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personalized medicine in lung cancer R4 김승민 Personalized Medicine in Lung Cancer • patients with specific types and stages of cancer should be treated according to standardized predetermined protocols • the molecular characterization of tumors genome wide RNA expression, DNA copy-number and sequence analyses, and microRNA and proteomic profiling • individualized selection of treatment as determined by the characteristics of the patient and the tumor. • Lung cancer EGFR TKI (gefitinib, erlotinib) ALK kinase inhibitor crizotinib EGFR TKI (gefitinib, erlotinib) Incidence of EGFR gene mutations (global data from literature; n=2880) EGFR mutation (%) 70 Ethnicity Gender Smoking Hx Histology 60 50 40 30 20 10 0 Non asian asian Male Female Non smoker AdenoNon-adeno EGFR mutations in NSCLC EGFR: First line VS second line ? EGFR: First line VS second line ? • EGFR TKI is recognized as a standard first-line therapy for patients with activating EGFR mutations. • All six randomized studies higher tumor response rates and longer progression-free survival • none of these studies has been able to demonstrate improvement in overall survival (OS). • the use of first- or second-line EGFR TKI and explore the potential differences between the two orders of administration IPASS Endpoints Patients Primary • Chemonaïve • Age ≥18 years • Adenocarcinoma histol Gefitinib (250 mg / day) Secondary ogy • Never or light ex-smok ers* • Life expectancy ≥12 weeks • PS 0-2 • Measurable IV disease stage IIIB / • Progression-free survival (no n-inferiority) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m2) 3 weekly# • Objective response rate • Overall survival • Quality of life • Disease-related symptoms • Safety and tolerability Exploratory • Biomarkers • EGFR mutation • EGFR-gene-copy number • EGFR protein expression • Mok et al NEJM 2009 IPASS second line EGFR-TKI • Use of second-line and/or third-line EGFR TKI in patients with EGFR mutation • multiple prospective single-arm studies, retrospective biomarker analyses of phase II studies, and limited subgroup analysis from phase III studies • Current data on treatment outcomes of second- and/or third-line EGFR therapy are inconsistent, and there is a possible explanation for the lower tumor response rates First-line Therapy • difference in exposure to EGFR TKI • difference in quality of life • better tolerance by patients with poor performance status • deferral of whole-brain radiation therapy for patients with brain metastasis First-line Therapy • difference in exposure to EGFR TKI • difference in quality of life • better tolerance by patients with poor performance status • deferral of whole-brain radiation therapy for patients with brain metastasis First-line Therapy • difference in exposure to EGFR TKI • difference in quality of life • better tolerance by patients with poor performance status • deferral of whole-brain radiation therapy for patients with brain metastasis EGFR: First line VS second line ? ALK in lung cancer Introduction • ALK rearrangement several distinctive clinicopathologic features. • Absence of smoking history.. among patients with ALK-positive lung cancer, more than 90% are never- or light smokers (as 10 pack-years). • younger age at diagnosis • adenocarcinoma histology • absence of other oncogenic drivers. • study of crizotinib was in progress when EML4-ALK was reported in lung cancer. Introduction • NCCN Current guidelines all patients with advanced, non squamous NSCLC for both EGFR mutation and ALK rearrangement. • newly diagnosed, ALK-positive patients can be prescribed crizotinib in the first-line setting. • the NCCN does recommend crizotinib as first-line therapy in advanced, ALK-positive NSCLC. • This recommendation to use crizotinib as first-line therapy is largely based on our experience with EGFR-mutant NSCLC Bone metastases and skeletal-related events • Mechanisms Personalized Medicine in Lung Cancer • histologic subtype is clearly an important factor in selecting among standard cytotoxic chemotherapies • the presence of key oncogenic alterations predicts responsiveness to selective targeted therapies activating mutations and chromosomal rearrangements • Lung cancer EGFR TKI (gefitinib, erlotinib) ALK kinase inhibitor crizotinib EGFR TKI Ex: gefitinib, erlotinib • First line VS second line • Six randomized studies improvement in tumor response rate and PFS over platinum-based combination chemotherapy difference in exposure to EGFR TKI difference in quality of life better tolerance by patients with poor performance status deferral of whole-brain radiation therapy for patients with brain metastasis ALK inhibitor • ALK is now a validated kinase target in lung and other cancers. ALK-positive cancers are oncogene • ALK-positive lung cancer demonstrated impressive activity and clinical benefit • patients with ALK-positive lung cancer invariably relapse with crizotinib as a result of the development of resistance