Selumetinib is a potent, selective MEK inhibitor with efficacy in several tumor models. This study compared selumetinib with capecitabine in patients with advanced or metastatic pancreatic cancer who had been pretreated with a gemcitabine-based regimen. In this randomized, multicenter phase II study (NCT00372944), patients received either 100 mg oral selumetinib twice daily or 1,250 mg/m(2) oral capecitabine twice daily for 2 weeks followed by a 1-week break, given in 3-weekly cycles. The primary endpoint was overall survival. In all 70 patients were randomized. The median survival was 5.4 months in the selumetinib group and 5.0 months in the capecitabine group (hazard ratio 1.03; two-sided 80% confidence interval = 0.68,1.57; P = 0.92). Disease progression events occurred in 84% and 88% of patients in the selumetinib and capecitabine treatment groups, respectively. Gastrointestinal adverse events (nausea, vomiting and diarrhea) were commonly observed in both treatment groups. Other frequently reported adverse events were acneiform dermatitis and peripheral edema with selumetinib, and palmar-plantar erythrodysaesthesia with capecitabine. There was no statistically significant difference in overall survival between selumetinib and capecitabine as second-line treatment in patients with advanced pancreatic cancer. Selumetinib was well tolerated with a manageable safety profile.