1 Adjuvant mFOLFOX6 +/- Adjuvant mFOLFOX6 +/- cetuximab in patients cetuximab in patients with K- with K- ras mutant ras mutant resected stage III resected stage III colon cancer colon cancer Richard Goldberg, Daniel Sargent, Stephen Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven Alberts Kahlenberg, Suresh Nair, Steven Alberts * Coordinating group Cooperative Group Trial N0147 NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG
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Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutant resected stage III colon cancer
Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutant resected stage III colon cancer. Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven Alberts. - PowerPoint PPT Presentation
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Adjuvant mFOLFOX6 +/- cetuximab Adjuvant mFOLFOX6 +/- cetuximab in patients in patients with K-ras mutantwith K-ras mutant
resected stage III colon cancerresected stage III colon cancer
Adjuvant mFOLFOX6 +/- cetuximab Adjuvant mFOLFOX6 +/- cetuximab in patients in patients with K-ras mutantwith K-ras mutant
resected stage III colon cancerresected stage III colon cancer
Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven AlbertsGill, Morton Kahlenberg, Suresh Nair, Steven Alberts
Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven AlbertsGill, Morton Kahlenberg, Suresh Nair, Steven Alberts
* Coordinating group
Cooperative Group Trial N0147NCCTG*, CALGB, ECOG, NCIC,
NSABP, SWOG
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DisclosuresDisclosuresDisclosuresDisclosures
• Dr Goldberg has received Dr Goldberg has received honoraria, consulting fees or honoraria, consulting fees or research support from research support from • Bristol Meyers SquibbBristol Meyers Squibb• ImCloneImClone• sanofi-aventissanofi-aventis
• Dr Goldberg has received Dr Goldberg has received honoraria, consulting fees or honoraria, consulting fees or research support from research support from • Bristol Meyers SquibbBristol Meyers Squibb• ImCloneImClone• sanofi-aventissanofi-aventis
OS: FOLFOX +/- Cmab by OS: FOLFOX +/- Cmab by K-ras status K-ras status
OS: FOLFOX +/- Cmab by OS: FOLFOX +/- Cmab by K-ras status K-ras status
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Duration of TherapyDuration of TherapyDuration of TherapyDuration of Therapy
K-Ras WT
CycleCycle FOLFOXFOLFOX
(N=871)(N=871)
FOLFOX+FOLFOX+
CmabCmab
(N=925)(N=925)
P-valueP-value
66 89%89% 79%79% <0.0001<0.0001
88 85%85% 75%75% <0.0001<0.0001
1010 82%82% 72%72% <0.0001<0.0001
1212 78%78% 67%67% <0.0001<0.0001
K-Ras Mut
CycleCycle FOLFOXFOLFOX
(N=374)(N=374)
FOLFOX+FOLFOX+
CmabCmab
(N=343)(N=343)
P-valueP-value
66 87%87% 87%87% 0.740.74
88 84%84% 81%81% 0.310.31
1010 81%81% 76%76% 0.090.09
1212 75%75% 70%70% 0.100.10
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Was adverse impact of Cetuximab Was adverse impact of Cetuximab due to dosing issues?due to dosing issues?
Was adverse impact of Cetuximab Was adverse impact of Cetuximab due to dosing issues?due to dosing issues?
• In post-hoc analysis, attempted to In post-hoc analysis, attempted to identify ‘ideal’ patientsidentify ‘ideal’ patients• First 6 cycles with First 6 cycles with >> 80% dose 80% dose
intensity for all drugsintensity for all drugs• Consider only patients aged < 70Consider only patients aged < 70
• If no benefit in these pts (young, If no benefit in these pts (young, >> 80% 80% dose rec’d), then adverse impact not dose rec’d), then adverse impact not likely due to reduced dosinglikely due to reduced dosing
• In post-hoc analysis, attempted to In post-hoc analysis, attempted to identify ‘ideal’ patientsidentify ‘ideal’ patients• First 6 cycles with First 6 cycles with >> 80% dose 80% dose
intensity for all drugsintensity for all drugs• Consider only patients aged < 70Consider only patients aged < 70
• If no benefit in these pts (young, If no benefit in these pts (young, >> 80% 80% dose rec’d), then adverse impact not dose rec’d), then adverse impact not likely due to reduced dosinglikely due to reduced dosing
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Was adverse impact of Cetuximab Was adverse impact of Cetuximab due to dosing issues?due to dosing issues?
