非小細(xì)胞肺癌表皮生長因子受體酪氨酸激酶抑制劑（英文）課件

1、Epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancerYuh-Min Chen, MD, PhD.Chest Dept., Taipei VGH9/13/20221YMCSurvival(anti-apoptosis)PI3-KActivation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of carcinogenesisEGFR-TKEGFRLi

2、gandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalaban et al 1996; Akimoto et al 1999; Wells 1999; Woodburn 1999; Hanahan 2000; Raymond et al 2000 Cyclin D1pYpYpY9

3、/13/20222YMCRppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignalling MoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonal AntibodiesEGFR Tyrosine Kinase Inhibitors9/13/20223YMCIDEAL 1 and 2 trial designGefitinib250 mg/dayGefitinib500 mg/dayContinue gefi

4、tinib until diseaseprogression or unacceptable toxicityIDEAL, IressaTM Dose Evaluation in Advanced Lung cancerRandomisationIDEAL 1 (n=209)1 or 2 prior regimensIDEAL 2 (n=216)2 prior regimensPrimary endpointsObjective tumour responseSymptom improvement (IDEAL 2)Safety (IDEAL 1)9/13/20224YMCMedian tim

5、e to improvement - symptoms and QOL*Time of 1st assessmentMedian time toimprovement, daysSymptom/QOLmeasureLCSFACT-L8*29*9/13/20225YMCIDEAL 1 and 2: overall survival by symptom improvement (250 mg/day)Probability1.00.80.60.40.20.0IDEAL 1Months from randomisationImprovementNo improvement2740183013.33

6、.5Patients(n)Deaths(n)Median (months)024681012141618204458265613.63.7Patients (n)Deaths(n)Median (months)1.00.80.60.40.20.0ProbabilityIDEAL 2Months from randomisation02468101214161820Douillard et al 2002; Lynch et al 20039/13/20226YMCISEL (IRESSA Survival Evaluation in Lung Cancer): Clinical Trial D

7、esignRandomisation Gefitinib (250 mg) + *BSCPlacebo + *BSC SURVIVALSecondary:TTF, ORQoL, safetyPrimaryendpoint:ENDBENEFIT2:1 ratio A double blind Phase III survival study comparing IRESSA (250mg) plus BSC vs. placebo plus BSC in patients with advanced NSCLC who have received 12 prior chemotherapy re

8、gimens and are refractory or intolerant to their most recent regimen1692 patients in 210 centres across 28 countries 342 patients of oriental origin No Japanese/US sites*BSC= Best Supportive CareLancet 2005;366:1527-37 9/13/20227YMCJ Chemother 2005;17:6799/13/202210YMCRESULTS3 CR, 9 PR, with a R.R.

9、of 33.3% SD 14, control rate of 72.2%All treatment-related toxicities were few and mild in severity, except one patient suffered from reversible grade 3 interstitial pneumonitis J Chemother 2005;17:6799/13/202211YMC% SurvivalMedian survival: 9.5 months One-year survival rate: 45.1%J Chemother 2005;1

10、7:6799/13/202212YMCImprovement in Survival with Tarceva42.5% improvement in median survivalSurvival distribution functionSurvival time (months)HR=0.73, p0.001*1.000.750.500.250051015202530TarcevaPlacebo N Engl J Med 2005;353:12332 Tarceva (n=488) Placebo (n=243) Median survival (months) 6.7 4.7 1-ye

11、ar survival (%) 31 21 9/13/202216YMCBR.21: Time to symptom deterioration (months)Placebo Tarceva179179153n348353298n1.9(1.82.8)2.9(24.8)3.7(24.9)Median(95% CI)0.022.8 (2.43)Pain0.014.7(3.86.2)Dyspnea0.044.9(3.87.4)Cough p value*Median(95% CI)*Log-rank test, unadjusted for multiple symptoms Bezjak A,

12、 et al. J Clin Oncol 2006;24:38317Shepherd F, et al. N Engl J Med 2005;353:123329/13/202217YMCTRUST: Tarceva MO18109An expanded access clinical program of Tarceva (erlotinib) in pts with advanced stage IIIB/IV NSCLCLung Cancer 20089/13/202218YMCPatient Population & ResponseFrom May 2005 to July 2006

13、, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of Tarceva. 9/13/202219YMC0.000.250.500.751.00Progression free survival (Months)061020Censored observationsFig. 1Free from progression8421214161822Time to disease progressi

14、on of 299 NSCLC pts treated with erlotinib. The median time to disease progression was 5.6 months (95% C.I.: 4.4 6.5 months, 45 pts censored)9/13/202221YMCEGFR-TKI vs. chemotherapeutic agents in salvage chemotherapy9/13/202222YMCIn conclusion, both chemotherapeutic agents, such as docetaxel alone or

