Originally published as JCO Early Release 10.1200/JCO.2007.13.1193 on April 7 2008

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EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer

Alberto F. Sobrero, Joan Maurel, Louis Fehrenbacher, Werner Scheithauer, Yousif A. Abubakr, Manfred P. Lutz, M. Eugenia Vega-Villegas, Cathy Eng, Ernst U. Steinhauer, Jana Prausova, Heinz-Josef Lenz, Christophe Borg, Gary Middleton, Hendrik Kröning, Gabriele Luppi, Oliver Kisker, Angela Zubel, Christiane Langer, Justin Kopit, Howard A. Burris, III

From the Department of Medical Oncology, Ospedale San Martino, Genoa; Department of Oncology and Hematology, Policlinico, Modena, Italy; Department of Medical Oncology, Hospital Clínic Barcelona, CIBERehd, Barcelona; Hospital Universitario Marques de Valdecilla, Santander, Spain; Clinical Division of Oncology, Department of Medicine I and Cancer Center, Medical University Vienna, Austria; Caritasklinik St. Theresia, Saarbrücken; Department of Hematology/Oncology, Klinikum Kassel, Kassel; Oncological Practice, Magdeburg; Merck KGaA, Darmstadt, Germany; Department of Radiotherapy and Oncology, University Hospital Motol, Prague, Czech Republic; Department of Medical Oncology, INSERM U645, University Hospital, Besançon, France; St Luke's Oncology Centre, Guildford, United Kingdom; Kaiser Permanente Medical Center Northern California, Vallejo; Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; Florida Oncology Associates, Jacksonville, FL; M.D. Anderson Cancer Center, Houston, TX; Bristol-Myers Squibb, Wallingford, CT; and the Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN

Corresponding author: Alberto F. Sobrero, MD, Department of Medical Oncology, Ospedale San Martino, Genoa, 16132, Italy; e-mail: alberto.sobrero{at}hsanmartino.liguria.it

Purpose: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.

Patients and Methods: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m² day 1 followed by 250 mg/m² weekly) plus irinotecan (350 mg/m² every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).

Results: Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms.

Conclusion: Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

published online ahead of print at www.jco.org on April 7, 2008.

Sponsored by Merck KGaA, Bristol-Myers Squibb, and ImClone Systems.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2006; safety and efficacy results from this study were presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the quality of life results from this study were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.