Cancer Deaths in the U.S. Female Male

Increasing evidence EGFR overexpressed in NSCLC* 80-90% overexpression Correlated in many cases with a poor prognosis** Decreased survival Increased metastasis *Salomon et al. 1995, Rusch et al 1993; B Rusch et al 1997; **Fontanini et al. 1995, Mukaida et al. 1991, Neal et al. 1992, Sainsbury et al EGFR Positive Squamous Cell Carcinoma EGFR Expression and Lung Cancer

EGFR and Lung Cancer Resectable stage I-IIIA NSCLC 130 patients 78% positive for EGFR Median follow-up 84 months Median survival time Overexpression worse (18 vs 50 months) 2-yr (43% vs 70%) 5-yr (31% vs 46%) EGFR overexpression predicts a shortened survival time Selvaggi et al. PASCO 2002; abs 1345

N U C L E U S Targeting Cellular Signal Pathways Apoptotic Pathway Proliferative Pathway Ras Raf MEKK ERK sek MAP kinase jnk/sapk C-myc C-jun PI3K Akt intermediates Apoptosis Y EGFR P P Rho-B Ki-67 TKI mAb

IMC-C225 and ZD1839 PropertyIMC-C225ZD1839 SpecificityExclusive to EGFREGFR but variable Target MOA/Activity External receptor Interrupts cell cycle Induces apoptosis Anti-angiogenesis Downregulates MMP Tyrosine kinase Same N/A Administration Dose Determination I.V. weekly Zero-order PK P.O. daily MTD-diarrhea BindingInternalizes receptorReversible Adverse EventsAcne-like rash Grade 3/4 hypersensitivity (4%) Acne-like rash Diarrhea

IMC-C225 Properties IgG1 (chimerized antibody) Exclusive for EGFR and its heterodimers Prevents repair and survival of tumor cells damaged by the effects of chemotherapy and radiotherapy Potentiates apoptosis Inhibits cell cycle progression Decreases production of angiogenic factors Inhibits invasion/metastasis

Docetaxel in Lung Cancer Activity in front-line lung cancer Survival in 2 nd -line lung cancer Managable toxicities Good drug to pair with novel compounds

Second-line NSCLC TAX 317B: Survival Median 7.5 vs 4.6 mo Log-rank p= year 37% vs 12%  2 p=0.003 T75 BSC Survival time (months) Cumulative Probability Docetaxel 75 mg/m 2 vs BSC Shepherd F, et al. J Clin Oncol 18: 2000

Second-Line NSCLC TAX 320: Overall Survival Survival time (months) Cumulative probability T100 T75 V/I T75 vs V/I 1-Year 30% vs 20% p=0.05,  2 Log-rank Test P= 0.13 Median 5.7 vs 5.6 mo (NSS) T100 vs V/I 1-Year 23% vs 20% Log-rank test p=0.58 Median 5.5 vs 5.6 mo (NSS) Fossella F, et al. J Clin Oncol 18: 2000 Docetaxel vs. Vinorelbine or Ifosfamide

Phase II Study of Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Cetuximab in Combination with Docetaxel in Patients with Recurrent NSCLC Dept. of Thoracic/Head & Neck Medical Oncology M. D. Anderson Cancer Center Poster Discussion ASCO 2002 Abstract #1168

Objectives Primary objective Determine the response rate of Cetuximab + Docetaxel to patients with refractory/recurrent NSCLC Secondary objectives: Safety/toxicity profile of Cetuximab Determining the duration of response & survival Kim ES, et al. Proc Am Soc Clin Oncol 2002

Diagnosis of pathologically confirmed NSCLC Progressive disease while receiving a cytotoxic chemotherapy regimen. Relapsed within 3 months after discontinuing a cytotoxic chemotherapy regimen. (The patient is allowed to take biologic therapy during this time). Uni-dimensionally measurable disease (RECIST) Must have received prior chemotherapy < 3 months of study entry (neurotoxicity must be ≤ Grade 1 at study entry). The patient has immunohistochemical evidence of EGFR expression (  1+). KPS of  60 at study entry Inclusion Criteria

Exclusion Criteria Has received prior anti-EGFR antibody therapy. Has received prior docetaxel chemotherapy. Has received EGFR small molecule therapy. No wide-field radiation within 4 weeks. No major surgery within 30 days.

Study Design Continue Docetaxel/ C225 REGISTRATION EGFR  1+ (IHC) DAY 1 DAY 8 DAY 15 Docetaxel 75 mg/m 2 q3 wks Cetuximab 400 mg/m 2 IV Cetuximab 250 mg/m 2 IV Off Study Progressive Disease Response or Stable Disease Kim ES, et al. Proc Am Soc Clin Oncol 2002

Patient Characteristics n = 41 Age (median) 60 range (31-76) SexMale21 Female20 Performance status (median) 1 range (0-2) EGFR Status1+, 2+18% 3+82%

Patient #10 Baseline 2 cycles

Patient #10 Baseline 4 cycles

Patient #16 Baseline 2 cycles

Toxicity Hematologic Grades1/2Grades3/4 Thrombocytopenia 01 Neutropenia 07 Neutropenic fever 33 Anemia 01

Patient #3

Patient #12

Patient #19

Pharmacokinetic Results Pre-Dose and 1-Hr Post Dose Concentration of C225 cycle C225 concentration (mg/ml)

Conclusions This combination of docetaxel with Cetuximab has shown encouraging results thus far in patients with refractory/progressive NSCLC. The safety and toxicity of this combination is tolerable. Early pharmacokinetic data shows no direct interaction. Final data soon TTP, survival Correlation of response to skin toxicity

Acknowledgements Edward S. Kim, M.D. Waun Ki Hong, M.D. M. D. Anderson Cancer Center Department of Thoracic/Head and Neck Medical Oncology Departments of Thoracic/Head and Neck Medical Oncology Surgical Oncology Radiation Oncology Pathology Biostatistics