0 adjuvant folfiri +/- cetuximab in patients with resected stage iii colon cancer ncctg intergroup...

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Adjuvant FOLFIRI +/- Cetuximab in Adjuvant FOLFIRI +/- Cetuximab in Patients with Resected Stage III Patients with Resected Stage III

Colon CancerColon CancerNCCTG Intergroup Phase III Trial NCCTG Intergroup Phase III Trial

N0147N0147

Adjuvant FOLFIRI +/- Cetuximab in Adjuvant FOLFIRI +/- Cetuximab in Patients with Resected Stage III Patients with Resected Stage III

Colon CancerColon CancerNCCTG Intergroup Phase III Trial NCCTG Intergroup Phase III Trial

N0147N0147

Jocelin Huang, Daniel J Sargent, Michelle R Jocelin Huang, Daniel J Sargent, Michelle R Mahoney, Stephen N Thibodeau, Thomas C Mahoney, Stephen N Thibodeau, Thomas C Smyrk, Frank A Sinicrope, Garth D Nelson, Smyrk, Frank A Sinicrope, Garth D Nelson,

Steven R AlbertsSteven R Alberts

ASCO GI Cancers SymposiumASCO GI Cancers Symposium

January 22, 2011January 22, 2011

Jocelin Huang, Daniel J Sargent, Michelle R Jocelin Huang, Daniel J Sargent, Michelle R Mahoney, Stephen N Thibodeau, Thomas C Mahoney, Stephen N Thibodeau, Thomas C Smyrk, Frank A Sinicrope, Garth D Nelson, Smyrk, Frank A Sinicrope, Garth D Nelson,

Steven R AlbertsSteven R Alberts

ASCO GI Cancers SymposiumASCO GI Cancers Symposium

January 22, 2011January 22, 2011

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DisclosuresDisclosures

NCI provided primary support for the NCI provided primary support for the trial trial

Additional grants to support the trial Additional grants to support the trial and its translational components and its translational components received from:received from:• Bristol-Myers SquibbBristol-Myers Squibb• ImClone SystemsImClone Systems• sanofi-aventissanofi-aventis• PfizerPfizer

NCI provided primary support for the NCI provided primary support for the trial trial

Additional grants to support the trial Additional grants to support the trial and its translational components and its translational components received from:received from:• Bristol-Myers SquibbBristol-Myers Squibb• ImClone SystemsImClone Systems• sanofi-aventissanofi-aventis• PfizerPfizer

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Background: Irinotecan in Adjuvant Therapy

Background: Irinotecan in Adjuvant Therapy

• Irinotecan has demonstrated antitumor activity against metastatic colorectal cancer used alone or with 5-FU/LV

• However, in resected stage III no statistically significant difference demonstrated in DFS and OS between FOLFIRI and 5FU/LV

• Irinotecan has demonstrated antitumor activity against metastatic colorectal cancer used alone or with 5-FU/LV

• However, in resected stage III no statistically significant difference demonstrated in DFS and OS between FOLFIRI and 5FU/LV

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Clinical Trials Evaluating Addition of Irinotecan to 5FU/LV in Resected CRC: No Benefit in DFS and OS

Clinical Trials Evaluating Addition of Irinotecan to 5FU/LV in Resected CRC: No Benefit in DFS and OS

PETACC-3 (FOLFIRI)• 3,018 patients with resected

stage II/III colon cancerDFS P=0.106OS P=0.09

ACCORD2 (FOLFIRI)• 400 patients with resected

high-risk stage III colon cancer (N2 or N1 with occlusion/perforation)DFS P=0.92OS P=0.99

CALGB 89803 (IFL)• 1,264 patients with resected

stage III colon cancerDFS P=0.85OS P=0.74

PETACC-3 (FOLFIRI)• 3,018 patients with resected

stage II/III colon cancerDFS P=0.106OS P=0.09

ACCORD2 (FOLFIRI)• 400 patients with resected

high-risk stage III colon cancer (N2 or N1 with occlusion/perforation)DFS P=0.92OS P=0.99

