课件：EGFR靶向治疗癌症.ppt

Current status of EGFR-targeted cancer therapy S, Surgery; RT, Radiotherapy;CT, Chemotherapy/hormone therapyEGFR, epidermal growth factor receptor Pre-malignancy Localized tumors Locally/ regionally advanced disease Advanced/ metastatic disease S RT CT + RT CT EGFR-targeted therapy Potential treatment options for EGFR-targeted therapies The concept Targeted therapy for a broad range of common solid tumors (including lung, breast, prostate, colon, ovarian, and gastric) Clinical trials Proof of concept well-tolerated therapy tumor responses in several tumor types The potential Improved outcomes in the treatment of common solid tumors From concept to clinical trials Tumor response mAbs TKIs K K K mAbs, monoclonal antibodies; TKIs, tyrosine kinase inhibitors Clinical development of anticancer agents Typical cytotoxicOBD MTD MTD OBD Toxicity Antitumor effect Effect Target Dose OBD MTD Novel targeted agentsOBD MTD OBD, optimal biologic dose; MTD, maximum tolerated doseRowinsky 2000 Dose Effect Target Antitumor effect 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/week) 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 trials Phase 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; Nakagawa 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 4.1 8.6 Monotherapy(n=111) 10.8 32.4 1.5 6.9 p value 0.007 0.001 0.001 0.48 *Cetuximab in combination with irinotecanTTP, time to pr