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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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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