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1、Current status of EGFR-targeted cancer therapy,S,Surgery;RT,Radiotherapy;CT,Chemotherapy/hormone therapyEGFR,epidermal growth factor receptor,Pre-malignancy,Localizedtumors,Locally/regionally advanced disease,Advanced/metastaticdisease,S,RT,CT+RT,CT,EGFR-targeted therapy,Potential treatment options
2、for EGFR-targeted therapies,The conceptTargeted therapy for a broad range of common solid tumors(including lung,breast,prostate,colon,ovarian,and gastric)Clinical trialsProof of conceptwell-tolerated therapytumor responses in several tumor types The potentialImproved outcomes in the treatment of com
3、mon solid tumors,From concept to clinical trials,Tumor response,mAbs,TKIs,mAbs,monoclonal antibodies;TKIs,tyrosine kinase inhibitors,Clinical development of anticancer agents,Typical cytotoxicOBD MTD,MTD,OBD,Toxicity,Antitumoreffect,Effect,Target,Dose,OBD,MTD,Novel targeted agentsOBD MTD,OBD,optimal
4、 biologic dose;MTD,maximum tolerated doseRowinsky 2000,Dose,Effect,Target,Antitumoreffect,Toxicity,Clinical development of EGFR-targeted therapies,Phase I trials failed to identify the MTD of cetuximab;the OBD was identified as the dose that saturated the antibody systemic clearance rate(200 mg/m2/w
5、eek)Gefitinib(IRESSA)Phase I trials did identify the MTD(700-1000 mg/day),but also showed that the OBD was 250 mg/day,as confirmed in Phase II trialsPhase I trials of erlotinib identified the MTD as 150 mg/day;this is the recommended dose,Baselga et al 2000;Baselga et al 2002;Herbst et al 2002;Nakag
6、awa et al 2003;Ranson et al 2002;Fukuoka et al 2003;Kris et al 2003;Hidalgo et al 2001,Cetuximab:approved for the treatment of advanced colorectal cancer,Partial response rate,%Disease control rate,%Median TTP,months Median survival,months,Combination*(n=218)22.9 55.5 4.18.6,Monotherapy(n=111)10.832
7、.4 1.56.9,p value0.0070.0010.0010.48,*Cetuximab in combination with irinotecanTTP,time to progression,Cunningham et al 2003,Gefitinib(250 mg/day):approved for the treatment of advanced NSCLC,Response rate,%Disease control rate,%Median survival,months1-year survival,%Symptom improvement*,%,IDEAL 1(n=
8、103)18.4 54.47.63540.3,IDEAL 2(n=102)11.8 42.26.52743.1,*Assessed in 67 symptomatic patients in IDEAL 1 and 102 symptomatic patients in IDEAL 2,Fukuoka et al 2003;Kris et al 2003,Erlotinib:awaiting approval for the treatment of advanced NSCLC,Perez-Soler et al 2003,Other EGFR-targeted therapies unde
9、r clinical development,EMD72000,h-R3,ABX-EGF,PKI-1066,CI-1033,EKB-569,mAbs,TKIs,Summary of current EGFR-targeted treatment options,To date,two EGFR-targeted therapies have been approved for the treatment of patients with advanced or metastatic CRC(cetuximab)or NSCLC(gefitinib)Approval of erlotinib for the treatment of advanced NSCLC is expected in 2004Several other EGFR-targeted therapies are undergoing clinical development,with the majority showing some activity in a range of solid tumors,
