A Novel Cytotoxic Agent for Refractory Colorectal Cancer

Although survival has improved for patients with metastatic colorectal cancer (mCRC) in the past decade, patients who are resistant to fluorinated pyrimidine–based chemotherapy and to agents that target vascular endothelial growth factor and epidermal growth factor have a poor prognosis. Recent studies have focused on molecularly targeted drugs, but research also continues in the development of cytotoxic agents, such as TAS-102, which combines trifluridine (a thymidine based nucleic acid analogue) with tipiracil hydrochloride (an inhibitor of thymidine phosphorylase), permitting oral bioavailability of trifluridine.

Investigators now report results of the industry-sponsored, phase III, international, randomized, placebo-controlled, double-blind RECOURSE trial of TAS-102, which involved 798 patients with mCRC refractory to conventional therapies. Patients had received prior fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab therapies, and, if KRAS wild-type, anti–epidermal growth factor receptor monoclonal antibody therapy; most had received ≥4 prior regimens. Patients were randomized 2:1 to receive TAS-102 or placebo.

At median follow-up of 11.8 months, overall survival was improved with TAS-102 versus placebo (7.1 vs. 5.3 months; hazard ratio, 0.68; P<0.001). Median progression-free survival was similar with TAS-102 and placebo (2.0 and 1.7 months, respectively), but a significant improvement emerged with TAS-102 after 2 months (HR, 0.48; P<0.001). No difference in objective response rate was observed between TAS-102 and placebo (1.6% and 0.4%, respectively), but disease control favored TAS-102 (44% vs. 16%; P<0.001). Grade 3 or 4 toxicity was greater with TAS-102, but performance-status decline was slower.