1. 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

2. Protocol C-08 Disclosure: >50 YEARS
Norman Wolmark is an unpaid member of Genentech and Sanofi-Aventis advisory boards

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

4. NSABP C-08
mFF6 q2wk X 6 mo R
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: % ↓ ev rate (HR = 0.75)

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

7. Patient Characteristics
NSABP C-08
Patient Characteristics
mFF6
mFF6+B
< 60 yr
58.3
58.2
Male
49.8
49.9
Stage II (0)
24.9
Stage III (1-3)
45.4
45.5
Stage III (4+)
29.7
29.6

8. NSABP C-08 Grade 3+ Toxicities Increased with Bevacizumab (%)
<0.001
<0.0001 P
1.7
0.3
Wound Comp
2.7
0.8
Proteinuria
11.1
6.3
Pain 12
1.8
Hypertension
mFF6+B
mFF6
Median Duration of Bev = 11.5 months
Allegra et al JCO May 4, 2009

9. Roche's Avastin Fails in Study
APRIL 22, 2009, 7:19 A.M. ET
Roche's Avastin Fails in Study
By JEANNE WHALEN and JULIA MENGEWEIN

10. NSABP C-08
DFS

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

12. NSABP C-08
DFS HR P
mFF6+B
mFF6

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

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

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

16. Time-Treatment InteractionEv
mFF6+B
mFF
HR 1.07 P
Event-free at 1 Yr
DFS at 1 Yr
Ev 1yDFS
mFF6+B
mFF
HR 0.60 P
∆ 3.6
Time-Treatment Interaction
P = 0.001
NSABP C-08

17. NSABP C-08
DFS
and Stage
Sap submitted to fda limited to St III

18. DFS Stage II DFS Stage III
Ev 3yDFS
mFF6+B
mFF
HR 0.82 P
DFS Stage II
Ev 3yDFS
mFF6+B
mFF
HR 0.90 P
DFS Stage III
Δ 1.8
Δ 2.7
NSABP C-08

19. Was there a “rebound” or harmful effect associated with Bev?
NSABP C-08
Was there a “rebound”
or harmful effect
associated with Bev?

20. “Evasive Resistance” - ? ↑metastasis escape Response (dormancy)
Metastatic murine models; cytokine flare; class effect
Plagiarized from Paez-Ribes
Cancer Cell March ‘09 20

21. Status at 36 mo Med Follow-up
NSABP C-08
Status at 36 mo Med Follow-up
mFF6
mFF6+B P
Recurrence (N)
248
227 NS
Death (N)
146
132
Second Ca (N) 46 47
2yS Post Rec (%) 41 37
Rec Mult Sites (%) 18
Sites of Rec –
Primum non nocere 2 yrs post bev
Primum non nocere

22. Stage ll + lll FF4 FF4 + B Xelox + B
AVANT BO17920
Stage ll + lll
Strat: # Pos. N
12 ’04- 5 ‘07
N=3450
Randomize
FF4
FF4 + B
Xelox + B
Hope springs eternal

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
Gave bev 6 mo beyond chemo

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

25. The 2710 patients Acknowledgement The 292 NSABP centers
The NCI: U10CA-12027, , , and
Genentech
Sanofi-Aventis
Study Chair: Carmen Allegra
Statistician: Greg Yothers
The 2710 patients