1. Targeting VEGF for the Treatment of Colorectal Cancer Herbert Hurwitz Duke University Medical Center Durham, North Carolina, USA

2. Phase III trial of IFL ± BV in MCRC study design IFL bolus 5-FU 500mg/m 2 leucovorin 20mg/m 2 irinotecan 125mg/m 2 given 4/6 weeks Option of BV at PD No BV at PD Hurwitz H, et al. N Engl J Med 2004;350:2335–42 5-FU/LV bolus 5-FU 500mg/m 2 leucovorin 500mg/m 2 given 6/8 weeks Bevacizumab 5mg/kg every 2 weeks Previously untreated metastatic CRC PD Bolus IFL + placebo (n=412) Bolus IFL + bevacizumab (n=403) 5-FU/LV + bevacizumab (n=110)

3. Survival Probability of survival 1.0 0.8 0.6 0.4 0.2 0 010203040 Survival (months) IFL + placebo IFL + bevacizumab Median survival (months) IFL + placebo: 15.6 vs IFL + bevacizumab: 20.3 HR: 0.66, p=0.00004 HR = hazard ratio Source: Hurwitz H et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colon cancer. N Eng J Med 2004;350(23):2335-42. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

4. Bevacizumab plus chemotherapy in 1 st Line CRC StudyGroup AVF2107gBevacizumab/ IFL vs placebo/ IFL AVF2192gBevacizumab/ 5-FU vs placebo/ 5-FU AVF0780gBevacizumab/ 5-FU vs placebo/ 5-FU AVF2107gBevacizumab/ Arm 35-FU vs IFL/ 5-FU 0.20.40.6123456 PatientsLower Upper (n) CL HR CL 8130.550.670.82 2090.580.801.11 710.250.521.08 2100.530.741.03 CL = confidence limit HR

5. Adverse Events *p<0.01 vs placebo NB: not adjusted for different time on therapy IFL + placebo (n=397) IFL + bevacizumab (n=393) Any grade 3/4 event74.084.9* Event leading to study discontinuation 7.18.4 Event leading to death2.82.6 60-day mortality4.93.0 Patients (%) Hurwitz H, et al. N Engl J Med 2004;350:2335–42

6. IFL-related Adverse Events NB: not adjusted for different time on therapy Hurwitz H, et al. N Engl J Med 2004;350:2335–42

7. 2 nd Line FOLFOX-4 ± BV (E3200) study design FOLFOX4 Oxaliplatin 85mg/m 2 i.v. over 120 minutes, day 1 LV 200mg/m 2 i.v. over 120 minutes, days 1 and 2 5-FU 400mg/m 2 i.v. bolus followed by 5-FU 600mg/m 2 i.v. over 22 hours, days 1 and 2 Bevacizumab 10mg/kg every 2 weeks FOLFOX4 + placebo FOLFOX4 + bevacizumab Bevacizumab alone Giantonio B, et al. Proc Am Clin Oncol GI Symposium 2004 (Abstract 241) PS = performance status RT = radiotherapy Previously treated metastatic CRC Stratification factors: PS: 0 vs 1, 2 Prior RT

8. E3200: overall survival Probability 1.0 0.8 0.6 0.4 0.2 0 Overall survival (months) 0369121518212427303336 AliveDeadMedianTotal A: FOLFOX4 + bevacizumab2892464312.9 B: FOLFOX42902573310.8 C: Bevacizumab2432162710.2 HR=0.76 A vs B: p=0.0018 B vs C: p=0.95 HR = hazard ratio Source: With permission. Giantonio BJ et al. Presentation. ASCO 2005. Abstract 2 10.212.9 10.8

9. E3200: grade 3/4 toxicity FOLFOX4 + bevacizumab (n=287) FOLFOX4 (n=284) Bevacizumab (n=234) p-value Grade 3Grade 4Grade 3Grade 4 Grade 3 Grade 4A vs B Hypertension (%)512<1700.018 Bleeding (%)3<1 0200.011 Neuropathy (%)16<19 0.016 Vomiting (%)913<1500.010 Proteinuria (%)1000<100.25 Source: With permission. Giantonio BJ et al. Presentation. ASCO 2005. Abstract 2

10. TREE-1 and TREE-2 First-line metastatic CRC (n=223) FOLFOX + BV (5mg/kg every 2 weeks) CAPEOX + BV (7.5mg/kg every 3 weeks) bFOL + BV (5mg/kg every 2 weeks) PD Endpoints: grade 3/4 toxicity, response rate and time to progression TREE1 = same design w/o BV (n=150) bFOL = bolus 5-fluorouracil/oxaliplatin/leucovorin

