1 phase iii clinical trial of folfox with or without cetuximab in resected k-ras wild type stage 3...
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Phase III Clinical Trial of FOLFOX Phase III Clinical Trial of FOLFOX with or without Cetuximab in with or without Cetuximab in
Resected Resected K-ras wild typeK-ras wild type Stage 3 Stage 3 Colon Cancer: Colon Cancer:
Cooperative Group Trial N0147Cooperative Group Trial N0147(NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG)(NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG)
Phase III Clinical Trial of FOLFOX Phase III Clinical Trial of FOLFOX with or without Cetuximab in with or without Cetuximab in
Resected Resected K-ras wild typeK-ras wild type Stage 3 Stage 3 Colon Cancer: Colon Cancer:
Cooperative Group Trial N0147Cooperative Group Trial N0147(NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG)(NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG)
Steven Alberts, DanielSteven Alberts, Daniel Sargent, Thomas Smyrk, Anthony Sargent, Thomas Smyrk, Anthony Shields, Emily Chan, Richard Goldberg, Sharlene Gill, Shields, Emily Chan, Richard Goldberg, Sharlene Gill, Morton Kahlenberg, Stephen Thibodeau, Suresh NairMorton Kahlenberg, Stephen Thibodeau, Suresh Nair
Steven Alberts, DanielSteven Alberts, Daniel Sargent, Thomas Smyrk, Anthony Sargent, Thomas Smyrk, Anthony Shields, Emily Chan, Richard Goldberg, Sharlene Gill, Shields, Emily Chan, Richard Goldberg, Sharlene Gill, Morton Kahlenberg, Stephen Thibodeau, Suresh NairMorton Kahlenberg, Stephen Thibodeau, Suresh Nair
*: Coordinating group
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DisclosuresDisclosuresDisclosuresDisclosures
NCI provided primary support for the trial NCI provided primary support for the trial
Additional grants to support the trial and Additional grants to support the trial and its translational components received its translational components received from:from:• Bristol-Myers SquibbBristol-Myers Squibb• ImClone SystemsImClone Systems
• wholly-owned subsidiary of Eli Lilly and Companywholly-owned subsidiary of Eli Lilly and Company • sanofi-aventissanofi-aventis• PfizerPfizer
NCI provided primary support for the trial NCI provided primary support for the trial
Additional grants to support the trial and Additional grants to support the trial and its translational components received its translational components received from:from:• Bristol-Myers SquibbBristol-Myers Squibb• ImClone SystemsImClone Systems
• wholly-owned subsidiary of Eli Lilly and Companywholly-owned subsidiary of Eli Lilly and Company • sanofi-aventissanofi-aventis• PfizerPfizer
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Background: Adjuvant Background: Adjuvant StandardStandard
Background: Adjuvant Background: Adjuvant StandardStandard
• Combination of 5-FU, Oxaliplatin, and LV Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant establish as the standard of adjuvant therapy for resected stage 3 colon cancertherapy for resected stage 3 colon cancer
• MOSAICMOSAIC FOLFOX4 versus LV5FU2FOLFOX4 versus LV5FU2• NSABP C-07NSABP C-07 FLOX versus 5-FU/LVFLOX versus 5-FU/LV
3-year Disease Free Survival: 70%3-year Disease Free Survival: 70%
• Combination of 5-FU, Oxaliplatin, and LV Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant establish as the standard of adjuvant therapy for resected stage 3 colon cancertherapy for resected stage 3 colon cancer
• MOSAICMOSAIC FOLFOX4 versus LV5FU2FOLFOX4 versus LV5FU2• NSABP C-07NSABP C-07 FLOX versus 5-FU/LVFLOX versus 5-FU/LV
3-year Disease Free Survival: 70%3-year Disease Free Survival: 70%
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Potential Added Benefit of Potential Added Benefit of Targeted TherapyTargeted Therapy
Potential Added Benefit of Potential Added Benefit of Targeted TherapyTargeted Therapy
• Limitation of new chemotherapy Limitation of new chemotherapy drugs to improve outcomes drugs to improve outcomes
• Monoclonal antibodies against Monoclonal antibodies against EGFR and VEGF demonstrate EGFR and VEGF demonstrate improved outcome in metastatic improved outcome in metastatic colorectal cancer when colorectal cancer when combined with chemotherapycombined with chemotherapy
