NSABP Overall Survival and Updated Disease-Free Survival Results of the NSABP C-08 Trial Assessing...

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

NSABP

Traditional Therapeutic Development Paradigm

Safety

Activity in advanced disease

Efficacy in advanced disease

Test in adjuvant setting

NSABP

Recent Data Suggests this Paradigm for Adjuvant CRC

Development May be Flawed

Oxaliplatin success Irinotecan fail Cetuximab fail Bevacizumab fail

Batting .250!!

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, 20072 Saltz et al JCO April, 2008

NSABP

NSABP C-08

Stage ll + lll

mFF6+B

mFF6

Randomize

Strat: # Pos. N

NSABP

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