2013 asco gi winterhalder
TRANSCRIPT
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A CC 2013
, 04. A 2013
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C C C /
G . J C 2011
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C C C /
A . . 3501
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C C C /
A . . 3501
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C C C /
A . . 3501
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C C C /
A . . 3501
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C C C /
A . . 3501
C / :1.
2. E E
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Primary endpoint: PFS2
Secondary endpoints: OS, TTP2 (time to progression or death
after PS1)
Phase III CAIRO-3: Bevacizumab + CT
maintenance vs observation
UntreatedmCRC
(N=635)
CR
PR
SD
Bevacizumab+ XELOX PD2
Bevacizumab+ capecitabine
PD1
PDnot eligible
PFS2PFS1
Bevacizumab+ XELOX
Observation
Rn=558
Koopman M, et al. ASCO 2013 (Abstract No. 3502)
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C C CA 3
A . . 3502
2 D
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C C CA 3
A . . 3502
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C C CA 3
A . . 3502
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C C CA 3
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C C CA 3
A . . 3502
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Phase III CAIRO-3: Bevacizumab + CT
maintenance vs observation
*Primary endpoint Koopman M, et al. ASCO 2013 (Abstract No. 3502)
Maintenance treatment with bevacizumab + capecitabine significantly increased PFS1and PFS2 compared with observation
There was no significant increase in OS
Bev + CT maintenance Observation
Median PFS1, mo 8.5 4.1
HR (95% CI), p-value HR 0.44 (95% CI 0.360.53), p
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C C CA 3
A . . 3502
:1. F 1, F 2 2 D
2.
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C C CA 3
A . . 3502
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Bevacizumab continuation versusno continuation after first-line
chemo-bevacizumab therapy in patients with metastatic
colorectal cancer:a randomized phase III non-inferiority trial
Koeberle D, Betticher D, von Moos R, Dietrich D, Brauchli P,Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S,Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M,Popescu R, Schacher S, Hess V, Herrmann R
Swiss Group for Clinical Cancer Reseach
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Non-inferiority study hypothesis: no bevacizumab vs bevacizumab
Non-inferiority design based on bevacizumab maintenance as control arm
Primary endpoint: TTP Secondary endpoints: PFS, OS (both from start of 1st line treatment),
time to 2nd line treatment, safety, costs
Phase III SAKK 41/06: No bev vs bev
maintenance in 1st line mCRC
Koeberle D, et al. ASCO 2013 (Abstract No. 3503)
Untreated
mCRC(Per-protocol:N=262)
Bevacizumab +CT
(46 months)
Bevacizumab7.5 mg/kg q3 wks
Observation
Maintenance therapy
Until PDRNoPD
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Study design
First-line chemo-therapy + BEVfor 4-6 months
NoPD
Randomization1: 1
BEV continuation(7.5 mg/kg q 3 w)
until PD
No antitumor treatment(no BEV) until PDStratification factors:
Best response during first-line chemotherapy + BEV (CR/PR vs SD) Duration of first-line chemotherapy + BEV (16-20 vs 21-24 weeks) Type of chemotherapy (Irinotecan + 5-FU vs Oxalipaltin + 5-FU vs
Fluoropyrimidine mono) Disease burden (metastases in one organ vs multiple organs) Center
Study conducted in 26 sites in Switzerland (accrual period 2007-2012)
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SAKK 41/06: No bev vs bev maintenance
*Primary endpoint Koeberle D, et al. ASCO 2013 (Abstract No. 3503)
Study failed to demonstrate non-inferiority of no bevacizumab(observation alone)
Bevacizumabmaintenance Observation
Median PFS, mo 9.5 8.5HR (95% CI), p-value HR 0.75 (95% CI 0.580.96), p=0.021
Median TTP*, mo 4.1 2.9
HR (95% CI), p-value HR 0.74 (95% CI 0.570.95), p=0.47Median OS, mo 25.1 22.8
