1. Cytotoxic Chemotherapy Produces Limited Benefit in Stage IV NSCLC All recent randomized chemotherapy studies have similar results Median survival: 8 mo 1-y survival: 34% A paradigm shift is needed! Adapted from Schiller JH et al. N Engl J Med. 2002;346:92, with permission. Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel 100 80 60 40 20 0 051015202530 Months Survival (%)

2. VEGF A Key Mediator of Angiogenesis Binding and activation of VEGFR Environmental factors (Hypoxia, pH) Growth factors Hormones (EGF, bFGF, PDGF, IGF-1, IL-1 , IL-6, estrogen) Genes involved in tumorigenesis (p53, p73, src, ras, vHL, Scr-Abl) P P P P ANGIOGENESIS ProliferationSurvivalMigration Endothelial cell activation Increased VEGF levels VEGF = vascular endothelial growth factor; EGF = epidermal growth factor; bFGF = basic fibroblastic growth factor; PDGF = platelet-derived growth factor; IGF = insulin-like growth factor; IL = interleukin; VEGFR = VEGF receptor. Adapted from Gerber H-P, et al. Cancer Res. 2005;65:671, with permission from the American Association for Cancer Research.

3. rhuMAb VEGF Bevacizumab Humanized to avoid immunogenicity Humanized to avoid immunogenicity –93% human, 7% murine Recognizes all isoforms of VEGF, K d = 1.1 nmol/L Recognizes all isoforms of VEGF, K d = 1.1 nmol/L Terminal t 1/2 = 20 days Terminal t 1/2 = 20 days 1st phase I done at MDACC 1st phase I done at MDACC Gerber H-P, et al. Cancer Res. 2005;65:671.

4. Bevacizumab Phase III Study (E4599) BV 15 mg/kg q3wk until progression or unacceptable toxicity 1st-line treatment of patients with stage IIIB with malignant pleural effusion, stage IV, or recurrent NSCLC (N = 878) 1st-line treatment of patients with stage IIIB with malignant pleural effusion, stage IV, or recurrent NSCLC (N = 878) Bevacizumab 15 mg/kg + PC q3wk (BV/PC) × 6 (unless progression or unacceptable toxicity) Bevacizumab 15 mg/kg + PC q3wk (BV/PC) × 6 (unless progression or unacceptable toxicity) Paclitaxel 200 mg/m 2 + carboplatin AUC 6 mg/mL/min (PC) q3wk x 6 (unless progression or unacceptable toxicity) Paclitaxel 200 mg/m 2 + carboplatin AUC 6 mg/mL/min (PC) q3wk x 6 (unless progression or unacceptable toxicity) (No crossover permitted) Endpoints Primary: Overall survival Secondary: Response rates Progression-free survival Toxicity Sandler A, et al. N Engl J Med. 2006;355:2542. Stratified by Disease stage Degree of weight loss Prior radiotherapy Measurable disease

5. Phase III Trial of Bevacizumab Overall Survival BV/PC PC HR: 0.79, P =.003 0 20 40 60 80 100 Overall Survival (%) 0642481830 122436 Month Median 12.3 mo Median 10.3 mo Adapted from Sandler A, et al. N Engl J Med. 2006;355:2442, with permission. PC = paclitaxel/carboplatin; BV = bevacizumab; HR = hazard ratio.

6. Phase III Trial of Bevacizumab Adverse Events 5.2 2.0Febrile neutropenia 2 2.30.5Pulmonary hemorrhage 1 3.0 1.4Arterial thrombotic events 1 * Some events are reported as >1 site. 3.0 0.0Severe proteinuria 2 7.0 0.7Hypertension (grade 3 or 4) 2 0.9 0.0 Gastrointestinal perforation 1 4.71.1Severe or fatal hemorrhage 1,* BV/PC (n = 427) PC (n = 440) Event Patients (%) 1. Avastin (bevacizumab). Product Information. San Francisco, CA: Genentech; 2006. 2. Sandler A, et al. N Engl J Med. 2006;355:2542. PC = paclitaxel; BV = bevacizumab.

