Drug Improves Survival in Refractory Colorectal Cancer

A cytotoxic thymidine analog extended survival and slowed disease progression in patients with advanced-stage colorectal cancer, with few side effects. According to a study published in The New England Journal of Medicine, the drug, TAS-102 (Taiho Pharmaceutical), was active in patients who had exhausted standard treatments with fluoropyrimidines including 5-fluorouracil (5-FU).

TAS-102 is an orally administered combination of trifluridine and tipiracil hydrochloride, which slows metabolism of the active compound. Preclinical studies showed the drug was active against cell lines resistant to 5-FU, and positive results in a small clinical trial in Japan 2 years ago spurred the new study—a randomized, double-blind, placebo-controlled phase III trial that enrolled 800 patients in the United States, Japan, Europe, and Australia whose cancers had failed to respond to 5-FU. The subjects received repeated cycles of TAS-102 or placebo twice a day for 5 days, followed by 2 days of rest, for 2 weeks, and then 2 weeks off drug.

Overall median survival was significantly longer among those taking TAS-102 compared with placebo (7.1 months versus 5.3 months). The TAS-102 group also showed a longer time to progression, more tumor responses, better disease control, and a delay in the worsening of symptoms compared with the placebo group.

For a cytotoxic drug, the treatment caused surprisingly few side effects. Significant toxicity was uncommon, with little nausea and hair loss. The most frequent adverse event was leukopenia, affecting 38% of the treatment group.

“This is an exciting new drug,” says Richard M. Goldberg, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, who was not involved in the study. “It is oral, the toxicity profile is favorable, and the dosing schedule is fairly easy. Most importantly, the activity profile was positive in a heavily pretreated group where the expectation of benefit was small,” he says. In addition, the drug appeared effective “in virtually every subset of patients, including those patients whose tumors harbor a RAS mutation, a particularly underserved population in colorectal cancer.”

Although the increase in survival was small, the consistent positive signal in people whose cancer failed to respond to other available treatments is promising, according to study leader Robert J. Mayer, MD, of Dana-Farber Cancer Institute in Boston, MA. “This appears to be a compound working in a different way [than 5-FU], and the results certainly justify examining TAS-102 in additional trials, not at the tail end of a series of therapies, but much earlier,” Mayer says.

TAS-102 is currently under FDA review.