1. Pilot Experience with Adjuvant FOLFIRI +/- Cetuximab in Patients with Resected Stage III Colon Cancer – NCCTG Intergroup N0147 J. Huang*, D. J. Sargent*, M. R. Mahoney*, A. F. Shields, E. Chan, R. M. Goldberg, S. Gill, M. S. Kahlenberg, J. T. Quesenberry, T. C. Smyrk, A. Grothey*, F. Sinicrope*, S. G. Nair, S. R. Alberts*; Mayo Clinic, Rochester, MN * ; National Surgical Adjuvant Breast and Bowel Project; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Vanderbilt University Medical Center, Nashville, TN; University of North Carolina at Chapel Hill, Chapel Hill, NC; British Columbia Cancer Agency, Vancouver, BC; University of Texas Health Science Center at San Antonio, San Antonio, TX; St. Luke's Regional Medical Center, Sioux City, IA; Mayo Clinic College of Medicine, Rochester, MN; Lehigh Valley Hospital, Allentown, PA BACKGROUND  Irinotecan (CPT-11) has demonstrated antitumor activity against metastatic colorectal cancer used alone or with 5-fluorouracil (5FU)/leucovorin (LV).  Two arms with CPT-11, 5FU, and LV (FOLFIRI) +/- Cetuximab (Cmab) were originally included in N0147. However, after CALGB 89803 (J Clin Oncol 25:3456, 2007), PETACC-3 (J Clin Oncol 27:3117, 2009), and Accord02 (Ann Oncol 20:674, 2009) showed no benefit to the 3-drug combination in adjuvant therapy, the CPT-11 arms of N0147 were discontinued.  We report the outcomes for patients given FOLFIRI +/- Cmab. METHODS  Patients with resected stage 3 colon cancer signed informed consent and were randomized to one of 6 arms including:  12 biweekly cycles of CPT-11 180 mg/m2 d1 with LV 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 without (Arm B, FOLFIRI)  Or with Cmab (Arm E) 400 mg/m2 d1 cycle 1 then Cmab at 250 mg/m2 d1 & 8.  Primary endpoint was 3-year disease-free survival (DFS).  Secondary endpoints included overall survival (OS) and toxicity. RESULTS  146 patients (Arm B-106, Arm E-40) were enrolled.  Median follow-up on 79 patients in Arm B was 60 months and 59 months in Arm E for 37 patients.  WtKRAS (vs. Mt) status was associated with trends in improved DFS (HR=0.6 [95% CI 0.3-1.1], p = 0.10) and OS (HR 0.7 [95% CI 0.3-1.5], p = 0.34), in all treatment groups combined.  The addition of Cmab improved DFS and OS in the overall group and within wtKRAS pts.  Grade > 3 non-hematologic adverse effects were significantly increased in the Cmab-containing arm (46 vs 68%, p=0.02). Figure 1: Disease-free Survival – Wt-Kras (n=95) Table 1: Baseline Characteristics REFERENCES 1.Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. Aug 2007;25(23):3456- 3461. 2.Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. Apr 2009;20(4):674-680. 3.Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. Jul 2009;27(19):3117-3125. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer. Figure 2: Disease-free Survival – Mt-Kras (n=46) Patient CharacteristicFOLFIRI (N = 106) FOLFIRI+Cmab (N = 40) Median (range) Age (years)57 (25-82)59 (30-82) Gender Female Male 47% 53% 45% 55% Median (range) Follow-up (months) N = 79 60 (3-72) N = 37 59 (2-67) Tumor Characteristic FOLFIRI (N=106) FOLFIRI+Cmab (N=40) 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% K-ras mutation status Wild-type Mutant Missing 65% 31% 4% 65% 33% 2% Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=6969.8%(60%-82%)0.31(0.09-1.03)0.04 FOLFIRI + C225 N=2692.3%(83%-100%) Figure 3: Disease-free Survival – All Groups (n=146) CONCLUSIONS  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.Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=3356.3%(41%-76%)0.45(0.13-1.53)0.19 FOLFIRI + C225 N=1382.5%(63%-100%) Arm 3 Year Rates (95% CI) HR P-valueFOLFIRIN=10666.7%(58%-77%)0.44(0.20-0.97)0.04 FOLFIRI + C225 N=4086.6%(76%-98%) *C225 = Cetuximab UPDATED ABSTRACT Background: Irinotecan (CPT-11) has antitumor activity against metastatic colorectal cancer alone or with 5-fluorouracil (5FU)/leucovorin (LV). Two arms with CPT-11, 5FU, and LV (FOLFIRI) +/- Cetuximab (Cmab) were originally included in N0147. However, after CALGB 89803 (J Clin Oncol 25:3456, 2007), PETACC-3 (J Clin Oncol 27:3117, 2009), and Accord02 (Ann Oncol 20:674, 2009) showed no benefit to a CPT-11 combination in adjuvant therapy, the CPT-11 arms of N0147 were discontinued. We report the outcomes for patients given FOLFIRI and FOLFIRI+Cmab (F-Cmab). Methods: Patients with resected stage III colon cancer were randomized to one of 6 arms including 12 biweekly cycles of FOLFIRI (CPT-11 180 mg/m2 d1 with LV 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1,2) without or with Cmab 400 mg/m2 d1 cycle 1, then 250 mg/m2 d1, 8. Primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Results: 146 evaluable patients (Arm B-106, Arm E-40) were enrolled; median follow-up was 59.6 months (range 1.5-72). In pts with wtKRAS (vs mt) cancers, trends towards improved DFS (HR=0.6 [95% CI 0.3-1.1], p = 0.10) and OS (HR 0.7 [95% CI 0.3-1.5], p = 0.34) were observed without regard to treatment. The addition of Cmab improved DFS and OS in the overall group and within wtKRAS patients. Grade >= 3 non-hematologic adverse effects were significantly increased in the Cmab arm (46% vs. 68%, p = 0.02). Conclusion: In this small randomized comparison, trends for improved DFS and OS with the addition of Cmab to FOLFIRI were observed in patients with resected stage III colon cancer patients, regardless of KRAS status. Table 2: Toxicity – Grade 3-4 FOLFIRIFOLFIRI+Cmab Neutropenia14%10% Febrile Neutropenia2%3% Acne0%18% Nausea10%0% Diarrhea14%15% Paresthesias0%10% Infarction0%8% Overall53%68%