1. NSABP Overall Survival and Updated Disease-Free Survival Results of the NSABP C-08 Trial Assessing Bevacizumab in Stage II & III Colon Cancer CJ Allegra, GA Yothers, MJ O'Connell, S Sharif, NJ Petrelli, LH Colangelo, N Wolmark

2. NSABP Traditional Therapeutic Development Paradigm Safety Activity in advanced disease Efficacy in advanced disease Test in adjuvant setting

3. NSABP Recent Data Suggests this Paradigm for Adjuvant CRC Development May be Flawed  Oxaliplatinsuccess  Irinotecanfail  Cetuximabfail  Bevacizumabfail Batting.250!!

4. NSABP Oxaliplatin + Bev in Advanced CRC E3200 – FOLFOX +/- bev in previously treated CRC 1 –577 patients randomized –ORR 22.7% v 8.6% (p<0.0001) –PFS 7.3 v 4.7 months (p<0.0001) –OS 12.9 v 10.8 months (p=0.001) NO16966 – XELOX/FOLFOX +/- bev in untreated CRC 2 –1401 patients randomized –ORR 38% v 38% (p=0.99) –PFS 9.4 v 8.0 months (p=0.0023) –OS 21.3 v 19.9 months (p=0.077 1 Giantonio et al JCO April, 2007 2 Saltz et al JCO April, 2008

5. NSABP NSABP C-08 Stage ll + lll mFF6 + B mFF6 Randomize Strat: # Pos. N

6. NSABP mFOLFOX 6 + B q2w 6 mo B: 5 mg/kg IV q2 wks x 1yr 400 2400 (46 hrs) 85 400 Ox 5FU LV

7. NSABP C-08 Accrual mFF6mFF6+B Randomized Lost / Ineval Analysis 1356 18 1338 1354 16 1338

8. NSABP mFF6mFF6+B < 60 yr58.358.2 Male49.849.9 Stage II (0)24.9 Stage III (1-3)45.445.5 Stage III (4+)29.729.6 C-08 Patient Characteristics (%)

9. NSABP Grade 3+ Toxicities Increased with Bevacizumab (%) <0.001 <0.0001 P 1.70.3 Wound Comp 2.70.8 Proteinuria 11.16.3 Pain 121.8 Hypertension mFF6+BmFF6

10. NSABP Grade 3+ Toxicities During the 9 mo Period Beginning 3 mo post Therapy Completion (%) mFF6mFF6+B Hypertension0.60.7 Pain1.1 Proteinuria0.10 ATE0.10.5 VTE0.40.2 Hemorrhage0.3

11. NSABP

13. Borderline significant detriment post landmark. Time-Treatment Interaction Remains Significant P < 0.0001. C-08 DFS – Median FU 56 mos.

14. NSABP

18. Possible Explanations for the Apparent Decrease in Survival After Relapse Bev changes the biology of the disease to a more aggressive phenotype –do not see expected change in OS Bev is less effective and/or less frequently used in patients previously exposed to bev –do not see expected change in OS Bev alters our ability to detect an existing recurrence until later since CT relies on differences in vascularity & permeability –would not expect a change in OS

19. NSABP Conclusions Time varying effect of Bev on recurrence is still evident with 56 mos F/U Bev delays recurrence and may interfere with relapse detection during treatment, but does not prevent recurrence No evidence in C-08 for a negative impact of Bev exposure on DFS, time to recurrence, OS, or CC specific survival Our data further call into question our traditional paradigm of adjuvant colon drug development & support the need for new testing platforms in patients with minimal disease e.g. Stage 4 NED 19

20. NSABP Special Thank You NSABP investigators Our patients NSABP Ops office Clinical trials nurses and coordinators NSABP leadership and colleagues –Drs. Wolmark, O’Connell, Yothers & Sharif Industry & NCI Colleagues –Dr. Meg Mooney