ABSTRACT Introduction FOLFOX4 is widely used as a 1st-line treatment for metastatic colorectal cancer (mCRC). UFT (tegafur/uracil) combined with leucovorin is also well established as a monotherapy in this setting, with phase II studies suggesting that these agents may be safely and effectively combined with oxaliplatin (UFOX). The multicenter, open-label, randomized phase II FUTURE study, designed prior to the demonstration of the predictive significance of tumor KRAS mutational status in patients with mCRC receiving cetuximab, investigated the efficacy and safety of UFOX plus cetuximab versus FOLFOX4 plus cetuximab as 1st-line therapy in mCRC. Methods Patients ≥18 years with untreated, nonresectable mCRC were eligible. Patients were randomized 1:1, stratified by Kohne's criteria, to 4-weekly cycles of UFOX (UFT [tegafur 250 mg/m2/day, uracil 560 mg/m2/day; in three divided doses] and leucovorin 90 mg/day, in three divided doses, orally, days 1–21; oxaliplatin 85mg/m2, intravenously, days 1, 15) plus cetuximab or FOLFOX4 (intravenous: oxaliplatin 85 mg/m2, days 1 and 15; leucovorin 200 mg/m2 followed by 5-fluorouracil, 400 mg/m2 bolus, followed by 600 mg/m2 infused over 22 hours, days 1, 2, 15, 16) plus cetuximab. Cetuximab was administered weekly as a 400 mg/m2 initial infusion followed by 250 mg/m2/week thereafter. Treatment was continued until disease progression, withdrawal of consent, or the occurrence of unacceptable toxicity. Crossover was not permitted. Investigators assessed response to treatment every 8 weeks, based on radiological imaging. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) population, with secondary endpoints including response, overall survival (OS) and safety. All analyses were exploratory. Stratified 2-sided log-rank tests were used to compare treatment groups with respect to PFS and OS and stratified Cochran-Mantel-Haenszel (CMH) tests for best overall response. Results Recruitment was curtailed when the predictive significance of tumor KRAS mutation status became apparent. Between February 2007 and June 2008, 302 patients were randomized; 152 to UFOX plus cetuximab and 150 to FOLFOX4 plus cetuximab, with 180/302 (60%: 87/152 [57%] and 93/150 [62%], respectively) evaluable for tumor KRAS status. Baseline characteristics were generally balanced between the ITT and KRAS wild-type population treatment groups. Exposure to treatment as measured by relative dose intensity for 5-fluorouracil/tegafur (limited data for tegafur), oxaliplatin and cetuximab marginally favored the UFOX over the FOLFOX4 arm for each agent. For PFS and response rate, outcomes favored FOLFOX4 plus cetuximab compared with UFOX plus cetuximab across all populations (Table). However, OS was comparable between treatment groups. In the safety population, the most common grade 3–5 adverse events in the FOLFOX4 plus cetuximab arm and the UFOX plus cetuximab arm, respectively, were: neutropenia (28.7% versus 0), diarrhea (9.3% versus 19.2%) and rash (9.3% versus 6.6%). The safety profiles in the KRAS wild-type and overall safety populations, according to treatment arm, were comparable. Conclusion In the 1st-line treatment of mCRC, UFOX plus cetuximab showed an acceptable safety profile but lower activity to that of FOLFOX4 plus cetuximab in relation to PFS and response. However, there was no clear difference between UFOX plus cetuximab and FOLFOX4 plus cetuximab with regard to OS. Table 1 .