• Limitation of new chemotherapy Limitation of new chemotherapy drugs to improve outcomes drugs to improve outcomes
• Monoclonal antibodies against Monoclonal antibodies against EGFR and VEGF demonstrate EGFR and VEGF demonstrate improved outcome in metastatic improved outcome in metastatic colorectal cancer when colorectal cancer when combined with chemotherapycombined with chemotherapy
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Initial 2-arm Design for N0147Initial 2-arm Design for N0147Initial 2-arm Design for N0147Initial 2-arm Design for N0147
Stage 3 Stage 3 Colon Colon CancerCancer
(N = 2300)(N = 2300)
RRAANNDDOOMMIIZZEE
mFOLFOX6 (12 cycles)mFOLFOX6 (12 cycles)• Oxaliplatin 85 mg/mOxaliplatin 85 mg/m22
• LV 400 mg/mLV 400 mg/m22 & & • 5-FU 2,400 mg/m5-FU 2,400 mg/m22 over 46 hrs over 46 hrs every 2 weeksevery 2 weeks
mFOLFOX6 + CetuximabmFOLFOX6 + Cetuximab (12 cycles)(12 cycles)• mFOLFOX6 mFOLFOX6 • Cetuximab days 1,8 Cetuximab days 1,8 - 400 mg/m- 400 mg/m22 loading dose loading dose - 250 mg/m- 250 mg/m22 weekly weekly
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Role of K-ras AnalysisRole of K-ras AnalysisRole of K-ras AnalysisRole of K-ras Analysis
• Ability to select patients based Ability to select patients based on K-ras status established in on K-ras status established in early 2008early 2008• Mutated K-ras (K-ras Mut) predicts Mutated K-ras (K-ras Mut) predicts
for lack of response to cetuximabfor lack of response to cetuximab• Wild type K-ras (K-ras WT) Wild type K-ras (K-ras WT)
maintain ability to respond to maintain ability to respond to cetuximabcetuximab
• Ability to select patients based Ability to select patients based on K-ras status established in on K-ras status established in early 2008early 2008• Mutated K-ras (K-ras Mut) predicts Mutated K-ras (K-ras Mut) predicts
for lack of response to cetuximabfor lack of response to cetuximab• Wild type K-ras (K-ras WT) Wild type K-ras (K-ras WT)
maintain ability to respond to maintain ability to respond to cetuximabcetuximab
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Report of K-ras ResultsReport of K-ras ResultsReport of K-ras ResultsReport of K-ras Results
(Bokemeyer et al, JCO 2009)
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Final Design for N0147 – June 2008Final Design for N0147 – June 2008Final Design for N0147 – June 2008Final Design for N0147 – June 2008
Stage 3 Stage 3 Colon Colon CancerCancer
(N = 3768)(N = 3768)
PPRREERREEGGIISSTTEERR
RRAANNDDOOMMIIZZEECentralize
d K-ras analysis
K-ras WT
K-ras Mut
RREEGGIISSTTEERR
Arm GArm G
•Adjuvant therapy Adjuvant therapy per primary per primary oncologistoncologist
•Report therapy Report therapy givengiven
•Annual status Annual status through year 8through year 8
Arm AArm AmFOLFOX6mFOLFOX6
Arm DArm DmFOLFOX6 + mFOLFOX6 +
CetuximabCetuximab
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K-ras AssessmentK-ras AssessmentK-ras AssessmentK-ras Assessment
• K-ras Testing: K-ras Testing: • Centralized testing performed in a Centralized testing performed in a
CLIA approved lab at Mayo ClinicCLIA approved lab at Mayo Clinic• DxS AssayDxS Assay using the using the Roche Roche
LightCycler 480LightCycler 480 platform platform• 99.2%99.2% of samples provided of samples provided
interpretable resultinterpretable result
• K-ras Testing: K-ras Testing: • Centralized testing performed in a Centralized testing performed in a
CLIA approved lab at Mayo ClinicCLIA approved lab at Mayo Clinic• DxS AssayDxS Assay using the using the Roche Roche
LightCycler 480LightCycler 480 platform platform• 99.2%99.2% of samples provided of samples provided
interpretable resultinterpretable result
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Goals for N0147Goals for N0147Goals for N0147Goals for N0147
• PrimaryPrimary• Compare Compare disease free survival (DFS)disease free survival (DFS)
between mFOLFOX6 and mFOLFOX6 between mFOLFOX6 and mFOLFOX6 + cetuximab in patients with+ cetuximab in patients with K-ras WTK-ras WT
• SecondarySecondary• Compare Compare overall survivaloverall survival in the two in the two
groups groups • AssessAssess toxicitiestoxicities resulting from the resulting from the
