Efficacy and Safety of Everolimus in Extrapancreatic Neuroendocrine Tumor: A Comprehensive Review of Literature

Abstract

Background. Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs. Patients and Methods. Asystematicreviewofthepublisheddata was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary. Results. The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was

A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

“…The safety profile of CC-223 appears to be comparable with the previously characterized class of approved mTOR inhibitors [3, 17–19], notwithstanding the increased incidence and severity of certain TRAEs. However, toxicity generally emerged early into treatment and was well-managed either by aggressive dose adjustments or standard treatment interventions.…”

Lanreotide Induces Cytokine Modulation in Intestinal Neuroendocrine Tumors and Overcomes Resistance to Everolimus

“…Currently, based on the results of several clinical trials, everolimus (a pharmacologically active inhibitors of mTOR) is approved for the treatment of advanced pancreatic, gastrointestinal and lung NETs (22,23). Moreover, everolimus should be considered a valid therapeutic option for extrapancreatic NETs (24). However, one-third of NET patients show primary insensitivity (primary resistance) to treatment with everolimus, while in others the disease is initially stabilized and then develops resistance (acquired resistance) and disease progression; this could depend on the genetic instability and the heterogeneity of tumor cells (25).…”

Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies

“…An increased tumor grade [ 42 , 172 , 179 , 223 ], presence of a poorly-differentiated tumor [ 175 ] and an increasing Ki-67 index [ 173 ] are reported to correlate with worse outcomes with SSA treatment ( Table 2 , Right Panel). Some studies reported that a Ki-67 threshold of 5% was more predictive of PFS with SSA treatment than the cut-off value proposed by 2010 WHO classification to separate G1 and G2 (i.e., <3%) [ 172 , 224 ]. SSA therapy is less effective in patients with bone and peritoneal metastases [ 173 ], as well as with any liver metastases [ 42 ] or a high hepatic tumor load [ 173 , 174 , 177 , 179 , 225 ], suggesting its limited role in advanced panNEN patients with aggressive tumors.…”