1 Phase III Clinical Trial of FOLFOX with or without Cetuximab in Resected K-ras wild type Stage 3 Colon Cancer: Cooperative Group Trial N0147 (NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG) Steven Alberts, Daniel Sargent, Thomas Smyrk, Anthony Shields, Emily Chan, Richard Goldberg, Sharlene Gill, Morton Kahlenberg, Stephen Thibodeau, Suresh Nair *: Coordinating group

2 DisclosuresDisclosures NCI provided primary support for the trial Additional grants to support the trial and its translational components received from: Bristol-Myers Squibb Bristol-Myers Squibb ImClone Systems ImClone Systems wholly-owned subsidiary of Eli Lilly and Company wholly-owned subsidiary of Eli Lilly and Company sanofi-aventis sanofi-aventis Pfizer Pfizer NCI provided primary support for the trial Additional grants to support the trial and its translational components received from: Bristol-Myers Squibb Bristol-Myers Squibb ImClone Systems ImClone Systems wholly-owned subsidiary of Eli Lilly and Company wholly-owned subsidiary of Eli Lilly and Company sanofi-aventis sanofi-aventis Pfizer Pfizer

3 Background: Adjuvant Standard Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant therapy for resected stage 3 colon cancer Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant therapy for resected stage 3 colon cancer MOSAIC FOLFOX4 versus LV5FU2 MOSAIC FOLFOX4 versus LV5FU2 NSABP C-07 FLOX versus 5-FU/LV NSABP C-07 FLOX versus 5-FU/LV 3-year Disease Free Survival: 70% Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant therapy for resected stage 3 colon cancer Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant therapy for resected stage 3 colon cancer MOSAIC FOLFOX4 versus LV5FU2 MOSAIC FOLFOX4 versus LV5FU2 NSABP C-07 FLOX versus 5-FU/LV NSABP C-07 FLOX versus 5-FU/LV 3-year Disease Free Survival: 70%

4 Potential Added Benefit of Targeted Therapy Limitation of new chemotherapy drugs to improve outcomes Limitation of new chemotherapy drugs to improve outcomes Monoclonal antibodies against EGFR and VEGF demonstrate improved outcome in metastatic colorectal cancer when combined with chemotherapy Monoclonal antibodies against EGFR and VEGF demonstrate improved outcome in metastatic colorectal cancer when combined with chemotherapy Limitation of new chemotherapy drugs to improve outcomes Limitation of new chemotherapy drugs to improve outcomes Monoclonal antibodies against EGFR and VEGF demonstrate improved outcome in metastatic colorectal cancer when combined with chemotherapy Monoclonal antibodies against EGFR and VEGF demonstrate improved outcome in metastatic colorectal cancer when combined with chemotherapy

5 Initial 2-arm Design for N0147 Stage 3 ColonCancer (N = 2300) RANDOMIZE mFOLFOX6 (12 cycles) Oxaliplatin 85 mg/m 2 Oxaliplatin 85 mg/m 2 LV 400 mg/m 2 & LV 400 mg/m 2 & 5-FU 2,400 mg/m 2 over 46 hrs 5-FU 2,400 mg/m 2 over 46 hrs every 2 weeks every 2 weeks mFOLFOX6 + Cetuximab (12 cycles) mFOLFOX6 mFOLFOX6 Cetuximab days 1,8 Cetuximab days 1, mg/m 2 loading dose mg/m 2 loading dose mg/m 2 weekly mg/m 2 weekly

6 Role of K-ras Analysis Ability to select patients based on K-ras status established in early 2008 Ability to select patients based on K-ras status established in early 2008 Mutated K-ras (K-ras Mut) predicts for lack of response to cetuximab Mutated K-ras (K-ras Mut) predicts for lack of response to cetuximab Wild type K-ras (K-ras WT) maintain ability to respond to cetuximab Wild type K-ras (K-ras WT) maintain ability to respond to cetuximab Ability to select patients based on K-ras status established in early 2008 Ability to select patients based on K-ras status established in early 2008 Mutated K-ras (K-ras Mut) predicts for lack of response to cetuximab Mutated K-ras (K-ras Mut) predicts for lack of response to cetuximab Wild type K-ras (K-ras WT) maintain ability to respond to cetuximab Wild type K-ras (K-ras WT) maintain ability to respond to cetuximab

7 Report of K-ras Results (Bokemeyer et al, JCO 2009)

8 Final Design for N0147 – June 2008 Stage 3 ColonCancer (N = 3768) PREREGISTER RANDOMIZE Centralized K-ras analysis K-ras WT K-ras Mut REGISTER Arm G Arm G Adjuvant therapy per primary oncologistAdjuvant therapy per primary oncologist Report therapy givenReport therapy given Annual status through year 8Annual status through year 8 Arm A mFOLFOX6 Arm D mFOLFOX6 + Cetuximab

