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

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

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

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

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)

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

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

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

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

NSABP C-08 DFS

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

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

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

NSABP C-08 HR 0.08 0.05 0.02 0.004 0.0004

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

Time-Treatment Interaction 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 NSABP C-08

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

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

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

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

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

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

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

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

The 2710 patients Acknowledgement The 292 NSABP centers The NCI: U10CA-12027, -69974, -37377, and -69651 Genentech Sanofi-Aventis Study Chair: Carmen Allegra Statistician: Greg Yothers The 2710 patients