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

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R Treatment A: mFOLFOX6 (12 cycles) Treatment B: mFOLFOX6 + Cetux (12 cycles) N=2300 Primary Outcome: DFS Initial Study Design

R Treatment A: mFOLFOX6 (12 cycles) Treatment B: mFOLFOX6 + Cetux (12 cycles) N=3768 Primary Outcome: DFS Revised Study Design KRAS WT ONLY

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

RESULTS : KRAS-WT FOLFOX FOLFOX + Cetuximab HR (95% CI) p-value 3 Yr DFS (median, mos) 75.8%72.3% 1.2 ( ) p= Yr OS (median, mos) 87.8%83.9% 1.3 ( ) 0=0.13

Gr 3/4 TOXICITY FOLFOXFOLFOX+ Cetuximab Neutropenia10%13% Febrile Neutropenia1%3% Hypersensitivity2%6% Rash/Acne0%19% Nausea3%4% Diarrhea9%15% Peripheral Neuropathy 4%5% Overall51%71%

Reasons for Discontinuation Reason Arm A <60 (N=493) Arm A (N=270) Arm A >70 (N=108) Arm D <60 (N=494) Arm D (N=288) Arm D >70 (N=143) Completion 77.9%78.9%77.8%70.2%67.0%51.1% Refusal 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%

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

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

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

Dose Intensity (% with > 80%) K-ras WT ArmOxaliplatin5-FUCetuximab FOLFOX (N=672) 69%85%N/A FOLFOX + Cmab (N=645) 61%74%63% P-value0.0003< ArmOxaliplatin5-FUCetuximab FOLFOX (N=613) 50%81%N/A FOLFOX + Cmab (N=582) 44%65%55% P-value0.03< Cycle 6 Cycle 10

13 “Idealized” Patient Comparison: Time to Recurrence – K-Ras WT All Patients “Ideal” Patients Arm 3 Year Rates (95% CI) HR P- value FOLFOXN= %( %)1.2( )0.35 FOLFOX + Cmab N= %( %) Arm 3 Year Rates (95% CI) HR P- value FOLFOXN= %( %)1.2( )0.98 FOLFOX + Cmab N= %( %)

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

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