CALGB 89803 (IFL)• 1,264 patients with resected

stage III colon cancerDFS P=0.85OS P=0.74

LV/5-FU2

FOLFIRI

12 cycles planned

R

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N0147: Initial Design in 2001N0147: Initial Design in 2001

Planned Accrual: 3750

FOLFIRI

5-FU 400 mg/m2 + Bolus CPT-11 180 mg/m2 + LV 400 mg/m2 & 5-FU 2,400 mg/m2 over 46 hrs Q 2 w

mFOLFOX6

5-FU 400 mg/m2 + Oxaliplatin 85 mg/m2 + LV 400 mg/m2 & 5-FU 2,400 mg/m2 over 26 hrs Q 2 w

mFOLFOX6 FOLFIRI

Planned Accrual: 3750

FOLFIRI

5-FU 400 mg/m2 + Bolus CPT-11 180 mg/m2 + LV 400 mg/m2 & 5-FU 2,400 mg/m2 over 46 hrs Q 2 w

mFOLFOX6

5-FU 400 mg/m2 + Oxaliplatin 85 mg/m2 + LV 400 mg/m2 & 5-FU 2,400 mg/m2 over 26 hrs Q 2 w

mFOLFOX6 FOLFIRI

RR

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N0147: First Design ChangeN0147: First Design Change

• Addition of Cetuximab Sept-04• 6 arm design

• FOLFIRI +/- cetuximab

• FOLFOX +/- cetuximab

• FOLFOX FOLFIRI +/- cetuximab


• FOLFIRI +/- cetuximab

• FOLFOX +/- cetuximab

• FOLFOX FOLFIRI +/- cetuximab

R

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N0147: FOLFIRI +/- CetuximabN0147: FOLFIRI +/- Cetuximab


• FOLFIRI +/- Cetuximab (Cmab)

• FOLFOX +/- Cmab

• FOLFOX FOLFIRI +/- Cmab


• FOLFIRI +/- Cetuximab (Cmab)

• FOLFOX +/- Cmab

• FOLFOX FOLFIRI +/- Cmab

R

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Goals for N0147 FOLFIRI +/- Cmab Arms

Goals for N0147 FOLFIRI +/- Cmab Arms

• Primary• Compare disease free survival (DFS)

between FOLFIRI and FOLFIRI + Cmab in patients with wild-type (WT) K-ras and mutant (MT) K-ras

• Secondary• Compare overall survival (OS) in the two

groups • Assess toxicities resulting from the

addition of Cmab

• Primary• Compare disease free survival (DFS)

between FOLFIRI and FOLFIRI + Cmab in patients with wild-type (WT) K-ras and mutant (MT) K-ras

• Secondary• Compare overall survival (OS) in the two

groups • Assess toxicities resulting from the

addition of Cmab

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K-ras AssessmentK-ras Assessment

K-ras Testing: • Centralized testing performed in a

CLIA approved lab at Mayo Clinic• DxS Assay using the Roche

LightCycler 480 platform• 99.2% of samples provided

interpretable result

K-ras Testing: • Centralized testing performed in a

CLIA approved lab at Mayo Clinic• DxS Assay using the Roche

LightCycler 480 platform• 99.2% of samples provided

interpretable result

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Eligibility for N0147Eligibility for N0147

• Inclusion• Completely resected colon

adenocarcinoma• > 1 pathologically confirmed lymph

node identified• Age > 18 years• Acceptable liver and kidney

function• Standard hematologic parameters

• Inclusion• Completely resected colon

adenocarcinoma• > 1 pathologically confirmed lymph

node identified• Age > 18 years• Acceptable liver and kidney

function• Standard hematologic parameters

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Eligibility for N0147Eligibility for N0147

• Exclusion• Evidence of metastatic disease

• En bloc resection for locally advanced disease allowed

• Prior chemotherapy or radiation for colon cancer

• Prior or concurrent malignancies within 5 years

• Clinically significant peripheral neuropathy

• Exclusion• Evidence of metastatic disease

• En bloc resection for locally advanced disease allowed

• Prior chemotherapy or radiation for colon cancer

• Prior or concurrent malignancies within 5 years

• Clinically significant peripheral neuropathy

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N0147: FOLFIRI +/- CmabN0147: FOLFIRI +/- Cmab

