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Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer

Josep Tabernero, Eric Van Cutsem, Eduardo Díaz-Rubio, Andrés Cervantes, Yves Humblet, Thierry André, Jean-Luc Van Laethem, Patrick Soulié, Esther Casado, Chris Verslype, Javier Sastre Valera, Giampaolo Tortora, Fortunato Ciardiello, Oliver Kisker, Aimery de Gramont

From Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona; Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid; Servicio de Onco-Hematología, Hospital Clínico Universidad de Valencia, Valencia, Spain; University Hospital Gasthuisberg, Leuven; Université Catholique de Louvain, Cliniques Universitaires St Luc; Hôpital Universitaire Erasme, Brussels, Belgium; Hôpital Tenon; Medical Oncology Service, Hospital Saint-Antoine; Centre Paul Papin, Angers, France; Medical Oncology Service, University of Naples "Federico II"; Medical Oncology Service, Second University of Naples, Naples, Italy; and Medical Sciences Oncology, Merck KGaA, Darmstadt, Germany

Address reprint requests to Josep Tabernero, MD, Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain; e-mail: jtabernero{at}vhebron.net

Purpose: This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor–expressing metastatic colorectal cancer (mCRC).

Patients and Methods: The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m² during week 1, then 250 mg/m² weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m² on day 1; leucovorin 200 mg/m² on days 1 and 2, followed by fluorouracil 400 mg/m² bolus then 600 mg/m² intravenous infusion during 22 hours on days 1 and 2).

Results: The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.

Conclusion: Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; at the 29th Meeting of the European Society for Medical Oncology, October 29-November 2, 2004, Vienna, Austria; at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; at the 13th European Cancer Conference, October 30-November 3, 2005, Paris, France; and at the American Society of Clinical Oncology Gastrointestinal Symposium, January 19-21, 2007, Orlando, FL.

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

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