nsabp overall survival and updated disease-free survival results of the nsabp c-08 trial assessing...
DESCRIPTION
NSABP Recent Data Suggests this Paradigm for Adjuvant CRC Development May be Flawed Oxaliplatinsuccess Irinotecanfail Cetuximabfail Bevacizumabfail Batting.250!!TRANSCRIPT
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
NSABP
C-08Accrual
mFF6 mFF6+B
RandomizedLost / InevalAnalysis
1356 181338
1354 161338
NSABP
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 (%)
NSABP
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
NSABP
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
NSABP
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
NSABP
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
NSABP
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
NSABP
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
NSABP
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
NSABP
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
NSABP
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
NSABP
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