addition of cetuximab addition of cetuximab
• PrimaryPrimary• Compare Compare disease free survival (DFS)disease free survival (DFS)
between mFOLFOX6 and mFOLFOX6 between mFOLFOX6 and mFOLFOX6 + cetuximab in patients with+ cetuximab in patients with K-ras WTK-ras WT
• SecondarySecondary• Compare Compare overall survivaloverall survival in the two in the two
groups groups • AssessAssess toxicitiestoxicities resulting from the resulting from the
addition of cetuximab addition of cetuximab
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N0147 Analysis planN0147 Analysis planN0147 Analysis planN0147 Analysis plan
• Sample size: 2070 K-ras WT Sample size: 2070 K-ras WT patients to provide 515 DFS eventspatients to provide 515 DFS events• 90% power to detect HR of 1.33 90% power to detect HR of 1.33
(based on assumed 3 yr DFS on (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level FOLFOX of 70%, two-sided test, level 0.05)0.05)
• Intent-to-treat analysisIntent-to-treat analysis
• Protocol specified interim analyses Protocol specified interim analyses after 25%, 50%, and 75% of eventsafter 25%, 50%, and 75% of events
• Sample size: 2070 K-ras WT Sample size: 2070 K-ras WT patients to provide 515 DFS eventspatients to provide 515 DFS events• 90% power to detect HR of 1.33 90% power to detect HR of 1.33
(based on assumed 3 yr DFS on (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level FOLFOX of 70%, two-sided test, level 0.05)0.05)
• Intent-to-treat analysisIntent-to-treat analysis
• Protocol specified interim analyses Protocol specified interim analyses after 25%, 50%, and 75% of eventsafter 25%, 50%, and 75% of events
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Eligibility for N0147Eligibility for N0147Eligibility for N0147Eligibility for N0147
• InclusionInclusion• Completely resected colon Completely resected colon
adenocarcinomaadenocarcinoma• >> 1 pathologically confirmed lymph 1 pathologically confirmed lymph
node identifiednode identified• Age Age >> 18 years 18 years• Acceptable liver and kidney Acceptable liver and kidney
functionfunction• Standard hematologic parametersStandard hematologic parameters
• InclusionInclusion• Completely resected colon Completely resected colon
adenocarcinomaadenocarcinoma• >> 1 pathologically confirmed lymph 1 pathologically confirmed lymph
node identifiednode identified• Age Age >> 18 years 18 years• Acceptable liver and kidney Acceptable liver and kidney
functionfunction• Standard hematologic parametersStandard hematologic parameters
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Eligibility for N0147Eligibility for N0147Eligibility for N0147Eligibility for N0147
• ExclusionExclusion• Evidence of metastatic diseaseEvidence of metastatic disease
• En bloc resection for locally En bloc resection for locally advanced disease allowedadvanced disease allowed
• Prior chemotherapy or radiation for Prior chemotherapy or radiation for colon cancercolon cancer
• Prior or concurrent malignancies Prior or concurrent malignancies within 5 yearswithin 5 years
• Clinically significant peripheral Clinically significant peripheral neuropathyneuropathy
• ExclusionExclusion• Evidence of metastatic diseaseEvidence of metastatic disease
• En bloc resection for locally En bloc resection for locally advanced disease allowedadvanced disease allowed
• Prior chemotherapy or radiation for Prior chemotherapy or radiation for colon cancercolon cancer
• Prior or concurrent malignancies Prior or concurrent malignancies within 5 yearswithin 5 years
• Clinically significant peripheral Clinically significant peripheral neuropathyneuropathy
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Final Study PopulationFinal Study PopulationFinal Study PopulationFinal Study Population
• 2967 patients from 478 sites accrued 2967 patients from 478 sites accrued to arms A, D, and Gto arms A, D, and G• 62% K-ras WT62% K-ras WT
• 1864 randomized to A (FOLFOX) or D 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab)(FOLFOX + cetuximab)• Trial halted on findings of planned Trial halted on findings of planned
interim analysisinterim analysis• 90% of planned accrual90% of planned accrual