9 K-ras Assessment K-ras Testing: K-ras Testing: Centralized testing performed in a CLIA approved lab at Mayo Clinic Centralized testing performed in a CLIA approved lab at Mayo Clinic DxS Assay using the Roche LightCycler 480 platform DxS Assay using the Roche LightCycler 480 platform 99.2% of samples provided interpretable result 99.2% of samples provided interpretable result K-ras Testing: K-ras Testing: Centralized testing performed in a CLIA approved lab at Mayo Clinic Centralized testing performed in a CLIA approved lab at Mayo Clinic DxS Assay using the Roche LightCycler 480 platform DxS Assay using the Roche LightCycler 480 platform 99.2% of samples provided interpretable result 99.2% of samples provided interpretable result

10 Goals for N0147 Primary Primary Compare disease free survival (DFS) between mFOLFOX6 and mFOLFOX6 + cetuximab in patients with K-ras WT Compare disease free survival (DFS) between mFOLFOX6 and mFOLFOX6 + cetuximab in patients with K-ras WT Secondary Secondary Compare overall survival in the two groups Compare overall survival in the two groups Assess toxicities resulting from the addition of cetuximab Assess toxicities resulting from the addition of cetuximab Primary Primary Compare disease free survival (DFS) between mFOLFOX6 and mFOLFOX6 + cetuximab in patients with K-ras WT Compare disease free survival (DFS) between mFOLFOX6 and mFOLFOX6 + cetuximab in patients with K-ras WT Secondary Secondary Compare overall survival in the two groups Compare overall survival in the two groups Assess toxicities resulting from the addition of cetuximab Assess toxicities resulting from the addition of cetuximab

11 N0147 Analysis plan Sample size: 2070 K-ras WT patients to provide 515 DFS events Sample size: 2070 K-ras WT patients to provide 515 DFS events 90% power to detect HR of 1.33 (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level 0.05) 90% power to detect HR of 1.33 (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level 0.05) Intent-to-treat analysis Intent-to-treat analysis Protocol specified interim analyses after 25%, 50%, and 75% of events Protocol specified interim analyses after 25%, 50%, and 75% of events Sample size: 2070 K-ras WT patients to provide 515 DFS events Sample size: 2070 K-ras WT patients to provide 515 DFS events 90% power to detect HR of 1.33 (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level 0.05) 90% power to detect HR of 1.33 (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level 0.05) Intent-to-treat analysis Intent-to-treat analysis Protocol specified interim analyses after 25%, 50%, and 75% of events Protocol specified interim analyses after 25%, 50%, and 75% of events

12 Eligibility for N0147 Inclusion Inclusion Completely resected colon adenocarcinoma Completely resected colon adenocarcinoma > 1 pathologically confirmed lymph node identified > 1 pathologically confirmed lymph node identified Age > 18 years Age > 18 years Acceptable liver and kidney function Acceptable liver and kidney function Standard hematologic parameters Standard hematologic parameters Inclusion Inclusion Completely resected colon adenocarcinoma Completely resected colon adenocarcinoma > 1 pathologically confirmed lymph node identified > 1 pathologically confirmed lymph node identified Age > 18 years Age > 18 years Acceptable liver and kidney function Acceptable liver and kidney function Standard hematologic parameters Standard hematologic parameters

13 Eligibility for N0147 Exclusion Exclusion Evidence of metastatic disease Evidence of metastatic disease En bloc resection for locally advanced disease allowed En bloc resection for locally advanced disease allowed Prior chemotherapy or radiation for colon cancer Prior chemotherapy or radiation for colon cancer Prior or concurrent malignancies within 5 years Prior or concurrent malignancies within 5 years Clinically significant peripheral neuropathy Clinically significant peripheral neuropathy Exclusion Exclusion Evidence of metastatic disease Evidence of metastatic disease En bloc resection for locally advanced disease allowed En bloc resection for locally advanced disease allowed Prior chemotherapy or radiation for colon cancer Prior chemotherapy or radiation for colon cancer Prior or concurrent malignancies within 5 years Prior or concurrent malignancies within 5 years Clinically significant peripheral neuropathy Clinically significant peripheral neuropathy

14 Final Study Population 2967 patients from 478 sites accrued to arms A, D, and G 2967 patients from 478 sites accrued to arms A, D, and G 62% K-ras WT 62% K-ras WT 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab) 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab) Trial halted on findings of planned interim analysis Trial halted on findings of planned interim analysis 90% of planned accrual 90% of planned accrual Median follow-up 23 months Median follow-up 23 months 2967 patients from 478 sites accrued to arms A, D, and G 2967 patients from 478 sites accrued to arms A, D, and G 62% K-ras WT 62% K-ras WT 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab) 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab) Trial halted on findings of planned interim analysis Trial halted on findings of planned interim analysis 90% of planned accrual 90% of planned accrual Median follow-up 23 months Median follow-up 23 months

