Emerging use of everolimus in the treatment of neuroendocrine tumors

Abstract

Neuroendocrine tumors (NETs) consist of a diverse family of malignancies, which are derived from neuroendocrine cells, most commonly originating from the gastroenteropancreatic (GEP) tract or the bronchopulmonary system. In general, NETs are more indolent than epithelial tumors, with median survival rates of longer than 30 months. The upregulation of mTOR pathway has been shown to play a pivotal role in NET pathogenesis. Inhibition of mTOR protein with everolimus represents a progress in the treatment of advanced NETs. Everolimus has shown a significant improvement in progression-free survival (PFS) among patients with pancreatic NETs (pNETs) and nonfunctional GEP and lung NETs in the Phase III RAD001 in Advanced Neuroendocrine Tumors (RADIANT)-3 and RADIANT-4 studies, respectively. In addition, the combination of everolimus with octreotide showed a clinically significant improvement versus octreotide alone in functional NETs in the RADIANT-2 trial. These studies led to the US Food and Drug Administration (FDA) and European Medical Agency (EMA) approval of everolimus. Safety profile of everolimus is generally acceptable. The most common adverse events are stomatitis, diarrhea, rash and fatigue. There is a growing range of novel treatment options in the setting of NETs, but there are no data comparing the activity of different treatment strategies. Thus, treatment decisions are based on different aspects, such as clinical course, patient symptomatology, primary tumor site, tumor functionality, rate of progression and burden of disease. Further research is required to clarify the treatment sequencing to achieve the maximum prolongation in survival and maintenance of quality of life. Future research should concentrate on identification of predictive biomarkers for benefit from different therapies, and studies should also include quality of life as an important measurement in this disease.

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

“…Recent reviews have pinpointed that clinical trials on GEP-NETs need to be improved by exploiting molecular markers derived from the accumulated knowledge on altered pathways. These may help patient stratification and possibly predict response to therapy (23, 33). Moreover, according to the data summarized in the present review, the knowledge of differences in pathway alterations between NET types and between single cases is going to become fundamental to devise the best combination of treatments.…”

“…Recurrent deregulations have been traced back to a reduced number of core pathways. These include DNA damage repair, chromatin remodeling/histone methylation, telomere alteration, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway, and cell cycle/proliferation; approved drugs such as sunitinib and everolimus offer possible therapeutic options for the latter (23–25).…”

Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium

“…Finally, we will give an overview of the open questions and expected developments after this milestone, especially with regard to targeted therapy ( Capdevila et al . 2017 , Gajate et al . 2017 ).…”

Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR

“…mTOR emerged several years ago as an attractive target for HCC, as it is hyperactivated in 50%-60% of HCC and is associated with high-grade tumors and worst case prognosis (14)(15)(16)(17). Blocking tumor growth by inhibiting mTOR has led to the approval of the rapamycin family of allosteric drugs (rapalogs) in the treatment of a number of cancers (18,19). Nevertheless, the rapalog everolimus (RAD001) did not improve overall survival in the phase III EVOLVE-1 trial for advanced HCC after sorafenib failure (20).…”