Telotristat
Regulatory sources consulted
Approved indications
- Treatment of carcinoid-syndrome diarrhoea, together with a somatostatin analogue, in adults inadequately controlled by that analogue.
Contraindications
Absolute
- History of hypersensitivity to telotristat; reactions have included angioedema, rash and pruritus.
Clinical warnings
- Major warning · Severe constipation, faecaloma, intestinal obstruction or perforation may occur. Stop treatment if severe constipation or severe, persistent or worsening abdominal pain develops. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4ac9d62-887c-4c8f-b04d-a5f31cec7c86
- Major warning · Liver-enzyme elevations have occurred; monitor them before and during treatment when clinically indicated. — https://cima.aemps.es/cima/dochtml/ft/1171224001/FT_1171224001.html
Drug interactions
- ModerateShort-acting octreotide
Mechanism: It significantly reduces systemic exposure to telotristat ethyl and its active metabolite.
Recommendation: Give short-acting octreotide at least 30 minutes after telotristat.
https://cima.aemps.es/cima/dochtml/ft/1171224001/FT_1171224001.html
- ModerateCYP2B6 substrates
Mechanism: Telotristat may reduce their systemic exposure and efficacy.
Recommendation: Monitor clinical response and adjust the substrate if efficacy is inadequate.
https://cima.aemps.es/cima/dochtml/ft/1171224001/FT_1171224001.html
- ModerateCYP3A4 substrates
Mechanism: Telotristat may reduce exposure to and efficacy of CYP3A4 substrates, including ethinylestradiol.
Recommendation: Monitor response and reassess the efficacy of concomitant treatment, including hormonal contraception.
https://cima.aemps.es/cima/dochtml/ft/1171224001/FT_1171224001.html
- ModerateCES2 substrates
Mechanism: Telotristat may alter exposure to carboxylesterase 2 substrates.
Recommendation: If coadministration is unavoidable, monitor for reduced efficacy and adverse reactions.
https://cima.aemps.es/cima/dochtml/ft/1171224001/FT_1171224001.html
Adverse events
Common (≥1%)
Abdominal pain · Increased gamma-glutamyl transferase · Fatigue
Rare but serious
Intestinal obstruction or perforation · Faecaloma · Angioedema
Pregnancy and lactation
FDA category: No recomendado; requiere anticoncepción
Use adequate contraception during treatment. Treatment is not recommended during pregnancy or in women of childbearing potential without contraception and must not be used while breastfeeding.
Recent literature (PubMed)
The rapid evolution of novel, costly therapies for neuroendocrine neoplasia (NEN) warrants formal high-quality cost-effectiveness evaluation. Costs of individual investigations and therapies are high; and examples are presented. We aimed to review the last ten years of standalone health economic evaluations in NEN. Comparing to published standards, EMBASE, Cochrane library, Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database and the Health Technology Assessment (HTA) Database were searched for health economic evaluations (HEEs) in NEN published between 2010 and October 2019. Of 12 economic evaluations, 11 considered exclusively pharmacological treatment (3 studies of SSAs, 7 studies of sunitinib, everolimus and/or 177Lu-DOTATATE and 1 study of telotristat ethyl) and 1 compared surgery with intraarterial therapy. 7 studies of pharmacological treatment had placebo or best supportive care as the only comparator. There remains a paucity of economic evaluations in NEN with the majority industry funded. Most HEEs reviewed did not meet published health economic criteria used to assess quality. Lack of cost data collected from patient populations remains a significant factor in HEEs where clinical expert opinion is still often substituted. Further research utilizing high-quality effectiveness data and rigorous applied health economic analysis is needed.
