Background
Phase III, double-blind, placebo-controlled RCT. 135 patients with metastatic neuroendocrine tumors experiencing ≥4 bowel movements (BMs) per day despite stable-dose somatostatin analog (SSA) therapy. Carcinoid syndrome diarrhea is driven by excessive peripheral serotonin. Telotristat ethyl (Xermelo) is an oral tryptophan hydroxylase 1 (TPH1) inhibitor that blocks peripheral serotonin synthesis. Patients assigned 1:1:1 to placebo or one of two doses of telotristat ethyl, all added to ongoing SSA.
Interventions and follow up
Arm A: Telotristat ethyl 250 mg orally three times daily (TID) + stable SSA (n=45)
Arm B: Telotristat ethyl 500 mg orally TID + stable SSA (n=45)
Arm C (control): Placebo TID + stable SSA (n=45)
Primary endpoint: Change from baseline in BM frequency per day (averaged over 12-week double-blind period)
Median follow-up: 12 weeks double-blind; open-label extension (OLE) to 48 weeks with telotristat ethyl 500 mg TID
Arm B: Telotristat ethyl 500 mg orally TID + stable SSA (n=45)
Arm C (control): Placebo TID + stable SSA (n=45)
Primary endpoint: Change from baseline in BM frequency per day (averaged over 12-week double-blind period)
Median follow-up: 12 weeks double-blind; open-label extension (OLE) to 48 weeks with telotristat ethyl 500 mg TID
Results
BM frequency reduction vs placebo (estimated difference/day): −0.81 (250 mg, P<.001); −0.69 (500 mg, P<.001)
Durable response (≥30% BM reduction for ≥50% of treatment days): 44% (250 mg) vs 42% (500 mg) vs 20% (placebo)
Urinary 5-HIAA: Significantly reduced with both doses vs placebo at week 12 (P<.001)
Durable response (≥30% BM reduction for ≥50% of treatment days): 44% (250 mg) vs 42% (500 mg) vs 20% (placebo)
Urinary 5-HIAA: Significantly reduced with both doses vs placebo at week 12 (P<.001)
Adverse events
Overall: Mostly grade 1–2; no grade 4 treatment-related events and no treatment-related deaths; no new safety signals in the open-label extension.
Gastrointestinal: Nausea was the most notable new symptom with telotristat ethyl.
Hepatic: Asymptomatic GGT elevation observed in a minority of patients.
Gastrointestinal: Nausea was the most notable new symptom with telotristat ethyl.
Hepatic: Asymptomatic GGT elevation observed in a minority of patients.
Conclusions
Telotristat ethyl at 250 mg and 500 mg TID significantly reduced BM frequency and urinary 5-HIAA in carcinoid syndrome patients not adequately controlled by SSA. The 250 mg dose demonstrated comparable efficacy to 500 mg with a favorable tolerability profile. TELESTAR established TPH1 inhibition as the first new mechanism of action for carcinoid syndrome diarrhea in the SSA era.
Key Limitations
Key Limitations: The double-blind period was only 12 weeks; long-term efficacy data derive from the non-comparative OLE. The 500 mg dose showed no additional efficacy over 250 mg, suggesting a flat dose-response at higher exposures. Carcinoid flushing was not a primary or co-primary endpoint and benefit was inconsistent. The trial enrolled predominantly small-bowel NET with carcinoid syndrome; generalizability to other NET subtypes is uncertain.
Clinical Context
Telotristat ethyl 250 mg TID (Xermelo) received FDA approval in February 2017 for carcinoid syndrome diarrhea in combination with SSA, based on TELESTAR. It is the first and only approved oral TPH1 inhibitor, acting peripherally (poor CNS penetration). ENETS guidelines recommend telotristat ethyl as add-on therapy for SSA-refractory carcinoid syndrome diarrhea. It does not replace SSA but complements it.
References
References: Kulke MH et al, JCO 2017 (TELESTAR primary)