Everolimus in the management of metastatic neuroendocrine tumours

• Published in: Therapeutic advances in gastroenterology Vol. 10; no. 1; pp. 132 - 141
• Main Authors: Chan, David L., Segelov, Eva, Singh, Simron
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2017; Sage Publications Ltd; SAGE Publishing
• Subjects: Gastroenterology; Inhibitor drugs; Metastasis; Monoclonal antibodies; Neuroendocrine tumors; Reviews; Targeted cancer therapy; RADIANT; everolimus; review; neuroendocrine tumors
• ISSN: 1756-2848; 1756-283X; 1756-2848
• DOI: 10.1177/1756283X16674660

Neuroendocrine tumours are increasing in incidence and cause a variety of symptoms. The mammalian target of rapamycin (mTOR) pathway plays a key role in neuroendocrine tumour (NET) pathogenesis, leading to increased lipid synthesis, protein synthesis and cellular growth. Upregulation of this pathway is noted in both hereditary and sporadic NETs. This understanding has led to investigations of mTOR inhibitors as therapy for metastatic NETs. After promising preclinical findings, everolimus, an mTOR inhibitor, was trialled in the RADIANT-1−4 studies on patients with advanced, well differentiated NETs. RADIANT-3 and RADIANT-4 established the efficacy of everolimus in improving progression-free survival (PFS) for metastatic NET of pancreatic, lung and gastrointestinal origin, leading to the US Food and Drug Administration (FDA) approval for its use in tumour control in those settings. Everolimus treatment is generally well tolerated; common adverse events include stomatitis, diarrhoea, rash and hyperglycaemia. Although discontinuation rates are low, many patients may require dose modification to successfully continue therapy. The combination of everolimus with somatostatin analogues (SSAs) (such as octreotide or pasireotide) or other targeted agents such as bevacizumab has not produced additional incremental benefit, and dual biologic therapy is not used widely. Ongoing trials are investigating everolimus compared with chemotherapy, optimal sequencing of therapy and combination of everolimus with radiotherapy. Future research should concentrate on identification of predictive biomarkers for benefit from mTOR therapy and include quality of life as a measure.