Neuroendocrine tumors (NETs) are heterogeneous neoplasms with different molecular characteristics and prognosis. Although slow-growing, NETs are often diagnosed at an advanced stage. The treatment choice depends on primary site, extent, grade, growth rate, somatostatin receptor status, functional status, performance status, and comorbidities. Precise knowledge of the biological and molecular features of NETs has led to the development of novel therapies. Therapeutic options include somatostatin analogs, multi-targeted tyrosine kinase inhibitors (e.g., sunitinib), or mammalian targets of rapamycin (mTOR) inhibitors (e.g., everolimus), telotristat ethyl, chemotherapy, and peptide-receptor radionuclide therapy. Pivotal studies that led to approval, treatment-related adverse events, and safety concerns, as demonstrated in clinical trials and real-world clinical practice. Questions, such as the optimal timing, selection, and sequence of therapies, and biomarkers that predict response to the novel agents in an individual patient, remain to be answered. We propose a stepwise approach for the management of advanced Gastro-entero-pancreatic (GEP)-NETs that utilizes a multidisciplinary team of experts. Biomarkers may assist in both the diagnosis and post-treatment follow-up in patients with GEP-NETs. The next decade of research on GEP-NETs is promising and should provide new insights into the molecular underpinnings of this disease, therapy selection, and the sequencing of the available therapies, along with the potential role of AL in NET pharmacotherapy.
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors, ranging from well-differentiated, slow-growing neuroendocrine tumor (NET) with long-term survival, to aggressive high-grade neuroendocrine carcinoma (NEC). Advances in treatment and earlier diagnosis have led to improved survival outcomes; however, data regarding patients' quality of life (QoL) during therapy and in the post-treatment phase remain limited. This narrative review aims to analyze available data on QoL in NEN patients undergoing medical therapies, including nutritional considerations, to improve and personalize therapeutic strategies. A literature search was performed using online databases, including MEDLINE (via PubMed) and Scopus, employing multiple keyword combinations up to October 2024. Somatostatin analogs (SSAs) and radioligand therapy (RLT) have demonstrated good tolerability profiles and efficacy on QoL, especially in patients with carcinoid syndrome, impacting on both physical and emotional domains. In contrast, multikinase inhibitors have been associated with declines in general health status, and sexual and physical function. Data on chemotherapy are conflicting, with some evidence suggesting a favorable QoL profile due to tumor control. Interestingly, approximately 30% of NEN survivors report persistence of symptoms related to depression. Both treatment-related side effects and disease-related symptoms may impact QoL, affecting nutritional status, which should be carefully considered. Despite standardized QoL, assessments are lacking in nutritional studies, and adherence to a Mediterranean diet seems to positively influence symptom burden in NEN patients. In conclusion, evidence supports that SSA and RLT contribute to improved QoL, likely due to symptom control. Further research is needed to better characterize the QoL impact of other therapies using standardized assessment tools, in order to optimize therapeutic management.
Carcinoid syndrome is the most frequent hormonal complication associated with neuroendocrine neoplasms. It was first reported in 1954, and the classical symptoms are diarrhoea, flushing and abdominal pain. It is caused by the secretion of several vasoactive substances, the most prominent being serotonin, which play a pathophysiological role in the clinical symptoms which characterise carcinoid syndrome. Therefore, the focus of carcinoid syndrome treatment is to reduce serotonin production and hence improve the patient's quality of life. There are a variety of management options for carcinoid syndrome including medical, surgical and loco-regional interventional radiological procedures. The most widely used are somatostatin analogues with three clinically approved drugs: lanreotide and octreotide (first-generation) and pasireotide (second-generation). Both everolimus and interferon used in combination with octreotide have shown significant reduction in urinary 5-hydroxyindoleacetic acid compared to octreotide alone. Telotristat ethyl has been increasingly utilised for patients with symptoms despite taking somatostatin analogues. It has also been shown to have a significant improvement in bowel movement frequency which was associated with a significant improvement in quality of life. Peptide receptor radionuclide therapy has proven symptomatic improvement in patients with uncontrolled symptoms. Chemotherapy is primarily reserved for patients with high proliferation tumours, with limited research on the efficacy in reducing symptoms. Surgical resection remains the optimal treatment due to being the only one that can achieve a cure. Liver-directed therapies are considered in patients where curative resection is not possible. There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome.
This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.