*: Coordinating group

1

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

2

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

3

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%

4

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

5

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

6

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

7

Report of K-ras ResultsReport of K-ras ResultsReport of K-ras ResultsReport of K-ras Results

(Bokemeyer et al, JCO 2009)

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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%

16

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%

17

Outcomes for K-ras WT Outcomes for K-ras WT PatientsPatients

Outcomes for K-ras WT Outcomes for K-ras WT PatientsPatients

18

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

19

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)


(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


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)


(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


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)


(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


N=945N=945

83.9%83.9%

(80.3%-87.6%)(80.3%-87.6%)

22

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

23

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%

24

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%

25

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

26

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

27

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

*: Coordinating group

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