7. Rationale for Combination Targeted Therapy for Advanced NSCLC Herbst RS, et al. J Clin Oncol. 2005;23:2544. Reprinted with permission from the American Society of Clinical Oncology. bFGF = basic fibroblast growth factor; TGF-  = transforming growth factor alpha.

8. ChemotherapyBevacizumab +Bevacizumab + Alone (n = 41)Chemo (n = 40)Erlotinib (n = 39) Progression-free survival Median, months3.04.84.4 Adjusted hazard ratio* (95% Cl)NA0.66 (0.38, 1.16)0.72 (0.42, 1.23) Overall survival 6-month rate, %62.472.178.3 Response rate, n (%) CR.PR5 (12.2)5 (12.5)7 (17.9) CR/PR/SD16 (39.0)21 (52.5)20 (51.3) ChemotherapyBevacizumab +Bevacizumab + Alone (n = 41)Chemo (n = 40)Erlotinib (n = 39) Drug discontinuation due to AE, n (%)10 (24)10 (25)4 (10) SAEs, n (%)22 (54)16 (40)13 (33) Grade 5 drug-related AEs2 (5)3 (8)1 (3) Pulmonary hemorrhage (grade 3–5)02 (5)1 (3) Bevacizumab Combination Regimens Efficacy and Safety Summary EFFICACY SUMMARY SAFETY SUMMARY Fehrenbacher L, et al. 42nd ASCO; June 2-6, 2006. Abstract 7062. Courtesy of Dr. L. Fehrenbacher. *Adjusted by randomization stratification factors (ECOG PS, smoking history)

9. Ongoing Randomized Studies with Bevacizumab/Erlotinib Combined Atlas (1st-line) 1 Beta (2nd-line) 2 PD = progressive disease. 1. http://clinicaltrials.gov/ct/show/NCT00257608?order=1. 2. http://clinicaltrials.gov/ct/show/NCT00130728?order=8. 1st-line stage IIIb/IV NSCLC (N = 1150) 2nd-line NSCLC (N = 650) Chemotherapy + bevacizumab x 4 RANDOMIZE (Patients w/o PD or sig. toxicity) Arm 1: bevacizumab + placebo to PD Arm 2: bevacizumab + erlotinib to PD RANDOMIZE Arm 1: erlotinib + placebo to PD Arm 2: erlotinib + bevacizumab to PD

10. Characteristics of VEGFR TKIs DrugHalf-Life (h)IC 50 (nM)*Other VEGFR-1VEGFR-2VEGFR-3PDGFRc-kit Sunitinib 1 44917810RET Sorafenib 2,3 25–48—90205768BRAF, Raf-1, V599E BRAF, Flt-3, FGFR-1 AZD2171 4 13–355<1<32 AMG 706 5 5–7236884RET ZD6474 6 ~1201600401101.1EGFR, TI-2, FGFR1 AG013736 7,8 2–51.20.250.29 Vatalanib 9 3–65439195567364 *Biochemical IC 50 values were determined using slightly different methods between the studies and are not directly comparable. 1. Mendel DB, et al. Clin Cancer Res. 2003;9:327. 2. Wilhelm SM, et al. Cancer Res. 2004;64:7099. 3. www.rxlist.com/cgi/generic/nexavar_cp.htm. 4. Wedge SR, et al. Cancer Res. 2005;65:4389. 5. Polverino A, et al. Cancer Res. 2006;66:8715. 6. Wedge SR, et al. Cancer Res. 2002;62:4645. 7. Rugo HS, et al. J Clin Oncol. 2005;23:5474. 8. Morabito A, et al. Oncologist. 2006;11:753. 9. Hess-Stumpp H, et al. ChemBioChem. 2005;6:550. New agent, BIBF 1120 reported to be a triple angiokinase inhibitor that targets VEGF, FGF, and PDGF receptors.