1.  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

2. 1.0 0.6 0.8 0.2 0.0 0.4 0162144101286 Probability of Survival Survival Time (Months) 5.65.1 27 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

3. 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)

4. *HR and P-value adjusted for stratification factors at randomization and HER1/EGFR status Adapted from Shepherd FA, et al. N Engl J Med, 353:123-132, 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) 6.7 4.7 1-y survival (%) 31.2 21.5 Months Erlotinib Placebo 100 80 60 40 20 0 0612182430 No. at Risk Placebo24310750900 Erlotinib4882551452340

5. BR.21 Survival Across Subgroups Adapted from Tarceva ® (erlotinib) Product Information. Melville, NY: OSI Pharmaceuticals, Inc, and Genentech, Inc; 2007. Courtesy of Dr. A. Sandler, MD. FactorsNHR95% CI Gender Male4750.760.6–0.9 Female2560.800.6–1.1 Smoking status Never smoked1460.420.3–0.6 Current/ex-smoker5450.870.7–1.0 Ethnicity Caucasian5670.790.6–1.0 Asian910.610.4–1.0 EGFR status EGFR-positive1850.680.5–0.9 EGFR-negative1410.610.6–1.4 EGFR unmeasured4050.770.6–1.0 Performance status 0–14860.730.6–0.9 2–32450.770.6–1.0 Histology Adenocarcinoma3650.710.6–0.9 Squamous cell carcinoma2220.670.5–0.9 Other histology1441.040.7–1.5 Prior regimens 13640.760.6–1.0 >23670.750.6–1.0 1.000.500.001.502.00 Decreased risk of death Increased risk of death

6. 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

7. Cetuximab in Advanced NSCLC ReferenceRegimenN Overall Response Rate (%) Median Survival (Mo) 1-Year Survival (%) *Lilenbaum ASCO 2005 Cetuximab663.38.143 Thienelt J Clin Oncol 2005 Carboplatin/paclitaxel/ cetuximab 31261140 Rosell ASCO 2004 Cisplatin/vinorelbine/ cetuximab Cisplatin/vinorelbine 43 35 28 8.3 7.0 32 26 Robert J Clin Oncol 2005 Carboplatin/gemcitabine/ cetuximab 352910.246 *Kim ASCO 2003 Docetaxel/cetuximab47257.5— Kelly ASCO 2006 Chemotherapy + cetuximab Chemotherapy → cetuximab 106 119 37 25 10 9 49 43 *1 or more prior therapies

8. 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

9. 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

10. 1. CCI-779 protocol available at: http://www.clinicaltrials.gov/ct/show/NCT00079235?order=1. 2. Milton DT, et al. J Clin Oncol. 2005;23(No. 16S):646s. Abstract 7104. 3. Kris MG, et al. J Clin Oncol. 2007;25(No. 18S). Abstract 7575. 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