ResectedResectedStage 3 Stage 3 Colon Colon CancerCancer

(N = 146)(N = 146)

RRAANNDDOOMMIIZZEE

FOLFIRI (12 cycles)FOLFIRI (12 cycles)• Irinotecan 180 mg/mIrinotecan 180 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

FOLFIRI + CetuximabFOLFIRI + Cetuximab (12 cycles)(12 cycles)• FOLFIRI FOLFIRI • 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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Final Study PopulationFinal Study Population

• 156 patients accrued to arms B (111) and E (45)

• 5 cancels (2-B, 3-E) did not receive treatment - removed from analysis

• 7 ineligible patients (4-B, 3-E)

• 2 ineligible patients (1-B, 1-E) included in analysis because deemed ineligible due to time delay for starting treatment

• Other 5 ineligible patients (3-B, 2-E) removed from analysis

• Final: 146 patients (106-B, 40-E) included in analysis

• 156 patients accrued to arms B (111) and E (45)

• 5 cancels (2-B, 3-E) did not receive treatment - removed from analysis

• 7 ineligible patients (4-B, 3-E)

• 2 ineligible patients (1-B, 1-E) included in analysis because deemed ineligible due to time delay for starting treatment

• Other 5 ineligible patients (3-B, 2-E) removed from analysis

• Final: 146 patients (106-B, 40-E) included in analysis

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Patient Characteristic FOLFIRI(N = 106)

FOLFIRI+Cmab(N = 40)

Median (range) Age (years) 57 (25-82) 59 (30-82)

Gender Female Male

47%53%

45%55%

Race Caucasian African American Other

90%6%4%

85%8%7%

Median (range) Follow-up (months)

N = 7960 (3-72)

N = 3759 (2-67)

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Tumor Characteristic FOLFIRI(N=106)

FOLFIRI+Cmab(N=40)

Bowel Obstruction Yes No

14%86%

10%90%

Bowel Perforation Yes No

8%92%

5%95%

Histology High Low

23%77%

25%75%

Lymph Node Involvement 1 - 3 > 3

65%35%

65%35%

T Stage T1 or T2 T3 T4

16%70%14%

12%78%10%

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K-ras mutation status

FOLFIRI(N=106)

FOLFIRI + Cmab(N=40)

Wild-type Mutant Missing

65%31%4%

65%33%2%

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Disease-free Survival: WT-Kras (n=95)

Disease-free Survival: WT-Kras (n=95)

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60

Time (Months)

% A

liv

e a

nd

Dis

ea

se

Fre

e

FOLFIRI

FOLFIRI + C225

FOLFOX: 75.8%

FOLFOX + C225: 72.3%

ArmArm 3 Year Rates 3 Year Rates

(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-valueP-value

FOLFIRIFOLFIRI

N=69N=69

69.8%69.8%

(60%-82%)(60%-82%)

0.310.31

(0.09-(0.09-1.03)1.03)

0.040.04

FOLFIRI + C225FOLFIRI + C225

N=26N=26

92.3%92.3%

(83%-100%)(83%-100%)

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Disease-free Survival: MT-Kras (n=46)

Disease-free Survival: MT-Kras (n=46)

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60

Time (Months)

% A

liv

e a

nd

Dis

ea

se

Fre

e

FOLFIRI

FOLFIRI + C225

FOLFOX: 67.2%

FOLFOX + Cmab: 64.2%


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-valueP-value

FOLFIRIFOLFIRI

N=33N=33

56.3%56.3%

(41%-76%)(41%-76%)

0.450.45

(0.13-(0.13-1.53)1.53)

0.190.19


N=13N=13

82.5%82.5%

(63%-100%)(63%-100%)

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Disease-free Survival (n=146)Disease-free Survival (n=146)

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60

Time (Months)

% A

live

an

d D

isea

se F

ree

FOLFIRI

FOLFIRI + C225

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60

Time (Months)

% A

live

an

d D

isea

se F

ree

FOLFIRI

FOLFIRI + C225

FOLFOX: 75.8%



(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-valueP-value

FOLFIRIFOLFIRI

N=106N=106

66.7%66.7%

(58%-77%)(58%-77%)