• Median follow-up 23 monthsMedian follow-up 23 months
• 2967 patients from 478 sites accrued 2967 patients from 478 sites accrued to arms A, D, and Gto arms A, D, and G• 62% K-ras WT62% K-ras WT
• 1864 randomized to A (FOLFOX) or D 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab)(FOLFOX + cetuximab)• Trial halted on findings of planned Trial halted on findings of planned
interim analysisinterim analysis• 90% of planned accrual90% of planned accrual
• Median follow-up 23 monthsMedian follow-up 23 months
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Patient CharacteristicPatient Characteristic FOLFOXFOLFOX(N=909)(N=909)
FOLFOX+CmabFOLFOX+Cmab(N=955)(N=955)
Age (years)Age (years) Median (Range)Median (Range)
• 14% 70+ years of age14% 70+ years of age 58 (19 - 84)58 (19 - 84) 58 (25 - 86)58 (25 - 86)
GenderGender FemaleFemale MaleMale
46%46%54%54%
48%48%52%52%
RaceRace CaucasianCaucasian African AmericanAfrican American OtherOther
87%87%5%5%8%8%
86%86%6%6%8%8%
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Tumor CharacteristicTumor Characteristic FOLFOXFOLFOX(N=909)(N=909)
FOLFOX+CmabFOLFOX+Cmab(N=955)(N=955)
Bowel ObstructionBowel Obstruction YesYes NoNo
15%15%85%85%
16%16%84%84%
Bowel PerforationBowel Perforation YesYes NoNo
5%5%95%95%
5%5%95%95%
HistologyHistology High High Low Low
27%27%73%73%
27%27%73%73%
Lymph Node InvolvementLymph Node Involvement 1 - 31 - 3 > 3> 3
56%56%44%44%
57%57%43%43%
T StageT Stage T1 or T2T1 or T2 T3T3 T4T4
13%13%76%76%11%11%
16%16%72%72%11%11%
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Outcomes for K-ras WT Outcomes for K-ras WT PatientsPatients
Outcomes for K-ras WT Outcomes for K-ras WT PatientsPatients
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Disease Free Survival (N=1847)Disease Free Survival (N=1847)Disease Free Survival (N=1847)Disease Free Survival (N=1847)
ArmArm 3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-P-valuevalue
FOLFOXFOLFOX
N=902N=902
75.8%75.8%
(72.1%-79.6%)(72.1%-79.6%)
1.21.2
(0.96-1.5)(0.96-1.5)
0.220.22
FOLFOX + FOLFOX + CmabCmab
N=945N=945
72.3%72.3%
(68.5%-76.4%)(68.5%-76.4%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36Time (Months)
% A
live
and
Dis
ease
Fre
e
Fre
e
FOLFOXFOLFOX + Cmab
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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 F
ree
FOLFOX
FOLFOX + Cmab
Disease Free SurvivalDisease Free SurvivalAge<70 (N=1589)Age<70 (N=1589)
Disease Free SurvivalDisease Free SurvivalAge<70 (N=1589)Age<70 (N=1589)
ArmArm 3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-valueP-value
FOLFOXFOLFOX
N=790N=790
74.8%74.8%
(70.8%-79.1%)(70.8%-79.1%)
1.101.10
(0.86-(0.86-1.40)1.40)
0.760.76
FOLFOX + FOLFOX + CmabCmab
N=799N=799
73.4%73.4%
(69.2%-77.9%)(69.2%-77.9%)
20
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 F
ree
FOLFOX
FOLFOX + Cmab
Disease Free SurvivalDisease Free SurvivalAgeAge>>70 (N=258)70 (N=258)
Disease Free SurvivalDisease Free SurvivalAgeAge>>70 (N=258)70 (N=258)
ArmArm 3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-valueP-value
FOLFOXFOLFOX
N=112N=112
80.9%80.9%
(73.0%-89.8%)(73.0%-89.8%)
1.791.79
(1.01-3.18)(1.01-3.18)
0.030.03
FOLFOX + FOLFOX + CmabCmab
N=146N=146
66.1%66.1%
(56.8%-77.0%)(56.8%-77.0%)
21
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Time (Months)
%A
liv
e
FOLFOXFOLFOX + Cmab
Overall Survival (N=1847)Overall Survival (N=1847)Overall Survival (N=1847)Overall Survival (N=1847)
ArmArm 3 Year Rates 3 Year Rates
(95% CI)(95% CI)
HR HR
(95% CI)(95% CI)
P-valueP-value
FOLFOXFOLFOX
N=902N=902
87.8%87.8%
(84.7%-90.9%)(84.7%-90.9%)
1.31.3
(0.96-1.8)(0.96-1.8)
0.130.13
FOLFOX + FOLFOX + CmabCmab
N=945N=945
83.9%83.9%
(80.3%-87.6%)(80.3%-87.6%)
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0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3
Hazard Ratio
Low HistologyHigh Histology
Stage T4Stage T3
Age > 65Age < 65
Age < 70Age > 70
1-3 Nodes> 4 Nodes
Age > 60Age < 60
FemaleMale
Forest Plot for DFSForest Plot for DFSForest Plot for DFSForest Plot for DFS
Favors FOLFOX Favors FOLFOX alonealone
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Toxicity – Grade 3-4Toxicity – Grade 3-4Toxicity – Grade 3-4Toxicity – Grade 3-4
Arm AArm A Arm DArm D