15、 gemcitabine + vinorelbine, and gefitinib, are appropriate salvage regimens for Chinese NSCLC pts who have failed previous chemotherapy. However, gefitinib has a better safety profile and probably better survival than the chemotherapeutic agents, and would be an appropriate alternative choice for sa

16、lvage chemotherapy, even in a second-line setting for Chinese pts. J Thorac Oncol 2006;1:545-509/13/202223YMCEfficacy of Salvage Therapy in NSCLCTrialScheduleR.R.,% MTP, MM Sur, M1-Yr, %Single agent Gemcitabine1200 mg/m2 D1,8,15 q4 wks12.52.17.540 Docetaxel 3535 mg/m2 D1,8,15 q4 wks17.24.28.433.4 40

17、40 mg/m2 D1,8 q3 wks10.93.57.435 7575 mg/m2 D 1 q3 wks6.12.87.830.3 Gefitinib250 mg daily33.34.79.340.8Doublet Docetaxel+IfosfamideD 60 mg/m2 + I 3 gm/m2 D1 q3 wks1058.226.1 Docetaxel+GemcitabineD 30 mg/m2 + G 800 mg/m2 D1,8 q3 wks36.13.85.733.3 Vinorelbine+GemcitabineV 20 mg/m2 + G 800 mg/m2 D1,8,1

18、5 q4 wks31.3 4.68.334.3 Vinorelbine+CisplatinV 20 mg/m2 D1,8,15 + C 50 mg/m2 D1 q4 wks9.53.77.619.79/13/202224YMCSalvage Chemotherapy (n=342)Grade Neutroopenia9/13/202225YMCSalvage Chemotherapy (n=342)Grade FatigueDocetaxel40 and vinorelbine plus cisplatin induced more frequent severe fatigue than o

19、ther regimens. Patients that received single-agent gemcitabine and gefitinib reported no severe fatigue sensation. 9/13/202226YMCInterestINTEREST (gefitinib vs. docetaxel in pts with LA or meta. NSCLC pre-treated with platinum-based chemotherapyWCLC 20071466 pts from Mar 2004 to Feb 20069/13/202227Y

20、MCInterestQoF and symptom improvementWCLC 20079/13/202228YMCInterestWCLC 20079/13/202229YMCInterestOverall survival9/13/202230YMCClinical characteristics & response rate (pt number=1974)Int J Clin Oncol 2006;11:19089/13/202231YMCEGFR MutationEur J Cancer 2006:17-23N Engl J Med 2004;350:2129-399/13/2

21、02232YMCFailure of Doublet Chemotherapy plus EGFR-TKIINTACT I, IITRIBUTE, TALENT9/13/202233YMCGiaccone. JCO 2004;22:777Overall Survival of INTACT-1 in Each Treatment Group (GEM+CDDP c/s Iressa)Poor survival for those use Iressa with GEM+CDDP9/13/202234YMCCan we further prolong disease-free survival

22、and overall survival ?Failure of doublet chemotherapy plus TKIINTACT I, II (Gefitinib); TRIBUTE, TALENT (Erlotinib)Majority performed in Caucasian ptsUnknown for Asian pts with high EGFR mutation rateTo assess the efficacy of adding chronic intermittent low-dose vinorelbine to gefitinib treatment fo

23、r adenocarcinoma of lung who failed two or more regimens of chemotherapy. 9/13/202235YMC9/13/202236YMCConclusionsAddition of low-dose vinorelbine to gefitinib has shown high efficacy in adenocarcinoma lung cancer patients who have failed two previous regimens of chemotherapy. Given the fact that the

24、re are four negative phase III randomized trials of EGFR TKIs with chemotherapy (INTACT I and II, TRIBUTE, TALENT),only studies in selected EGFR mutation-enriched patient populations can be justified at this time for further clinical trials combining chemotherapy with EGFR TKIs. 9/13/202237YMC% Free

25、 from Progression1-year progression-free survival rate was 57.1% in the GV arm and 21.2% in the G arm (p=0.008)9/13/202238YMCErlotinib induces G1 arrest which can block M-phase activity of docetaxelDocetaxel induces M-phase arrest and apoptosis that is enhanced by erlotinibSequence specific Interact

26、ionClin Lung Cancer 2006;7:3859/13/202239YMCFirst-line Asian Sequential Tarceva plus Chemotherapy Trial (FAST-ACT): Study DesignPlaceboErlotinib 150mg/dayPreviously untreated stage IIIB/IV NSCLC (n=150)R11PDSix cycles gemcitabine + cisplatin or carboplatin + placebo; q4wksSix cycles gemcitabine (d1,

