Current status of EGFR-targeted cancer therapy

1. Current status of EGFR-targeted cancer therapy

2. Potential treatment options for EGFR-targeted therapies Locally/ regionally advanced disease Advanced/ metastatic disease Localized tumors Pre-malignancy S RT CT + RT CT EGFR-targeted therapy S, Surgery; RT, Radiotherapy;CT, Chemotherapy/hormone therapyEGFR, epidermal growth factor receptor

3. K K K From concept to clinical trials • 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 mAbs TKIs Tumor response mAbs, monoclonal antibodies; TKIs, tyrosine kinase inhibitors

4. Clinical development of anticancer agents Typical cytotoxicOBD >MTD Novel targeted agentsOBD <MTD Effect Effect Toxicity Toxicity Antitumor effect Target Target Antitumor effect Dose Dose MTD OBD OBD MTD OBD, optimal biologic dose; MTD, maximum tolerated doseRowinsky 2000

5. 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

6. 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 progression Cunningham et al 2003

7. Gefitinib (250 mg/day): approved for the treatment of advanced NSCLC IDEAL 1(n=103) 18.4 54.4 7.6 35 40.3 IDEAL 2(n=102) 11.8 42.2 6.5 27 43.1 Response rate, % Disease control rate, % Median survival, months 1-year survival, % Symptom improvement*, % *Assessed in 67 symptomatic patients in IDEAL 1 and 102 symptomatic patients in IDEAL 2 Fukuoka et al 2003; Kris et al 2003

8. Response rate, % Disease control rate, % Median survival, months 1-year survival, % n=57 12.3 50.9 8.4 40 Erlotinib: awaiting approval for the treatment of advanced NSCLC Perez-Soler et al 2003

9. K K K Other EGFR-targeted therapies under clinical development EMD72000 mAbs h-R3 ABX-EGF PKI-1066 TKIs CI-1033 EKB-569

10. 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 2004 • Several other EGFR-targeted therapies are undergoing clinical development, with the majority showing some activity in a range of solid tumors