0.440.44

(0.20-(0.20-0.97)0.97)

0.040.04


N=40N=40

86.6%86.6%

(76%-98%)(76%-98%)

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Overall Survival: WT-Kras (n=95)

Overall Survival: WT-Kras (n=95)

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72

Time (Months)

% A

live

FOLFIRI

FOLFIRI + C225


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-valueP-value

FOLFIRIFOLFIRI

N=69N=69

85.2%85.2%

(77%-94%)(77%-94%)

0.340.34

(0.08-(0.08-1.48)1.48)

0.130.13


N=26N=26

92.0%92.0%

(82%-100%)(82%-100%)

FOLFOX: 87.8%


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Overall Survival: MT-Kras (n=46)

Overall Survival: MT-Kras (n=46)

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72

Time (Months)

% A

live

FOLFIRI

FOLFIRI + C225


(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-valueP-value

FOLFIRIFOLFIRI

N=33N=33

80.6%80.6%

(68%-96%)(68%-96%)

0.220.22

(0.03-(0.03-1.73)1.73)

0.120.12


N=13N=13

90.9%90.9%

(75%-100%)(75%-100%)

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Overall Survival (n=146)Overall Survival (n=146)

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72

Time (Months)

% A

live

FOLFIRI

FOLFIRI + C225

FOLFOX: 87.8%



(95% CI)(95% CI)

HR HR

(95% CI)(95% CI)

P-valueP-value

FOLFIRIFOLFIRI

N=106N=106

84.4%84.4%

(78%-92%)(78%-92%)

0.300.30

(0.09-(0.09-1.00)1.00)

0.040.04


N=40N=40

91.8%91.8%

(83%-100%)(83%-100%)

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Toxicity – Grade 3-4Toxicity – Grade 3-4

FOLFIRI FOLFIRI + Cmab

Neutropenia 14% 10%Febrile Neutropenia 2% 3%Acne 0% 18%Nausea 10% 0%Diarrhea 14% 15%Paresthesias 0% 10%Infarction 0% 8%Overall 53% 68%

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Reasons for DiscontinuationReasons for Discontinuation

Reason FOLFIRI FOLFIRI + Cmab

Completion 79% 70%

Refusal 8% 13%

Adverse Event 8% 18%

Other 6% 0%

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ConclusionsConclusionsConclusionsConclusions• Adjuvant FOLFIRI resulted in a 3-year Adjuvant FOLFIRI resulted in a 3-year

DFS lower than that expected for DFS lower than that expected for FOLFOXFOLFOX

• Trends for improved DFS and OS Trends for improved DFS and OS with the addition of Cmab were with the addition of Cmab were observed in patients with resected observed in patients with resected stage III colon cancer patients, stage III colon cancer patients, regardless of KRAS statusregardless of KRAS status

• Possible different synergistic effect Possible different synergistic effect between FOLFIRI and Cmab than between FOLFIRI and Cmab than with FOLFOX and Cmabwith FOLFOX and Cmab

• Adjuvant FOLFIRI resulted in a 3-year Adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for DFS lower than that expected for FOLFOXFOLFOX

• Trends for improved DFS and OS Trends for improved DFS and OS with the addition of Cmab were with the addition of Cmab were observed in patients with resected observed in patients with resected stage III colon cancer patients, stage III colon cancer patients, regardless of KRAS statusregardless of KRAS status

• Possible different synergistic effect Possible different synergistic effect between FOLFIRI and Cmab than between FOLFIRI and Cmab than with FOLFOX and Cmabwith FOLFOX and Cmab

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AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgments• All of the participating patients

• Collaboration with North American groups

• Support of NCI, Bristol-Myers Squibb, sanofi-aventis, ImClone, and Pfizer

• Study team

• All of the participating patients

• Collaboration with North American groups

• Support of NCI, Bristol-Myers Squibb, sanofi-aventis, ImClone, and Pfizer

• Study team

0 adjuvant folfiri +/- cetuximab in patients with resected stage iii colon cancer ncctg intergroup...

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