Cetuximab Plus Irinotecan for Metastatic Colorectal Cancer (mCRC): Safety Analysis of the first 800 Patients in a Randomized Phase III Trial (EPIC): Abstract #3556 Y.A. Abubakr, C. Eng, V. Pautret, J.Maurel, W. Scheithauer, H. Kroning, A. Zubel, M.P. Lutz, L. Wong, A. Sobrero

Background Cetuximab has been proven to be safe and effective as a single agent in refractory colorectal cancer patients with an 11% response rate. In addition, cetuximab in combination with irinotecan showed a 23% response rate in a mixed refractory population in which 45% of subjects had received 3 or more lines of treatment [Cunningham et al, 2004]. These results provide a compelling rationale for combining irinotecan and cetuximab in an earlier and uniquely second-line treatment setting in this phase III study in order to evaluate effects on survival. EPIC is a randomized phase III study comparing cetuximab plus irinotecan to irinotecan in 2nd-line metastatic, EGFR-expressing mCRC patients (pts) (target N=1300 pts). Following an independent Data Safety Monitoring Board (DSMB) review of 400 pts., the pooled safety data was presented at ASCO 2005 ( # 3580). A pre-planned analysis of safety data of the first 800 patients was performed and is presented in a pooled fashion. An independent Data Safety Monitoring Board has intermittently reviewed the safety data. Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006

Study Schema Enrollment and Screening Randomization Study design: Phase III, randomized, open label, multicenter study * Randomization is stratified by study site and ECOG performance status (0-1, 2) Enrollment and Screening Randomization Cetuximab 400mg/m2 250mg/m2 loading dose weekly week #1 starting on of cycle #1 week #2 and Irinotecan 350mg/m2 every 3 weeks a Post-Treatment follow-up EGFR testing Eight hundred patients were randomized from May 2003 to March 2005 in Europe, Australia Asia and the US a or 300mg/m2 in patients > 70 years of age, with prior pelvic/abdominal radiation or ECOG of 2 Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006

Patient Demographics Age Median Range 61 y/o 21-90 Gender (%) Females 39 61 ECOG PS (%) 1 2 53 42 5 Race (%) White Asian Black Other 93 4 Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006

Total number of Cycles Total number 3629 Median 4 Range 1-23 Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006

Safety: Pooled Adverse Events of Interest Overall Drug-related All grades (%) Grade 3/4 (%) All grades HypoMg 14 1 N/A HypoK+ 21 4 HypoCa 16 2 Infusion Reaction Skin and SubQ tissue disorders 76 5 74 Atrial Fibrillation <1 Myocardial infarct Arrythmia (SVT) Ventricular dysfunction *Magnesium data only available for 109 subjects. Four patients (1%) experienced a serious, non-fatal hypersensitivity reaction (Grade 3 or 4) and were discontinued from protocol-therapy. Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006

Pooled Adverse Events (N=783) Overall Drug-related All grades (%) Grade 3/4 (%) All grades Asthenia/Fatigue 68 13 57 10 Neutropenic Fever 7 Thrombocytopenia 30 1 N/A Anemia 88 3 Diarrhea 78 21 76 Abdominal Cramping 34 19 Nausea 58 6 54 4 Vomiting 40 37 5 Anorexia 32 Dehydration 2 Dyspnea Deaths within 30 days of study therapy Treatment-related toxicity occurred in 5 patients (3 were neutropenia-related and 2 were the result of gastrointestinal toxicity). Disease related events occurred in 45 patients. “Other” events occurred in 6 patients: Respiratory failure due to ascites Pt fell at home, resulting in rt. femoral fx and hypotension. Exogenous hepatic coma Cardiac decompensation Bowel obstruction Pneumonia Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006

Conclusion: In this pooled analysis the incidence of the characteristic cetuximab and irinotecan toxicities does not seem to be increased as compared to reported incidences with Erbitux and Camptosar. The combination of irinotecan every 3 weeks and weekly cetuximab appears to be a feasible and safe regimen. The study completed its accrual of 1300 patients in February 2006. Efficacy results will be available in 2007. Abubakr, Eng, Pautret, et al: ASCO, #3556, 2006