Patients with carcinoid syndrome (CS) have worse symptoms and poorer quality of life compared with patients with neuroendocrine tumors but without CS, including poorer physical functioning, greater pain, lower social functioning, and less energy/more fatigue.1 Refractory diarrhea is one of the features of CS that frequently does not respond to somatostatin analogs (SSAs). Telotristat ethyl (Xermelo) is an oral medication that inhibits serotonin production by carcinoid tumor cells, does not affect serotonin production in the brain (therefore, does not cause changes in mood), results in a significant reduction in 5-hydroxyindole acetic acid (5-HIAA) production, improves flushing and diarrhea, and is now FDA approved for control of diarrhea associated with CS that is not responsive to SSAs.2-5
FDA approval of telotristat for this indication was largely based on the results of the phase 3 TELESTAR study, in which 135 patients with CS experiencing ≥4 bowel movements (BMs) per day despite stable-dose SSA therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day orally during a 12-week, double-blind treatment period.6 The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were –0.81 for telotristat ethyl 250 mg (P <.001) and ‒0.69 for telotristat ethyl 500 mg (P <.001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were –0.9, –1.7, and –2.1, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-HIAA versus placebo at week 12 (P <.001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in several patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment.
Subsequent interviews with 35 patients who had participated in the TELESTAR study were quite revealing. Patients reported that their excessive BM symptoms negatively affected their emotional, social, physical, and occupational well-being, but 54% were satisfied or very satisfied in the reduction in BM by telotristat at week 12.7 None of the patients taking placebo were satisfied with their results. There are, however, challenges and concerns with taking telotristat, including the need to involve specialty pharmacy and completion of the necessary forms, the high cost of the drug, the need for treating physicians to complete postmarketing surveillance reports, the issue that some patients develop constipation on the drug (especially in the peritoneal/partial small bowel obstruction [PSBO] phenotype), and the concern about whether this drug must be taken forever. Other issues open to discussion are whether this drug has an antitumor effect, if it prevents cardiac disease and if this is an issue, how to mitigate cost, and whether PSBO-phenotype patients should receive this therapy.
- Beaumont JL, et al. Pancreas. 2012;41:461-466.
- Liu Q, et al. J Pharmacol Exp Ther. 2008;325:47-55.
- Kulke MH, et al. Endocr Relat Cancer. 2014;21:705-714.
- Pavel M, et al. J Clin Endocrinol Metab. 2015;100:1511-1519.
- FDA News Release. www.fda.gov/newsevents/newsroom/pressannouncements/ucm544035.htm.
- Kulke MH, et al. J Clin Oncol. 2017;35:14-23.
- Anthony L, et al. Clin Ther. 2017;39:2158-2168.