15 Patient Characteristic FOLFOX(N=909)FOLFOX+Cmab(N=955) Age (years) Median (Range) Median (Range) 14% 70+ years of age14% 70+ years of age 58 ( ) 58 ( ) Gender Female Female Male Male46%54%48%52% Race Caucasian Caucasian African American African American Other Other87%5%8%86%6%8%

16 Tumor Characteristic FOLFOX(N=909)FOLFOX+Cmab(N=955) Bowel Obstruction Yes Yes No No15%85%16%84% Bowel Perforation Yes Yes No No5%95%5%95% Histology High High Low Low27%73%27%73% Lymph Node Involvement > 3 > 356%44%57%43% T Stage T1 or T2 T1 or T2 T3 T3 T4 T413%76%11%16%72%11%

17 Outcomes for K-ras WT Patients

18 Disease Free Survival (N=1847) Arm 3 Year Rates (95% CI) HR P- value FOLFOXN= %(72.1%-79.6%)1.2( )0.22 FOLFOX + Cmab N= %(68.5%-76.4%)

19 Disease Free Survival Age<70 (N=1589) Arm 3 Year Rates (95% CI) HR P-valueFOLFOXN= %(70.8%-79.1%)1.10 ( ) 0.76 FOLFOX + Cmab N= %(69.2%-77.9%)

20 Disease Free Survival Age>70 (N=258) Arm 3 Year Rates (95% CI) HR P-valueFOLFOXN= %(73.0%-89.8%)1.79( )0.03 FOLFOX + Cmab N= %(56.8%-77.0%)

21 Overall Survival (N=1847) Arm 3 Year Rates (95% CI) HR P-valueFOLFOXN= %(84.7%-90.9%)1.3( )0.13 FOLFOX + Cmab N= %(80.3%-87.6%)

22 Forest Plot for DFS Favors FOLFOX alone

23 Toxicity – Grade 3-4 Arm A Arm D Neutropenia10%13% Febrile Neutropenia 1%3% Hypersensitivity2%6% Rash/Acne0%19% Nausea3%4% Diarrhea9%15% Peripheral Neuropathy 4%5% Overall51%71%

24 Reasons for Discontinuation Reason Arm A <60(N=493) 60-69(N=270) >70 (N=108) Arm D <60(N=494) 60-69(N=288) >70 >70(N=143) Completion77.9%78.9%77.8%70.2%67.0%51.1% Refusal6.7%6.7%4.6%11.7%8.7%13.3% AE9.3%7.4%13.0%9.1%18.1%21.0% Other6.1%7.0%4.6%9.0%6.2%14.6%

25 ConclusionsConclusions No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon cancer No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon cancer Potential explanations Potential explanations Decreased tolerance with cetuximab Decreased tolerance with cetuximab Differences in dose intensity Differences in dose intensity Interaction with age: Interaction with age: Worse outcomes in older patients receiving cetuximab Worse outcomes in older patients receiving cetuximab Lessened ability to complete therapy Lessened ability to complete therapy No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon cancer No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon cancer Potential explanations Potential explanations Decreased tolerance with cetuximab Decreased tolerance with cetuximab Differences in dose intensity Differences in dose intensity Interaction with age: Interaction with age: Worse outcomes in older patients receiving cetuximab Worse outcomes in older patients receiving cetuximab Lessened ability to complete therapy Lessened ability to complete therapy

26 ConclusionsConclusions Mechanistic Mechanistic Cetuximab may have a different form of activity on micrometastatic disease compared to that observed in stage 4 disease Cetuximab may have a different form of activity on micrometastatic disease compared to that observed in stage 4 disease Differences in biology of earlier stage disease Differences in biology of earlier stage disease Current focus of correlative studies Current focus of correlative studies Mechanistic Mechanistic Cetuximab may have a different form of activity on micrometastatic disease compared to that observed in stage 4 disease Cetuximab may have a different form of activity on micrometastatic disease compared to that observed in stage 4 disease Differences in biology of earlier stage disease Differences in biology of earlier stage disease Current focus of correlative studies Current focus of correlative studies

27 AcknowledgmentsAcknowledgments Special thanks to all of the participating patients Special thanks to all of the participating patients Collaborative North American effort Collaborative North American effort Trial not possible without the support of NCI and that provided by Bristol-Myers Squibb, sanofi- aventis, ImClone, and Pfizer Trial not possible without the support of NCI and that provided by Bristol-Myers Squibb, sanofi- aventis, ImClone, and Pfizer Study Team Study Team Special thanks to all of the participating patients Special thanks to all of the participating patients Collaborative North American effort Collaborative North American effort Trial not possible without the support of NCI and that provided by Bristol-Myers Squibb, sanofi- aventis, ImClone, and Pfizer Trial not possible without the support of NCI and that provided by Bristol-Myers Squibb, sanofi- aventis, ImClone, and Pfizer Study Team Study Team