非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂英文.pptxVIP

非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂英文第1页/共58页 2023/5/262Survival(anti-apoptosis)PI3-KActivation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of carcinogenesisEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene 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 D1pYpYpY第2页/共58页 2023/5/263RppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignalling MoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonal AntibodiesEGFR Tyrosine Kinase Inhibitors第3页/共58页 2023/5/264IDEAL 1 and 2 trial designGefitinib250 mg/dayGefitinib500 mg/dayContinue gefitinib 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)第4页/共58页 2023/5/265Median time to improvement - symptoms and QOL*Time of 1st assessmentMedian time toimprovement, daysSymptom/QOLmeasureLCSFACT-L8*29*第5页/共58页 2023/5/266IDEAL 1 and 2: overall survival by symptom improvement (250 mg/day)Probability1.00.80.60.40.20.0IDEAL 1Months from randomisationImprovementNo improvement2740183013.33.5Patients(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 2003第6页/共58页 2023/5/267ISEL (IRESSA Survival Evaluation in Lung Cancer): Clinical Trial DesignRandomisation 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 NSCL