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

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Traditional Therapeutic Development Paradigm

Safety

Activity in advanced disease

Efficacy in advanced disease

Test in adjuvant setting

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Recent Data Suggests this Paradigm for Adjuvant CRC

Development May be Flawed

Oxaliplatin success Irinotecan fail Cetuximab fail Bevacizumab fail

Batting .250!!

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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, 20072 Saltz et al JCO April, 2008

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NSABP C-08

Stage ll + lll

mFF6+B

mFF6

Randomize

Strat: # Pos. N

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mFOLFOX 6 + B

q2w6 mo

B: 5 mg/kg IV q2 wks x 1yr

400 2400 (46 hrs)

85

400

Ox

5FU

LV

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C-08Accrual

mFF6 mFF6+B

RandomizedLost / InevalAnalysis

1356 181338

1354 161338

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mFF6 mFF6+B< 60 yr 58.3 58.2Male 49.8 49.9Stage II (0) 24.9 24.9Stage III (1-3) 45.4 45.5Stage III (4+) 29.7 29.6

C-08Patient Characteristics (%)

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Grade 3+ Toxicities Increased with Bevacizumab (%)

<0.001

<0.001<0.0001

<0.0001

P

1.70.3Wound Comp

2.70.8Proteinuria

11.16.3Pain

121.8Hypertension

mFF6+BmFF6

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Grade 3+ Toxicities During the 9 mo Period Beginning 3 mo post

Therapy Completion (%)

mFF6 mFF6+BHypertension 0.6 0.7Pain 1.1 1.1Proteinuria 0.1 0ATE 0.1 0.5VTE 0.4 0.2Hemorrhage 0.3 0.3

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C-08 Disease-free Survival - Median FU 56 mos.

Years from Randomization

Perc

ent A

live

and

Dis

ease

-free

0 1 2 3 4 5

020

4060

8010

0

mFF6, 1338 Pts, 375 EventsmFF6+Bev, 1335 Pts, 368 EventsHR = 0.93, 95% CI (0.81-1.08)P = 0.34

1180 1036 952 798 182 1240 1086 991 819 173

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C-08 DFS Hazard Rate Over Time

Years from Randomization

DFS

Haz

ard

Rat

e (E

vent

s/Pa

tient

-yea

r)

0 1 2 3 4

0.00

0.04

0.08

0.12

mFF6mFF6+Bev

Borderline significant detriment post landmark.Time-Treatment Interaction Remains Significant P < 0.0001.

C-08 DFS – Median FU 56 mos.Censored at 1.25 Years

Years from Randomization

Perc

ent A

live

and

Dis

ease

-free

0 0.25 0.50 0.75 1.00

020

4060

8010

0

mFF6, 1338 Pts, 171 EventsmFF6+Bev, 1335 Pts, 109 EventsHR = 0.61, 95% CI (0.48-0.78)P < 0.0001

Conditional on Event-free, 1.25 Years

Years from Randomization

1.25 2 3 4 5

mFF6, 1128 Pts, 204 EventsmFF6+Bev, 1204 Pts, 259 EventsHR = 1.20, 95% CI (1.00-1.44)P = 0.052

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C-08 Overall Survival

Years from Randomization

Perc

ent A

live

0 1 2 3 4 5

020

4060

8010

0

mFF6, 1341 Pts, 224 DeathsmFF6+Bev, 1337 Pts, 218 DeathsHR = 0.96, 95% CI (0.79-1.15)P = 0.64

1268 1205 1135 942 204 1289 1233 1163 950 204

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C-08 Colorectal Cancer Specific Survival

Years from Randomization

Perc

ent A

live

or D

ied

of O

ther

Cau

ses

0 1 2 3 4 5

020

4060

8010

0

mFF6, 1338 Pts, 176 Colon Cancer Deaths mFF6+Bev, 1335 Pts, 172 Colon Cancer DeathsHR = 0.96, 95% CI (0.78-1.18)P = 0.71

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C-08 Overall Survival in Stage III

Years from Randomization

Perc

ent A

live

0 1 2 3 4 5

020

4060

8010

0

mFF6, 1009 Pts, 194 DeathsmFF6+Bev, 1003 Pts, 200 DeathsHR = 1.02, 95% CI (0.83-1.24)P = 0.88

956 903 849 696 148 968 919 859 691 146

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C-08 Survival After Recurrence

Years from Recurrence to Death

Perc

ent A

live

Afte

r Rec

urre

nce

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

020

4060

8010

0C-08 Survival After Recurrence

mFF6, 283 Recur, 176 DeathsmFF6+Bev, 274 Recur, 172 DeathsHR = 1.16, 95% CI (0.94-1.43)P = 0.17

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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

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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

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