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Phase III Clinical Trial of FOLFOX with or without Cetuximab in Resected Stage 3 Colon Cancer: Cooperative Group Trial N0147 (NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG). Authors: Presented by Alberts and Goldberg Analysis By Scott Berry Date posted: June 21 2010. - PowerPoint PPT Presentation
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Phase III Clinical Trial of FOLFOX with or without Cetuximab in Resected
Stage 3 Colon Cancer:Cooperative Group Trial N0147(NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG)
Authors: Presented by Alberts and Goldberg
Analysis By Scott Berry
Date posted: June 21 2010
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Thank you for downloading this update. Please feel free to use it for educational purposes.
Please acknowledge OncologyEducation.ca and Dr. Berry when using these slides.
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R
Treatment A:
mFOLFOX6 (12 cycles)
Treatment B:
mFOLFOX6 + Cetux (12 cycles)
N=2300
Primary Outcome: DFS
Initial Study Design
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R
Treatment A:
mFOLFOX6 (12 cycles)
Treatment B:
mFOLFOX6 + Cetux (12 cycles)
N=3768
Primary Outcome: DFS
Revised Study DesignKRAS WT ONLY
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Trial Closed Early
• 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab)
– Trial halted on findings of planned interim analysis
– 90% of planned accrual
• Median follow-up 23 months
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RESULTS : KRAS-WT
FOLFOXFOLFOX + Cetuximab
HR (95% CI)
p-value
3 Yr DFS
(median, mos)
75.8% 72.3%1.2 (0.96-1.5)
p=0.22
3 Yr OS
(median, mos)
87.8% 83.9%1.3 (0.96-1.8)
0=0.13
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Gr 3/4 TOXICITYFOLFOX FOLFOX+ Cetuximab
Neutropenia 10% 13%
Febrile Neutropenia 1% 3%
Hypersensitivity 2% 6%
Rash/Acne 0% 19%
Nausea 3% 4%
Diarrhea 9% 15%
Peripheral Neuropathy
4% 5%
Overall 51% 71%
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Reasons for Discontinuation
Reason Arm A<60
(N=493)
Arm A60-69
(N=270)
Arm A >70
(N=108)
Arm D<60
(N=494)
Arm D 60-69
(N=288)
Arm D >70
(N=143)
Completion 77.9% 78.9% 77.8% 70.2% 67.0% 51.1%
Refusal 6.7% 6.7% 4.6% 11.7% 8.7% 13.3%
AE 9.3% 7.4% 13.0% 9.1% 18.1% 21.0%
Other 6.1% 7.0% 4.6% 9.0% 6.2% 14.6%
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Conclusions
• No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon cancer
• ? Explanation– Decreased tolerance with cetuximab– Differences in dose intensity– Interaction with age:
• Worse outcomes in older patients receiving cetuximab
• Lessened ability to complete therapy
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Was adverse impact of Cetuximab due to dosing
issues?
• In post-hoc analysis, attempted to identify ‘ideal’ patients– First 6 cycles with > 80% dose intensity for all
drugs– Consider only patients aged < 70
• If no benefit in these pts (young, > 80% dose rec’d), then adverse impact not likely due to reduced dosing
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Was adverse impact of Cetuximab due to dosing
issues?
• Comparison based on dosing not protected by randomization, thus possibly confounded with other reasons for stopping treatment
• Alternative– Use Time to Recurrence endpoint– Most sensitive– Least confounded
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Dose Intensity (% with > 80%) K-ras WT
Arm Oxaliplatin 5-FU Cetuximab
FOLFOX
(N=672)
69% 85% N/A
FOLFOX + Cmab
(N=645)
61% 74% 63%
P-value 0.0003 <0.0001
Arm Oxaliplatin 5-FU Cetuximab
FOLFOX
(N=613)
50% 81% N/A
FOLFOX + Cmab
(N=582)
44% 65% 55%
P-value 0.03 <0.0001
Cycle 6
Cycle 10
13
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Time (Months)
%Di
seas
e Fr
ee
FOLFOX
FOLFOX + Cmab
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Time (Months)
%Di
seas
e Fr
ee
FOLFOX
FOLFOX + Cmab
““Idealized” Patient Comparison: Idealized” Patient Comparison: Time to Recurrence – K-Ras WTTime to Recurrence – K-Ras WT““Idealized” Patient Comparison: Idealized” Patient Comparison: Time to Recurrence – K-Ras WTTime to Recurrence – K-Ras WT
All PatientsAll PatientsAll PatientsAll Patients ““Ideal” PatientsIdeal” Patients““Ideal” PatientsIdeal” Patients
ArmArm 3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-P-valuevalue
FOLFOXFOLFOX
N=902N=902
77.1%77.1%
(73.4-80.8%)(73.4-80.8%)
1.21.2
(0.9-1.5)(0.9-1.5)
0.350.35
FOLFOX FOLFOX + Cmab+ Cmab
N=945N=945
73.7%73.7%
(69.7-77.9%)(69.7-77.9%)
ArmArm 3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-P-valuevalue
FOLFOXFOLFOX
N=485N=485
75.9%75.9%
(71.0-81.0%)(71.0-81.0%)
1.21.2
(0.6-2.2)(0.6-2.2)
0.980.98
FOLFOX FOLFOX + Cmab+ Cmab
N=191N=191
77.7%77.7%
(70.7-85.3%)(70.7-85.3%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Time (Months)
% D
isea
se F
ree
FOLFOXFOLFOX + Cmab
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Was adverse impact of Cetuximab due to dosing
issues?
GOLDBERG:• While they had lower drug exposure, we don’t believe
that is the key reason based on the idealized patient analysis
• We believe that the explanation is related to tumor biology
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STUDY COMMENTARY
• Adding Cetuximab to adjuvant FOLFOX for resected Stage III colon cancer patients does not improve outcome
• Results do not appear to be explained by attendant increased toxicity / decreased dose intensity with combination
• ? Tumour Biology