Epidermal growth factor receptor- tyrosine kinase inhibitor in non- small-cell lung cancerYuhYuh-Min Chen, MD, PhD.-Min Chen, MD, PhD. Chest Dept., Taipei VGHChest Dept., Taipei VGHDate1YMCSurvival (anti-apoptosis)PI3-KActivation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of carcinogenesisEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcription Cell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/ maturationChemotherapy/ radiotherapy resistanceAngiogenesisMetastasisBalaban et al 1996; Akimoto et al 1999; Wells 1999; Woodburn 1999; Hanahan 2000; Raymond et al 2000 Cyclin D1pYpY pYDate2YMCRppR Extracellula rIntracellularMembranepK pKpppTGFaSubstrateSubstrateSignalling MoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonal AntibodiesEGFR Tyrosine Kinase InhibitorsDate3YMCIDEAL 1 and 2 trial designGefitinib 250 mg/dayGefitinib 500 mg/dayContinue gefitinib until disease progression or unacceptable toxicityIDEAL, IressaTM Dose Evaluation in Advanced Lung cancerRandomisation l IDEAL 1 (n=209) 1 or 2 prior regimensl IDEAL 2 (n=216) 2 prior regimensPrimary endpointsl Objective tumour responsel Symptom improvement (IDEAL 2)l Safety (IDEAL 1)Date4YMCMedian time to improvement -symptoms and QOL*Time of 1st assessmentMedian time to improvement, daysSymptom/QOL measureLCSFACT-L8*29*Date5YMCIDEAL 1 and 2: overall survival by symptom improvement (250 mg/day)Probability 1.00.80.60.40.20.0IDEAL 1Months from randomisationImprovement No improvement27 4018 3013.3 3.5Patients (n)Deaths (n)Median (months)0 2 4 6 8 101214 16182044 5826 5613.6 3.7Patients (n)Deaths (n)Median (months)1.00.80.60.40.20.0ProbabilityIDEAL 2Months from randomisation02 4 6 8 10 1214 16 1820Douillard et al 2002; Lynch et al 2003Date6YMCISEL (IRESSA Survival Evaluation in Lung Cancer): Clinical Trial DesignRandomisation Gefitinib (250 mg) + *BSCPlacebo + *BSCSURVIVALSecondary:TTF, ORQoL, safetyPrimary endpoint:E N DB E N E F I T2:1 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 regimens 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 Date7YMCISEL - Overall SurvivalPercent survivingTime (months)At risk: Gefitinib 1129 1023 901 761 588 455 325 245 175 113 76 45 19 9 IRESSA- PlaceboPlacebo 563 517 446 382 289 220 160 115 77 44 28 20 12 4 2GefitinibplaceboMedian (months)5.65.1 1 yr survival27%21%HR=0.89 (0.77, 1.02), p=0.0871 Stratified log rank test N=1692, deaths=976 Cox analysis, p=0.0299Date8YMCISEL Survival: OrientalsPercent survivingTime (months)At risk: Gefitinib 235 221 199 179 145 119 95 78 64 51 40 25 12 8 IRESSA- PlaceboPlacebo 107 97 84 74 56 43 35 29 22 13 8 7 3 1 15.5 M5.5 M9.5 M9.5 MDate9YMCJ Chemother 2005;17:679Date10YMCRESULTS 3 CR, 9 PR, with a R.R. 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;17:679Date11YMC% SurvivalMedian survival: 9.5 months Median survival: 9.5 months One-year survival rate: 45.1%One-year survival rate: 45.1%J Chemother 2005;17:679Date12YMC% SurvivalFig. 10102030405060708090100036912151821MonthsComplete or partial response (n=12) median 20.1MStable or progressive disease (n=24) median 4.7MSurvival according to response or not15.4月J Chemother 2005;17:679Date13YMCStudy Design of BR.21Stratified by:CentrePS(0/1 vs 2/3)Response to prior treatment(CR/PR:SD:PD)Prior regimens (1 vs 2)Prior platinum(yes vs no)Tarceva 150mg dailyPlaceboR A N D O M I S EPS = performance status21N Engl J Med 2005;353:12332Date14YMCBR.21: Significant clinical predictors of response to TarcevaTarceva treated pts (n)R.R. (%)p value*Gender Female (146)14.4 0.006 Male (281) 6.1 HistologyAdenocarcinoma (209)13.965 years8213.7Wu JY et al. AJRCCM 2008Date47YMCNo survival difference in 152 chemonaive or chemo-treated EGFR mutated patients in NTUH Chmo nave gefitinib (n=91)Chemotherapy treated gefitinib (n=61) log rank Chmo nave gefitinib (n=91)Chemotherapy treated gefitinib (n=61) log rank=0.24Wu JY et al. AJRCCM 2008Date48YMC2003.9.15 s/p 4 line C/T since 20010629, PS 3 FiO2 50%2003.9.29 Iressa 2 weeks PS 1 room airAnother 1.5 yearDate49YMCMs. Ree Hx No 31676887 75 Y/O 20021202 SOB for months, PS 2-3, NC 3L/min pre C/T20050804 post NGC; taxotere; under Iressa-N, PS 0Date50YMCs/p renal transplantation with adenocarcinoma, LUL, 2:1-112005;2:1-11KwakKwak et al. Pro Nat et al. Pro Nat AcadAcad Sci