的标靶治疗39非小细胞肺癌的标靶治疗40非小细胞肺癌的标靶治疗41 J Clin Oncol 2005;23:589299.J Clin Oncol 2007;25(12):1545-52.非小细胞肺癌的标靶治疗42非小细
17、胞肺癌的标靶治疗43Science 2004;304:1497-500 N Engl J Med 2004;350:2129-39 非小细胞肺癌的标靶治疗44非小细胞肺癌的标靶治疗45非小细胞肺癌的标靶治疗46Signal 2005;6:4-8.非小细胞肺癌的标靶治疗47非小细胞肺癌的标靶治疗48Cetuximab,Erbitux非小细胞肺癌的标靶治疗49非小细胞肺癌的标靶治疗50Expert Opin Pharmacother 2004;5:162133 非小细胞肺癌的标靶治疗51J Clin Oncol 2000;18:90414.非小细胞肺癌的标靶治疗52J Clin Oncol.200
18、5;23(34):8786-93.非小细胞肺癌的标靶治疗53 J Clin Oncol.2006;24(33):5253-58.非小细胞肺癌的标靶治疗54Bevacizumab,Avastin非小细胞肺癌的标靶治疗55非小细胞肺癌的标靶治疗56Carcinogenesis 2000;21:505-515.非小细胞肺癌的标靶治疗57J Clin Oncol 2004;22(11):2184-91.非小细胞肺癌的标靶治疗58非小细胞肺癌的标靶治疗60J Clin Oncol 2004;22(11):2184-91.非小细胞肺癌的标靶治疗61J Clin Oncol 2004;22(11):2184
19、-91.非小细胞肺癌的标靶治疗62N Engl J Med 2006;355:2542-50.非小细胞肺癌的标靶治疗63N Engl J Med 2006;355:2542-50.非小细胞肺癌的标靶治疗64N Engl J Med 2006;355:2542-50.非小细胞肺癌的标靶治疗65N Engl J Med 2006;355:2542-50.非小细胞肺癌的标靶治疗66非小细胞肺癌的标靶治疗67非小细胞肺癌的标靶治疗68非小细胞肺癌的标靶治疗69非小细胞肺癌的标靶治疗70N Engl J Med 2006;355:2542-50.非小细胞肺癌的标靶治疗71非小细胞肺癌的标靶治疗72非小细胞肺癌的标靶治疗73非小细胞肺癌的标靶治疗74