NeutropeniaNeutropenia 10%10% 13%13%Febrile NeutropeniaFebrile Neutropenia 1%1% 3%3%HypersensitivityHypersensitivity 2%2% 6%6%Rash/AcneRash/Acne 0%0% 19%19%NauseaNausea 3%3% 4%4%DiarrheaDiarrhea 9%9% 15%15%Peripheral Peripheral NeuropathyNeuropathy
4%4% 5%5%
OverallOverall 51%51% 71%71%
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Reasons for DiscontinuationReasons for DiscontinuationReasons for DiscontinuationReasons for Discontinuation
ReasonReason Arm AArm A<60<60
(N=493)(N=493)
Arm AArm A60-6960-69
(N=270)(N=270)
Arm A Arm A >>7070
(N=108)(N=108)
Arm DArm D<60<60
(N=494)(N=494)
Arm D Arm D 60-6960-69
(N=288)(N=288)
Arm DArm D >>7070
(N=143)(N=143)
CompletionCompletion 77.9%77.9% 78.9%78.9% 77.8%77.8% 70.2%70.2% 67.0%67.0% 51.1%51.1%
RefusalRefusal 6.7%6.7% 6.7%6.7% 4.6%4.6% 11.7%11.7% 8.7%8.7% 13.3%13.3%
AEAE 9.3%9.3% 7.4%7.4% 13.0%13.0% 9.1%9.1% 18.1%18.1% 21.0%21.0%
OtherOther 6.1%6.1% 7.0%7.0% 4.6%4.6% 9.0%9.0% 6.2%6.2% 14.6%14.6%
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ConclusionsConclusionsConclusionsConclusions• No benefit to adding cetuximab in patients with No benefit to adding cetuximab in patients with
resected stage 3 K-ras WT expressing colon resected stage 3 K-ras WT expressing colon cancercancer
• Potential explanationsPotential explanations• Decreased tolerance with cetuximabDecreased tolerance with cetuximab• Differences in dose intensityDifferences in dose intensity• Interaction with age: Interaction with age:
• Worse outcomes in older patients receiving cetuximabWorse outcomes in older patients receiving cetuximab• Lessened ability to complete therapyLessened ability to complete therapy
• No benefit to adding cetuximab in patients with No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon resected stage 3 K-ras WT expressing colon cancercancer
• Potential explanationsPotential explanations• Decreased tolerance with cetuximabDecreased tolerance with cetuximab• Differences in dose intensityDifferences in dose intensity• Interaction with age: Interaction with age:
• Worse outcomes in older patients receiving cetuximabWorse outcomes in older patients receiving cetuximab• Lessened ability to complete therapyLessened ability to complete therapy
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ConclusionsConclusionsConclusionsConclusions
• MechanisticMechanistic• Cetuximab may have a different Cetuximab may have a different
form of activity on micrometastatic form of activity on micrometastatic disease compared to that disease compared to that observed in stage 4 diseaseobserved in stage 4 disease
• Differences in biology of earlier Differences in biology of earlier stage diseasestage disease
• Current focus of correlative Current focus of correlative studiesstudies
• MechanisticMechanistic• Cetuximab may have a different Cetuximab may have a different
form of activity on micrometastatic form of activity on micrometastatic disease compared to that disease compared to that observed in stage 4 diseaseobserved in stage 4 disease
• Differences in biology of earlier Differences in biology of earlier stage diseasestage disease
• Current focus of correlative Current focus of correlative studiesstudies
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AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgments
• Special thanks to all of the Special thanks to all of the participating patientsparticipating patients
• Collaborative North American effort Collaborative North American effort
• Trial not possible without the Trial not possible without the support of NCI and that provided by support of NCI and that provided by Bristol-Myers Squibb, sanofi-aventis, Bristol-Myers Squibb, sanofi-aventis, ImClone, and Pfizer ImClone, and Pfizer
• Study TeamStudy Team
• Special thanks to all of the Special thanks to all of the participating patientsparticipating patients
• Collaborative North American effort Collaborative North American effort
• Trial not possible without the Trial not possible without the support of NCI and that provided by support of NCI and that provided by Bristol-Myers Squibb, sanofi-aventis, Bristol-Myers Squibb, sanofi-aventis, ImClone, and Pfizer ImClone, and Pfizer
• Study TeamStudy Team