HR (95% CI), p-value HR 0.83 (95% CI 0.611.12), p=0.218
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TTP subgroup analysis
0.5 0.727 1.0 1.5
BEV better no BEV better
allage < 60age > 60femalemaleWHO 0WHO 1FL CR/PRFL SD
FL dur 16-20FL dur 21-24FL iri + fluoFL oxa + fluoFL fluo mono1 organ>1 organs
Hazard Ratio (95% CI)
FL = First-line
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Cost analysis
Included resource use Base case 1) Low (-30%) High (+30%)
BEV continuation USD 5.58/mgBEV administration USD 372
Control visit to oncologist USD 165 115 215
In-patients USD 1600/day 1120/day 2080/day
CT-scan USD 663MRI USD 735
1) Swiss prices and Swiss health system
Not included costs: Laboratory tests, out-patient AE treatments,other out-patient treatments/care
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Cost analysis
BEV NO
BEV
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Summary
Non-inferiority could not be demonstrated
The difference in median TTP between BEVcontinuation versus no treatment after randomizationis 5 weeks
Overall survival in both arms is not significantlydifferent
Utility of BEV continuation needs to be balancedwith significantly higher treatment costs
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A . . 3506
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Primary endpoint: ORR
Secondary endpoints: PFS, OS, TFS, DpR, secondary resection rate,safety
Statistics: Designed to detect a difference of 12% in ORR induced by
FOLFIRI + cetuximab (62%) vs FOLFIRI + bevacizumab (50%)
284 evaluable patients needed to achieve 80% power for one-sidedFishers exact test at an alpha level of 2.5%
Patients with untreatedKRAS wt mCRC
N=592
FIRE-3: Head-to-head study of cetuximab + FOLFIRI vs
bevacizumab + FOLFIRI in 1st line mCRC
R
Cetuximab + FOLFIRI
Bevacizumab + FOLFIRI
Open-label, randomized, multicenter Phase III
DpR: deepness of response; TFS: time to failure of strategyKRAS wt: codons 12/13 Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
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A . . 3506
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FIRE-3: Evaluation of ORR
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
FOLFIRI +cetuximab
FOLFIRI +bevacizumab Odds ratio
(95% CI) p-value*ORR % 95% CI % 95% CI
ITT population(n=592) **
62.0 56.267.5 58.0 52.163.7 1.18(0.851.64) 0.183
Assessable forresponse
(n=526)72.2 66.277.6 63.1 57.168.9 1.52(1.052.19) 0.017
*Fishers exact test (one-sided)
** Unconfirmed response, investigator assessment Predefined per protocol: 3 cycles of chemotherapy and 1 CT scan following baseline
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297295
Numbersat risk
10099
1915
106
54
3
P r o
b a
b i l i t y o
f s u r v
i v a
l
Eventsn/N (%)
Median(months)
95% CI
FOLFIRI + cetuximab 250/297(84.2%)
10.0 8.810.8
FOLFIRI + bevacizumab 242/295(82.0%) 10.3 9.811.3
HR 1.06 (95% CI: 0.881.26)Log-rank p=0.547
FIRE-3: PFS (ITT)
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
0.75
1.0
0.50
0.25
0.012 24 36 48 60 72
Months since start of treatment
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297295
Numbersat risk
218214
111111
6047
2918
92
0.75
1.0
0.50
0.25
0.0
P r o
b a
b i l i t y o
f s u r v
i v a
l
FIRE-3: OS (ITT)
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
12 24 36 48 60 72Months since start of treatment
Eventsn/N (%)
Median(months)
95% CI
FOLFIRI + cetuximab 158/297(53.2%)
28.7 24.036.6
FOLFIRI + bevacizumab 185/295(62.7%) 25.0 22.727.6
HR 0.77 (95% CI: 0.620.96)Log-rank p=0.017
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297295
Numbersat risk
218214
111111
6047
2918
92
0.75
1.0
0.50
0.25
0.0
P r o
b a
b i l i t y o
f s u r v
i v a
l
FIRE-3: OS (ITT)
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
12 24 36 48 60 72Months since start of treatment
Eventsn/N (%)
Median(months)
95% CI
FOLFIRI + cetuximab 158/297(53.2%)
28.7 24.036.6
FOLFIRI + bevacizumab 185/295(62.7%) 25.0 22.727.6
HR 0.77 (95% CI: 0.620.96)Log-rank p=0.017
HR 1.0
HR 1.0HR !!!
