1. NSABP C08 adjuvant colon cancer Best of ASCO, Beirut, July 2009 Prof Eric Van Cutsem, MD, PhD Digestive Oncology Leuven, Belgium

2. A phase III trial assessing bevacizumab in stage II and III carcinoma of the colon: Results of NSABP Protocol C-08 N.Wolmark G.Yothers M.J.O’Connell S.Sharif N.Atkins T.E.Seay L.Feherenbacher S.O’Reilly and C.J.Allegra

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

4. NSABP C-08 R mFF6 q2wk X 6 mo Bev* q2wk X 1 yr *5mg/K

5. NSABP C-08 Duration: 09-04 - 10-06 Accrual: 2710 Med F-U: 35.6 mo End Pt: DFS (592 /603 ev) Stats: 25% ↓ ev rate (HR = 0.75)

6. NSABP C-08 Accrual mFF6 mFF6+B Randomized Lost / Ineval Analysis 1356 18 1338 1354 16 1334

7. mFF6mFF6+B < 60 yr 58.358.2 Male 49.849.9 Stage II (0) 24.9 Stage III (1-3) 45.445.5 Stage III (4+) 29.729.6 NSABP C-08 Patient Characteristics

8. <0.001 <0.0001 P 1.70.3 Wound Comp 2.70.8 Proteinuria 11.16.3 Pain 121.8 Hypertension mFF6+BmFF6 Allegra et al JCO May 4, 2009 Median Duration of Bev = 11.5 months NSABP C-08 Grade 3+ Toxicities Increased with Bevacizumab (%)

9. Ev 3yDFS mFF6+B 291 77.4 mFF6 312 75.5 HR 0.89 P 0.15 NSABP C-08 DFS % Yrs

10. NSABP C-08 DFS HR 0.89 P 0.15 mFF6+B mFF6

11. Was there a significant transient effect of bevacizumab? NSABP C-08 Cumulative HR over time

12. NSABP C-08 HR Yrs HR

13. NSABP C-08 HR 0.0004

14. NSABP C-08 HR 0.0004 0.004

15. NSABP C-08 HR 0.0004 0.004 0.02

16. NSABP C-08 HR 0.0004 0.004 0.02 0.05

17. NSABP C-08 HR 0.0004 0.004 0.02 0.05 0.08

18. Was there a significant interaction between the effect of Bev and time? NSABP C-08

19. Ev mFF6+B 216 mFF6 190 HR 1.07 P 0.48 Event-free at 1 Yr DFS at 1 Yr Ev 1yDFS mFF6+B 75 94.3 mFF6 122 90.7 HR 0.60 P 0.0004 ∆ 3.6 Time-Treatment Interaction P = 0.001

20. DFS and Stage NSABP C-08

21. Ev 3yDFS mFF6+B 40 87.4 mFF6 47 84.7 HR 0.82 P 0.35 DFS Stage II Δ 2.7 Ev 3yDFS mFF6+B 251 74.2 mFF6 265 72.4 HR 0.90 P 0.25 DFS Stage III Δ 1.8 NSABP C-08

22. mFF6mFF6+BP Recurrence (N) 248227NS Death (N) 146132NS Second Ca (N) 4647NS 2yS Post Rec (%) 4137NS Rec Mult Sites (%) 1818NS Sites of Rec ––NS NSABP C-08 Status at 36 mo Med Follow-up Primum non nocere

23. Conclusions The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS There was a transient benefit in DFS during the one year that bevacizumab was utilized

24. Conclusions Consideration should be given to clinical trials assessing longer duration of bevacizumab administration

25. Finding the Niche Bevacizumab in Adjuvant CRC or... “What if Norman’s Right?” Lee M. Ellis, MD Departments of Surgical Oncology and Cancer Biology UT MD Anderson Cancer Center Houston, Texas, USA

26. What Can We Learn From This Negative Trial? >2,500 patients participated in this trial –It is our responsibility to extract as much information and insight from this trial in order to advance the field The most interesting finding in this trial…. There “appeared” to be an early benefit in the FOLFOX + Bev arm – What is the biology behind this observation? – Can we use the knowledge of biology to design future trials?

27. Three Hypotheses/Possibilities Are Raised By The C08 Trial The addition of bevacizumab to FOLFOX does not add benefit…..at all There is some benefit to adding Bev to FOLFOX, but this is dependent upon the longer duration of bevacizumab + chemotherapy There is some benefit to adding Bev to FOLFOX, but this is dependent upon the longer duration of bevacizumab therapy

28. Is The Early Improvement in HR a Statistical Fluke? I do not think so There is biology to explain this observation AVANT trial for validation

29. If The Early Benefit is Real, It Should Also be Observed in the AVANT Adjuvant Colon Cancer Study n=3451 Stage III or high-risk stage II colon cancer FOLFOX4 q2wk Bev 7.5 mg/kg q3wk 24 Weeks 48 Weeks Stratified by stage and region 1:1:1 Bev 5 mg/kg, q2wk XELOX q3wk 3451 patients were enrolled between November 2004 and June 2007 Primary analysis: compare DFS between control and each treatment arm in stage III patients Projected final analysis time: Q3, 2010 FOLFOX4 q2wk Bevacizumab 7.5 mg/kg q3wk

30. Several Preclinical Studies Suggest That Anti- VEGF Therapy Can Accelerate Metastasis Could the initial benefit of Bev be offset by a later increase in metastasis?

31. 0.00.51.01.52.02.53.03.5 0 20 40 60 80 100 NO: It Does Not Appear That Bev Lead to a Paradoxical Increase in Metastasis BUT We Will Need Longer Follow-up to See If the Curves Cross There is no evidence from other CRC trials that Bev could lead to an increase in metastasis in CRC. But…..longer follow-up is necessary!! More on the need for longer follow-up later in this presentation The percent of patients with recurrence at multiple sites was the same in both arms (18/18%).

32. Three Hypotheses/Possibilities Are Raised By The C08 Trial The addition of bevacizumab to FOLFOX does not add benefit…..at all There is some benefit to adding Bev to FOLFOX, but this is dependent upon the longer duration of bevacizumab + chemotherapy –This implies that a longer duration of Bev + chemotherapy (if feasible) could lead to prolonged improvement in DFS There is some benefit to adding Bev to FOLFOX, but this is dependent upon the longer duration of bevacizumab therapy

33. The Purpose of Adjuvant CHEMOTHERAPY is to Increase the Cure Rate by Eradicating Microscopic Tumor Deposits! Did The Addition of Bevacizumab to FOLFOX Increase the Cure Rate? Sargent et al. “Evidence for Cure by Adjuvant Therapy in Colon Cancer……” JCO, 2009

34. 0.00.51.01.52.02.53.03.5 0 20 40 60 80 100 No! The Addition of Bevacizumab to FOLFOX Did Not Increase the Cure Rate - Eventually the Microscopic Tumor Deposits Became Macroscopic This is important and I will come back to this later in this talk. In the metastatic setting, the vast majority of patients who experience a response, do so within the first 4 months. There is no reason to believe that longer term combination therapy (or single agent Bev) will lead to more cures.

35. There Is Some Benefit To Adding Bev To FOLFOX, But This Is Dependent Upon The Longer Duration Of Bevacizumab Therapy If so, bevacizumab should be administered longer But…..there are issues! –How much longer? –How much will it cost? –What are the long term adverse events? –Is this feasible????? Hypothesis #3