27、 8) + cisplatin (d1) or carboplatin (d1) + erlotinib (d1528); q4wksPDStratified by centre, stage,histology, smoking statusStudy treatmentPost-treatmentScreeningPost-studyGemcitabine 1250mg/m2 (d1,8); cisplatin 75mg/m2 ORcarboplatin 5AUC (d1); erlotinib 150mg/day (d1528)PASCO 2008;26:a80319/13/202240

28、YMCTime to Disease Progression1.00.80.60.40.20024681012141618202224262830323436Time (weeks)384042444648505254565876727272646158585852505046373632261514787676766759585650434341352524221687121098755531054211111110No. at riskErlotinibPlaceboEarly and consistent separation of curvesMedian TTP(weeks)GC-e

29、rlotinib31.4GC-placebo24.1Log-rank test p=0.0185HR=0.56 95% CI: 0.370.8424.131.4PASCO 2008;26:a8031R.R.36.8%24.4%How long should chemotherapy be given (no PDS at maintenance phase)GEMCDDP dose (control arm) is less than usual Better for those Caucasians who have higher % of EGFR wild type9/13/202241

30、YMCFirst line treatment with EGFR-TKIs in those with EGFR mutated patients9/13/202242YMC98 pts underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations: exon 19 deletions (53%), L858R (26%) 31 pts received gefitinib, R.R. 55%, median progression-free survival 9.2 M. Therapy w

31、as well tolerated.J Clin Oncol 2008;26:2442-9 9/13/202243YMCPercent change in measurable tumor at best response, by individual patientJ Clin Oncol 2008;26:2442-9 9/13/202244YMC Kaplan-Meier curves for (A) progression-free survival and (B) overall survival among all treated ptsJ Clin Oncol 2008;26:24

32、42-9 PFS 9.2 MSur 17.5 M9/13/202245YMCGefitinib first line treatment in enriched EGFR-mutated NSCLC in NTUHN=106 (adenoca 97, non-adeno 9)Pt NoRR, %DCR, %Median TTF, MMedian OS, MAll10650.982.15.522.4EGFR mutated556987.3824 wild type352068.63.412.9 not done1656.393.85.6NRJCO 2008;26:2745-53Pt NoRR,

33、%Median TTF, MExon 19 deletion20958.9Exon 21 L858R2373.99.19/13/202246YMCPredictive Factors of Response to Gefitinib in 152 EGFR mutated patients in NTUHVariablesNoResponse rates (%)Univariate PMultivariate PN = 152 L858R7565.30.646 Del in Exon 197768.8 Chemonaive9175.80.0050.006 Chemo-treated6154.1

34、 Female11071.80.0450.053 Male4254.8 Smoker2254.60.175 Non-smoker13069.2 65 years8213.7Wu JY et al. AJRCCM 20089/13/202247YMCNo survival difference in 152 chemonaive or chemo-treated EGFR mutated patients in NTUH Chmo nave gefitinib (n=91) Chemotherapy treated gefitinib (n=61) log rankChmo nave gefit

35、inib (n=91) Chemotherapy treated gefitinib (n=61) log rank=0.24Wu JY et al. AJRCCM 20089/13/202248YMC2003.9.15 s/p 4 line C/T since 20010629, PS 3 FiO2 50%2003.9.29 Iressa 2 weeks PS 1 room airAnother 1.5 year9/13/202249YMCMs. Ree Hx No 31676887 75 Y/O 20021202 SOB for months, PS 2-3, NC 3L/min pre

36、C/T20050804 post NGC; taxotere; under Iressa-N, PS 09/13/202250YMCs/p renal transplantation with adenocarcinoma, LUL, & brain, meningeal carcinomatosisNot appropriate for chemotherapy, receive first line Tarceva with total disappearance of meningeal carcinomatosis & brain metastases (brain MRI follo

37、w-up 6 months after Tarceva treatment)Tarceva first line treatmentPatient still alive at present9/13/202251YMCT790MPao et al. PLoS Med 2005;2:1-11Kwak et al. Pro Nat Acad Sci USA 2005; 102: 7665-708 of 16 TKI treated had 2nd mutation: 7 of 8 was T790M Clin Cancer Res 2006;12:6494-501T790M accounts f

38、or 50% acquired resistance to EGFR-TKIsC-MET amplification accounts for 25%And 9/13/202252YMCEGFR and MET each independently activate ErbB3 in the resistant cellsAKTP13KP110P85PPPAdapted from review by C1 Arteaga Nature Medicile.2007EGFRErbB3MetEdu Session ASCO 20089/13/202253YMCThe IGF-IR pathway is activated by a loss of IGF Binding Proteins (IGFBPs)Cell SurvivalCell DeathEGFRErbB3IGFIGF-IRIGF-BPsEGFRgefit