New Developments in the Treatment of Neuroendocrine Tumours – RADIANT-4, NETTER-1 and Telotristat Etiprate

European Endocrinology, 2016;12(1):44–6 DOI: http://doi.org/10.17925/EE.2016.12.01.44

Abstract:

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose incidence has increased significantly in recent years, and whose optimal management remains controversial. We report the latest innovations in their management, in particular the results of three trials concerning the use of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in non-functional NETs of lung/ gastrointestinal (GI) origin, the first randomised trial of radiolabelled 177Lu-DOTATATE in patients with mid-gut NETs, and the use of the 5-HT synthesis inhibitor, telotristat etiprate, in patients with the carcinoid syndrome.
Keywords: Neuroendocrine tumours, treatment, everolimus, 177Lu-DOTATATE, 5-HT synthesis inhibitor, telotristat etiprate
Disclosure: Emilia Sbardella has nothing to disclose in relation to this article. Ashley Grossman has received consulting and lecture fees from Novartis, and was part of the NETTER-1 research trial. No funding was received in the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers.
Received: January 07, 2016 Published Online: February 29, 2016
Correspondence: Ashley Grossman, OCDEM, University of Oxford, Churchill Hospital, Headington, OX3 7LE, UK. E: ashley.grossman@ocdem.ox.ac.uk.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Neuroendocrine tumours (NETs) represent a heterogeneous group of neoplasms that originate from different types of neuroendocrine cells throughout the body.1 While previously considered to be relatively uncommon, their overall incidence has been reported as increasing for reasons which are unclear.2–4 Surgery is the only truly curative therapy, but there are now a variety of other treatment options although their specific use and sequencing remains controversial.3 However, somatostatin analogues (SSAs), particularly the long-acting formulations of octreotide and lanreotide, are highly effective for symptomatic patients with secretory syndromes, and recent studies have also shown their ability to retard tumour progression in the PROMID, CLARINET and RADIANT-2 trials.5–8 The multi-ligand SSA pasireotide was also shown to control the symptoms of carcinoid syndrome in patients with advanced NETs refractory/resistant to octreotide long-acting release (LAR) therapy.9 Recently, at the European Cancer Congress (ECC) of the European Society for Medical Oncology (ESMO) in Vienna, in September 2015, three trials were presented which provide novel data on therapeutic options.

Previous studies have demonstrated the efficacy of everolimus, an inhibitor of mammalian target of rapamycin (mTOR) (a serine–threonine kinase that stimulates cell growth, proliferation and angiogenesis)10–12 to slow tumour progression of pancreatic NETs (RADIANT-3)13 and symptomatic mid-gut tumours (RADIANT-2).7 RADIANT-4 was a placebo-controlled, double-blind, phase III study carried out in 13 European centres on the efficacy and safety of everolimus in patients with advanced, progressive, non-functional NETs of the lung and gut.14 Non-functional NETs are often diagnosed later when the cancer has become advanced, and at present there are limited treatment options available. This is particularly important for patients with lung carcinoids, as there is currently no approved treatment for such patients.The trial included 302 patients in which the patients were randomised (2:1) to everolimus (10 mg/d) or placebo and were stratified by tumour origin, World Health Organization performance status and prior SSA treatment. There was a statistically significant 52% reduction in the relative risk of progression or death in favour of everolimus, with a clinically relevant 7.1-month prolongation of progression-free survival (PFS) compared with those who had taken placebo. In addition, everolimus was well tolerated and its established safety profile confirmed.

Over many years, peptide receptor radionuclide therapy (PRRT) using radiolabelled octreotide has been extensively used for the treatment of progressive NETs, and while individual results have been encouraging, there has been no formal assessment of such therapy. For most NETs, molecular-targeted radiation therapy involves the systemic administration of a radiolabelled peptide designed to target somatostatin receptors on tumour cells with high affinity and specificity.15 Over the past 15 years, PRRT with the radiolabelled somatostatin receptor agonists, such as 90Y-DOTATOC, 177Lu-DOTATATE and 177Lu-DOTATOC, have been successfully used to target metastatic and inoperable NETs.15-16 Now, Strosberg and colleagues have presented data from the NETTER-1 trial,17 a phase III multicentre, stratified, open, randomised, controlled trial evaluating the efficacy of 177Lu-DOTA0- Tyr3-Octreotate (177Lu-DOTATATE or Lutathera® [Advanced Accelerator Applications, Saint-Genis-Pouilly, France]) in patients with inoperable, somatostatin receptor-positive mid-gut NETs progressing on LAR (20–30 mg every 3–4 weeks). The trial recruited 230 patients from 35 sites in eight European countries and 15 centres in the US, with grade 1–2 mid-gut NETs. Patients were randomised to receive either four administrations of Lutathera (7.4 GBq every 8 weeks) plus their octreotide LAR or ‘high-dose’ octreotide LAR (60 mg every 4 weeks). PFS was evaluated via Response Evaluation Criteria In Solid Tumors (RECIST) criteria every 12 weeks. The median PFS was not reached for Lutathera (in more than 25 months of treatment) but was 8.4 months for the high-dose octreotide LAR group (p<0.0001), with the number of disease progressions/deaths 23 in the Lutathera group and 67 in the Octreotide LAR group. The estimated PFS in the Lutathera arm was 40 months. This phase III trial showed a statistically significant increase in PFS in patients with advanced mid-gut NETs treated with Lutathera providing a valid therapeutic option with minimal adverse events.

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Keywords: Neuroendocrine tumours, treatment, everolimus, 177Lu-DOTATATE, 5-HT synthesis inhibitor, telotristat etiprate