Originally published as JCO Early Release 10.1200/JCO.2008.20.8397 on December 29 2008
Journal of Clinical Oncology, Vol 27, No 5 (February 10), 2009: pp. 663-671
© 2009 American Society of Clinical Oncology.
Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer
Carsten Bokemeyer,
Igor Bondarenko,
Anatoly Makhson,
Joerg T. Hartmann,
Jorge Aparicio,
Filippo de Braud,
Serban Donea,
Heinz Ludwig,
Gunter Schuch,
Christopher Stroh,
Anja H. Loos,
Angela Zubel,
Piotr Koralewski
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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