New Treatment Available for Neuroendocrine Tumor–Associated Diarrhea

On 28 February 2017, the Food and Drug Administration (FDA) approved the oral tryptophan hydroxylase (TPH) inhibitor, telotristat ethyl (Xermelo™, Lexicon Pharmaceuticals), at a dose of 250 mg in combination with a somatostatin analogue (SSA) for the treatment of metastatic neuroendocrine tumors (NETs)–associated carcinoid syndrome diarrhea that is inadequately controlled by SSA therapy alone.

Approval is based on the efficacy and safety analysis of the pivotal, double-blind, randomized, phase III, TELESTAR trial, in which a total of 135 patients with metastatic NETs–associated carcinoid syndrome diarrhea, uncontrolled by SSA, were randomized to receive either telotristat ethyl (250 mg or 500 mg three times daily; n = 45 per cohort) or placebo (n = 45), in addition to SSA. At 12 weeks follow-up, patients receiving telotristat ethyl experienced, at both doses, a statistically significant reduction from baseline in average bowel movement frequency compared to patients receiving placebo (P<.001). Exploratory analysis revealed that 33% of patients receiving 250 mg telotristat ethyl experienced a mean reduction of bowel movement frequency of two per day, compared to only 4% of those receiving placebo. Telotristat ethyl treatment was associated with a ≥30% reduction in bowel movement frequency for at least half of the study duration in 44% (250 mg) and 42% (500 mg) of patients versus 20% with placebo.

Telotristat ethyl was well tolerated, particularly at a dose of 250 mg. All-grade treatment-related adverse events (AEs) occurred in 82% of patients treated with the 250-mg dose versus 87% treated with placebo. The 500-mg dose was associated with an increase of AEs compared with placebo (93%). Mild to moderate nausea in 13.3% of patients was the most significant side effect associated with the FDA-approved dose of 250 mg. Importantly, patients receiving telotristat ethyl should be monitored for severe constipation due to a slight risk of intestinal perforation or intestinal obstruction. primelines-approved