Originally published as JCO Early Release 10.1200/JCO.2008.20.8397 on December 29 2008

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Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer

From the University Hospital, Hamburg-Eppendorf; South West German Comprehensive Cancer, University Hospital Tübingen, Tübingen; Merck Serono, Darmstadt Germany; State Medical Academy, City Clinical Hospital #4, Dnepropetrovsk, Ukraine; Moscow City Oncology Hospital #62, Moscow Area, Russian Federation; Hospital Universitario La Fe, Valencia, Spain; Istituto Europeo di Oncologia, Milan, Italy; Institutul Oncologic "Prof. Dr. Al. Trestioreanu" Bucuresti, Bucharest, Romania; Wilhelminenspital der Stadt Wien, Vienna, Austria; and Wojewódzki Szpital Specjalistyczny Oddzia Chemioterapii, Krakow, Poland.

Corresponding author: Carsten Bokemeyer, MD, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg-Eppendorf, Germany; e-mail: c.bokemeyer{at}uke.uni-hamburg.de.

Purpose This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated.

Patients and Methods Patients received cetuximab (400 mg/m² initial dose followed by 250 mg/m²/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m² on day 1, plus leucovorin 200 mg/m² and fluorouracil as a 400 mg/m² bolus followed by a 600 mg/m² infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233).

Results The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated.

Conclusion KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.

Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; 14th European Cancer Conference, September 23-27, 2007, Barcelona, Spain; 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL; and The ESMO International Symposium: 10th World Congress on Gastrointestinal Cancer, June 25-28, 2008, Barcelona, Spain.

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

Clinical Trials repository link available on JCO.org.

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