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malefemale
Gender:
1>1
Number ofmetastatic sites:
65>65
Age:
colonrectum
Localization:
noyes
Liver-limited disease:
yesno
Synchronous mets:
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FIRE-3 is the first head-to-head comparison of FOLFIRI + cetuximabversus FOLFIRI + bevacizumab in KRAS wild-type mCRC patients
The primary endpoint was not met : ORR favored FOLFIRI + cetuximabbut did not reach the level of significance within the ITT population
1st line treatment with FOLFIRI + cetuximab resulted in a clinicallymeaningful difference in median OS of 3.7 months (HR 0.77) whencompared with FOLFIRI + bevacizumab
Toxicity profiles were as expected and manageable for bothcombinations
FIRE-3: Conclusions
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
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Head-to-head trials of targeted agents in1st line mCRC
1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506);2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611); 3. NCT00265850;
4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446); 5. Schwartzberg LS, et al. ASCO 2013 (Abstract No. 3631)
FIRE-3 1
CALGB 80405 2,3
PEAK4,5
Patients with untreatedKRAS wt mCRC
N=592R
Cetuximab + FOLFIRICetuximab + FOLFIRI
Bev + FOLFIRIBev + FOLFIRI
Patients with untreatedKRAS wt mCRC
N~1200(after trial modification)
Cetuximab +FOLFOX/FOLFIRI
Cetuximab +FOLFOX/FOLFIRI
Bev +FOLFOX/FOLFIRI
Bev +FOLFOX/FOLFIRI
Bev + cetuximab +FOLFOX/FOLFIRI*Bev + cetuximab +FOLFOX/FOLFIRI*
*Arm closed to accrual as of 09/10/2009
Patients with untreatedKRAS wt mCRC
N=285R
Pani + mFOLFOX6Pani + mFOLFOX6
Bev + mFOLFOX6Bev + mFOLFOX6
R
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A F F 6 + B 1 2 C C ( , 2)
, . J C 31, 2013 ( ; 3631).
C C( =285)
A 8 ( 7 );
, ,
1:1
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EA B A
F 2 C C
, . J C 31, 2013 ( ; 3631).
Eventsn (%)
Median (95% CI)months
Panitumumab +mFOLFOX6 (n=142)
90 (63) 10.9 (9.413.0)
Bevacizumab +mFOLFOX6 (n=143)
94 (66) 10.1 (9.012.6)
Eventsn (%)
Median (95% CI)months
Panitumumab +mFOLFOX6 (n=88)
50 (57) 13.0 (10.915.1)
Bevacizumab +mFOLFOX6 (n=82)
60 (73) 9.5 (9.012.7)
A 2 ( ) A : 2,3,4 A / A
( % )
0
20
40
60
80
100
( % )
0
20
40
60
80
100
90
70
50
30
10
90
70
50
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0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
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EA B A
2 C C
, . J C 31, 2013 ( ; 3631).
Events
n (%)
Median (95% CI)
MonthsPanitumumab +mFOLFOX6 (n=142)
52 (37) 34.2 (26.6NR)
Bevacizumab +mFOLFOX6 (n=143)
78 (55) 24.3 (21.029.2)
Events
n (%)
Median (95% CI)
monthsPanitumumab +mFOLFOX6 (n=88)
30 (34) 41.3 (28.841.3)
Bevacizumab +mFOLFOX6 (n=82)
40 (49) 28.9 (23.931.3)
A 2 ( ) A ( 2,3,4 A / A )
( % )
( % )
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3834 36 40 42 44 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3834 36 40 42
0
20
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80
100
90
70
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100
90
70
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C :1. C
2. C
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+
H . A C 2013, A .4005-1825.
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H . A C 2013, A .4005-1825.
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EC G 0 37% 100 16%
1 62% 90 42%2 0.6% 80 35%
70 7%
39% 44%
16% 19%
88% 85%
+
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+
H . A C 2013, A .4005-1825.
+
46% 38%
F . 5% 3%
9% 13%D 13% 6%
F 24% 17%
9% 17%
+
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+
G
H . A C 2013, A .4005-1825.
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G A
171 430
9% 7%
D ( + D) 51% 33% ( ) 6.8 6.7
1 21% 22%
18 6% 9%
F ( ) 3.3 3.7
+
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+
A
H . A C 2013, A .4005-1825.
+
342 861
32% 23%
D ( + D) 70% 48%
( )(H )
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6.4(0.47)
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G ? ?
G ? ?
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G . 2010