 Angiogenesis Signaling Cascades EGFR PI3K MAPK Nucleus Gene Activation Cell Cycle Progression M G1G1 S G2G2 Fos P P MAPK = mitogen-activated protein kinase; P13K = phosphatidylinositol 3-kinase. Roskoski R Jr. Biochem Biophys Res Commun. 2004;319:1. Rowinsky EK. Annu Rev Med. 2004;55:433.  Survival  Proliferation  Invasion  Apoptosis  Metastasis Potential Consequences of EGFR Dysregulation Myc Jun

Probability of Survival Survival Time (Months) HR = 0.89 (95% CI, 0.77–1.02)*; P =.087 † 21 Gefitinib Placebo *From Cox regression model † From Log-rank test ISEL Trial No Survival Benefit with Gefitinib Reprinted from Lancet, 2005;366:1527, with permission from Elsevier. (n = 1129) Placebo (n = 563) Overall median survival (mo) 1-year survival (%) Gefitinib

Phase III BR.21 Study Design NSCLC Double-blind Stratified according to – Center – EC0G performance status (0/1 vs 2/3) – Best response to prior therapy (C or PR vs SD vs PD) – # prior regimens (1 vs 2) – Exposure to prior platinum Rx (Y/N) Erlotinib 150 mg/d Placebo RANDOMIZED 2:1 Shepherd FA, et al. N Engl J Med. 2005;353:123. (Erlotinib)(Placebo)

*HR and P-value adjusted for stratification factors at randomization and HER1/EGFR status Adapted from Shepherd FA, et al. N Engl J Med, 353: , Figure 1A. Copyright © 2005 Massachusetts Medical Society. All rights reserved. Phase III BR.21 Overall Survival Favors Erlotinib 42.5% Improvement in Median Survival Patients (%) *HR = 0.73, P <.001 Erlotinib n = 488 Placebo n = 243 Median survival (months) y survival (%) Months Erlotinib Placebo No. at Risk Placebo Erlotinib

BR.21 Survival Across Subgroups Adapted from Tarceva ® (erlotinib) Product Information. Melville, NY: OSI Pharmaceuticals, Inc, and Genentech, Inc; Courtesy of Dr. A. Sandler, MD. FactorsNHR95% CI Gender Male –0.9 Female –1.1 Smoking status Never smoked –0.6 Current/ex-smoker –1.0 Ethnicity Caucasian –1.0 Asian –1.0 EGFR status EGFR-positive –0.9 EGFR-negative –1.4 EGFR unmeasured –1.0 Performance status 0– –0.9 2– –1.0 Histology Adenocarcinoma –0.9 Squamous cell carcinoma –0.9 Other histology –1.5 Prior regimens –1.0 > – Decreased risk of death Increased risk of death

EGFR Monoclonal Antibody Cetuximab IgG1 (chimerized antibody) IgG1 (chimerized antibody) Exclusive for EGFR and its heterodimers Exclusive for EGFR and its heterodimers Prevents repair and survival of tumor cells damaged by effects of chemotherapy and radiotherapy Prevents repair and survival of tumor cells damaged by effects of chemotherapy and radiotherapy –Potentiates apoptosis –Inhibits cell-cycle progression –Decreases production of angiogenic factors –Inhibits invasion/metastasis Recent FDA approvals for squamous cell carcinoma of the head and neck and colorectal cancer Recent FDA approvals for squamous cell carcinoma of the head and neck and colorectal cancer

Cetuximab in Advanced NSCLC ReferenceRegimenN Overall Response Rate (%) Median Survival (Mo) 1-Year Survival (%) *Lilenbaum ASCO 2005 Cetuximab Thienelt J Clin Oncol 2005 Carboplatin/paclitaxel/ cetuximab Rosell ASCO 2004 Cisplatin/vinorelbine/ cetuximab Cisplatin/vinorelbine Robert J Clin Oncol 2005 Carboplatin/gemcitabine/ cetuximab *Kim ASCO 2003 Docetaxel/cetuximab — Kelly ASCO 2006 Chemotherapy + cetuximab Chemotherapy → cetuximab *1 or more prior therapies

Other Targeted Agents Mammalian target of rapamycin (mTOR) inhibitors Mammalian target of rapamycin (mTOR) inhibitors Insulin growth factor receptor antagonists Insulin growth factor receptor antagonists Histone deacetylase inhibitors (HDACs) Histone deacetylase inhibitors (HDACs) Bortezomib Bortezomib Next-generation EGFR tyrosine kinase inhibitors Next-generation EGFR tyrosine kinase inhibitors –HKI-272 Toll-like receptor (TLR) antagonists Toll-like receptor (TLR) antagonists

Downstream Targets in the Tyrosine Kinase Pathway MAP = mitogen-activated protein; MEK = MAPK kinase; mTOR = mammalian target of rapamycin; P13K = phosphatidylinositol 3-kinase. Adapted from Cancer Control, 2003;10(2):125, with permission from H. Lee Moffitt Cancer Center and Research Institute, Inc. Receptor Tyrosine Kinase Cell Cycle Progression Proliferation Apoptosis CDKs P70S6K mTOR Akt P13K ERK/MAP kinase MEK Raf Ras

1. CCI-779 protocol available at: 2. Milton DT, et al. J Clin Oncol. 2005;23(No. 16S):646s. Abstract Kris MG, et al. J Clin Oncol. 2007;25(No. 18S). Abstract mTOR = mammalian target of rapamycin. Examples of mTOR Inhibitors Under Evaluation for Lung Cancer Temsirolimus (CCI-779): ongoing phase II trial in 1st-line therapy of stage IIIB or IV NSCLC 1 Temsirolimus (CCI-779): ongoing phase II trial in 1st-line therapy of stage IIIB or IV NSCLC 1 –Recent FDA approval for advanced renal cell carcinoma Everolimus (RAD 001): preliminary data from phase I/II studies in combination with EGFR tyrosine kinase inhibitors reported 2,3 ; phase II studies ongoing Everolimus (RAD 001): preliminary data from phase I/II studies in combination with EGFR tyrosine kinase inhibitors reported 2,3 ; phase II studies ongoing