Was adverse impact of Cetuximab Was adverse impact of Cetuximab due to dosing issues?due to dosing issues?
• Comparison based on dosing not Comparison based on dosing not protected by randomization, thus protected by randomization, thus possibly confounded with other reasons possibly confounded with other reasons for stopping treatmentfor stopping treatment
• AlternativeAlternative• Use Time to Recurrence endpointUse Time to Recurrence endpoint• Most sensitiveMost sensitive• Least confoundedLeast confounded
• Comparison based on dosing not Comparison based on dosing not protected by randomization, thus protected by randomization, thus possibly confounded with other reasons possibly confounded with other reasons for stopping treatmentfor stopping treatment
• AlternativeAlternative• Use Time to Recurrence endpointUse Time to Recurrence endpoint• Most sensitiveMost sensitive• Least confoundedLeast confounded
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Dose Intensity (% with Dose Intensity (% with >> 80%) 80%) K-ras WTK-ras WT
Dose Intensity (% with Dose Intensity (% with >> 80%) 80%) K-ras WTK-ras WT
Is K-ras prognostic in FOLFOX Is K-ras prognostic in FOLFOX treated patients?treated patients?
Is K-ras prognostic in FOLFOX Is K-ras prognostic in FOLFOX treated patients?treated patients?
K-ras K-ras StatusStatus
3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-P-valuevalue
WTWT
N=902N=902
75.8%75.8%
(72.1-79.6%)(72.1-79.6%)
0.70.7
(0.5-0.9)(0.5-0.9)
0.040.04
MutMut
N=374N=374
67.2%67.2%
(61.4-73.5%)(61.4-73.5%)
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0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Time (Months)
% A
live
and
Dis
ease
Fre
e
MutWT
Is K-ras prognostic in Is K-ras prognostic in FOLFOX+Cmab treated patients?FOLFOX+Cmab treated patients?
Is K-ras prognostic in Is K-ras prognostic in FOLFOX+Cmab treated patients?FOLFOX+Cmab treated patients?
K-ras K-ras StatusStatus
3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-P-valuevalue
WTWT
N=945N=945
72.3%72.3%
(68.5-76.4%)(68.5-76.4%)
0.70.7
(0.5-0.9)(0.5-0.9)
0.0040.004
MutMut
N=343N=343
64.2%64.2%
(58.7-70.2%)(58.7-70.2%)
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Why did patients with K-ras Mut Why did patients with K-ras Mut treated with Cetuximab do worse?treated with Cetuximab do worse?Why did patients with K-ras Mut Why did patients with K-ras Mut
treated with Cetuximab do worse?treated with Cetuximab do worse?
• While they had lower drug exposure, While they had lower drug exposure, we don’t believe that is the key reason we don’t believe that is the key reason based on the idealized patient analysisbased on the idealized patient analysis
• We believe that the explanation is We believe that the explanation is related to tumor biologyrelated to tumor biology
• While they had lower drug exposure, While they had lower drug exposure, we don’t believe that is the key reason we don’t believe that is the key reason based on the idealized patient analysisbased on the idealized patient analysis
• We believe that the explanation is We believe that the explanation is related to tumor biologyrelated to tumor biology
• The outcomes are surprisingThe outcomes are surprising
• Understanding the interactions of Understanding the interactions of tumor genotype and patient biology tumor genotype and patient biology challenge us.challenge us.
• The key to individualizing care lies The key to individualizing care lies in that understanding.in that understanding.
• We hope to find the answers in the We hope to find the answers in the tumor blockstumor blocks
• The outcomes are surprisingThe outcomes are surprising
• Understanding the interactions of Understanding the interactions of tumor genotype and patient biology tumor genotype and patient biology challenge us.challenge us.
• The key to individualizing care lies The key to individualizing care lies in that understanding.in that understanding.
• We hope to find the answers in the We hope to find the answers in the tumor blockstumor blocks