0 Adjuvant FOLFIRI +/- Cetuximab in Patients with Resected Stage III Colon Cancer NCCTG Intergroup Phase III Trial N0147 Jocelin Huang, Daniel J Sargent, Michelle R Mahoney, Stephen N Thibodeau, Thomas C Smyrk, Frank A Sinicrope, Garth D Nelson, Steven R Alberts ASCO GI Cancers Symposium January 22, 2011 Jocelin Huang, Daniel J Sargent, Michelle R Mahoney, Stephen N Thibodeau, Thomas C Smyrk, Frank A Sinicrope, Garth D Nelson, Steven R Alberts ASCO GI Cancers Symposium January 22, 2011

1 Disclosures 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 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 sanofi-aventis sanofi-aventis Pfizer Pfizer

2 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

3 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 cancer DFS P=0.106 OS P=0.09 ACCORD2 (FOLFIRI) 400 patients with resected high-risk stage III colon cancer (N 2 or N 1 with occlusion/perforation) DFS P=0.92 OS P=0.99 CALGB (IFL) 1,264 patients with resected stage III colon cancer DFS P=0.85 OS P=0.74 PETACC-3 (FOLFIRI) 3,018 patients with resected stage II/III colon cancer DFS P=0.106 OS P=0.09 ACCORD2 (FOLFIRI) 400 patients with resected high-risk stage III colon cancer (N 2 or N 1 with occlusion/perforation) DFS P=0.92 OS P=0.99 CALGB (IFL) 1,264 patients with resected stage III colon cancer DFS P=0.85 OS P=0.74 LV/5-FU2 FOLFIRI 12 cycles planned R

4 N0147: Initial Design in 2001 Planned Accrual: 3750 FOLFIRI 5-FU 400 mg/m 2 + Bolus CPT mg/m 2 + LV 400 mg/m 2 & 5-FU 2,400 mg/m 2 over 46 hrs Q 2 w mFOLFOX6 5-FU 400 mg/m 2 + Oxaliplatin 85 mg/m 2 + LV 400 mg/m 2 & 5-FU 2,400 mg/m 2 over 26 hrs Q 2 w mFOLFOX6  FOLFIRI Planned Accrual: 3750 FOLFIRI 5-FU 400 mg/m 2 + Bolus CPT mg/m 2 + LV 400 mg/m 2 & 5-FU 2,400 mg/m 2 over 46 hrs Q 2 w mFOLFOX6 5-FU 400 mg/m 2 + Oxaliplatin 85 mg/m 2 + LV 400 mg/m 2 & 5-FU 2,400 mg/m 2 over 26 hrs Q 2 w mFOLFOX6  FOLFIRI R R

5 N0147: First Design Change Addition of Cetuximab Sept-04 6 arm design FOLFIRI +/- cetuximab FOLFOX +/- cetuximab FOLFOX  FOLFIRI +/- cetuximab Addition of Cetuximab Sept-04 6 arm design FOLFIRI +/- cetuximab FOLFOX +/- cetuximab FOLFOX  FOLFIRI +/- cetuximab R

6 N0147: FOLFIRI +/- Cetuximab Addition of Cetuximab Sept-04 6 arm design FOLFIRI +/- Cetuximab (Cmab) FOLFOX +/- Cmab FOLFOX  FOLFIRI +/- Cmab Addition of Cetuximab Sept-04 6 arm design FOLFIRI +/- Cetuximab (Cmab) FOLFOX +/- Cmab FOLFOX  FOLFIRI +/- Cmab R

7 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

8 K-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

9 Eligibility 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

10 Eligibility 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

11 N0147: FOLFIRI +/- Cmab Resected Stage 3 ColonCancer (N = 146) RANDOMIZE FOLFIRI (12 cycles) Irinotecan 180 mg/m 2 Irinotecan 180 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 FOLFIRI + Cetuximab (12 cycles) FOLFIRI FOLFIRI 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

12 Final 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

13 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 = (3-72) N = (2-67)

14 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 > 3 65% 35% 65% 35% T Stage T1 or T2 T3 T4 16% 70% 14% 12% 78% 10%

15 K-ras mutation status FOLFIRI (N=106) FOLFIRI + Cmab (N=40) Wild-type Mutant Missing 65% 31% 4% 65% 33% 2%

16 Disease-free Survival: WT-Kras (n=95) FOLFOX: 75.8% FOLFOX + C225: 72.3%Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=6969.8%(60%-82%)0.31( )0.04 FOLFIRI + C225 N=2692.3%(83%-100%)

17 Disease-free Survival: MT-Kras (n=46) FOLFOX: 67.2% FOLFOX + Cmab: 64.2%Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=3356.3%(41%-76%)0.45( )0.19 FOLFIRI + C225 N=1382.5%(63%-100%)

18 Disease-free Survival (n=146) FOLFOX: 75.8% FOLFOX + Cmab: 72.3%Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN= %(58%-77%)0.44( )0.04 FOLFIRI + C225 N=4086.6%(76%-98%)

19 Overall Survival: WT-Kras (n=95) Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=6985.2%(77%-94%)0.34( )0.13 FOLFIRI + C225 N=2692.0%(82%-100%) FOLFOX: 87.8% FOLFOX + Cmab: 83.9%

20 Overall Survival: MT-Kras (n=46) Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=3380.6%(68%-96%)0.22( )0.12 FOLFIRI + C225 N=1390.9%(75%-100%)

21 Overall Survival (n=146) FOLFOX: 87.8% FOLFOX + Cmab: 83.9%Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN= %(78%-92%)0.30( )0.04 FOLFIRI + C225 N=4091.8%(83%-100%)

22 Toxicity – Grade 3-4 FOLFIRIFOLFIRI + Cmab Neutropenia14%10% Febrile Neutropenia2%3% Acne0%18% Nausea10%0% Diarrhea14%15% Paresthesias0%10% Infarction0%8% Overall53%68%

23 Reasons for Discontinuation ReasonFOLFIRIFOLFIRI + Cmab Completion79%70% Refusal8%13% Adverse Event8%18% Other6%0%

24 ConclusionsConclusions Adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX Adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients, regardless of KRAS status Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients, regardless of KRAS status Possible different synergistic effect between FOLFIRI and Cmab than with FOLFOX and Cmab Possible different synergistic effect between FOLFIRI and Cmab than with FOLFOX and Cmab Adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX Adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients, regardless of KRAS status Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients, regardless of KRAS status Possible different synergistic effect between FOLFIRI and Cmab than with FOLFOX and Cmab Possible different synergistic effect between FOLFIRI and Cmab than with FOLFOX and Cmab

25 AcknowledgmentsAcknowledgments 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