11. mFOLFOX6 – TREE-1 vs TREE-2 Response Rate *Not all responses confirmed. Hochster et al. ASCO, 2005. Abstract 3515. Updated from poster presentation. mFOLFOX6+ bevacizumab bFOL – bFOL+ bevacizumab CapeOx – CapeOx+ bevacizumab

12. TREE-2 Grade 3/4 Toxicities % of Patients Adverse Event mFOLFOX6 + Bevacizumab (n=71) bFOL + Bevacizumab (n=70) CapeOx + Bevacizumab (n=72) Vomiting31310 Dehydration6138 Diarrhea132720 Neutropenia451710 Febrile neutropenia310 Hand-foot syndrome0010 Neurotoxicity (gr. 3)141115 Hypertension9714 Bleeding441 Thrombosis (arterial)004 Proteinuria111 Any grade 3/4857375 Hochster et al. ASCO, 2005. Abstract 3515. Updated from poster presentation.

13. Possible BV-related Toxicity NB: not adjusted for different time on therapy *p<0.05 Hurwitz H, et al. N Engl J Med 2004;350:2335–42

14. GI Perforations in MCRC No. of Patients No. of Patients With GI Perforation (%) AVF2192g 5-FU/LV + placebo1040 (0) 5-FU/LV + bevacizumab1002 (2) AVF2107g IFL + placebo396 1 (0.3) IFL + bevacizumab392 6 (1.5) 5-FU/LV + bevacizumab1094 (3.7) E3200 Bevacizumab2343 (1.3) FOLFOX4 + placebo2840 (0) FOLFOX4 + bevacizumab2873 (1.0) Bevacizumab PI: (bevacizumab) PI; Giantonio et al. ASCO, 2005. Abstract 2. Updated from oral presentation; Kabbinavar et al. J Clin Oncol. 2005;23:3697.

15. Surgical wound healing complications The longest interval between last dose of therapy and dehiscence was 56 days Avastin PI February 2004

16. Bleeding complications during full dose anti- coagulation: IFL +/- BV *Median duration of warfarin therapy with bevacizumab = 181 vs 218 days Bevacizumab PI February 2004

17. Arterial Thromboembolic Events in Trials of Bevacizumab + Chemotherapy % of Patients Chemotherapy Alone (n=782) Bevacizumab + Chemotherapy (n=963) ATEs (overall)*1.94.4 Cerebrovascular0.51.9 Cardiovascular1.02.1 Fatal0.40.7 Rate/ 100pt*yrs3.15.5 (p=0.76) Hazard Ratio1.99 (p=0.03) *From an exploratory analysis pooling data from 5 randomized, controlled clinical trials of bevacizumab in combination with chemotherapy vs chemotherapy alone (N=1745). ATEs included cerebral infarction, myocardial infarction, transient ischemic attacks, and angina In multivariate analysis, only age >65 y and prior history of ATE were risk factors for developing ATEs Skillings et al. ASCO, 2005. Abstract 3019. Updated from poster presentation. Bevacizumab PI Bevacizumab therapy should be permanently discontinued in patients who experience a severe ATE

18. Arterial Thromboembolic Events (ATE) by Risk Group: Pooled Analysis No. of Patients/n (%)Hazard Ratio † Baseline Risk Factor Chemotherapy + Placebo Chemotherapy + BevacizumabPFSOS All patients13/782 (1.7)37/963(3.8)0.540.66 None5/490 (1.0)11/602(1.8)0.530.73 Age ≥65 y*7/279 (2.5)24/339(7.1)0.570.61 History of ATEs*2/59 (3.4)14/89(15.7)0.610.38 Age ≥65y + history of ATEs 1/46 (2.2)12/67(17.9)0.550.59 *These groups are not mutually exclusive; † Patients from AVF2107g only. Skillings et al. ASCO, 2005. Abstract 3019. Updated from poster presentation.

19. Conclusions The addition of bevacizumab to 5FU based chemotherapy improves survival, progression-free survival, and response rate for both 1 st and 2 nd line colorectal cancer Chemotherapy side effects are not increased HTN is common but is readily manageable Important but uncommon side effects include: arterial thromboembolic events, GI perforation, altered wound healing, proteinura, bleeding.