Everolimus for Advanced Pancreatic Neuroendocrine Tumors

Abstract

Background Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. Methods We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. Results The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). Conclusions Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.

A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors

“…This novel finding may have an immediate clinical application for distinguishing metastatic pancreatic endocrine tumors from other well-differentiated neuroendocrine carcinomas given that there are therapies (tyrosine kinase and mTOR inhibitors) specifically approved for pancreatic tumors. [8][9][10] In addition, a subset of 15 genes within the 92-gene assay panel showed promising discriminatory ability to subclassify the tumor site of origin of neuroendocrine tumors. Further investigation of these genes may have diagnostic and theranostic value.…”

“…The site of origin for neuroendocrine carcinoma has become increasingly important for grading/staging purposes, 1,2 for new clinical management guidelines, [3][4][5][6][7] and for primary site-specific targeted therapy. [8][9][10] When a primary site cannot be identified, tumors generally are treated according to the presumed aggressiveness of the tumor, as determined by a combination of the tumor grade [11][12][13][14] and available clinical and radiographic information about tumor metabolism. 14 Because neuroendocrine carcinoma subtyping for site of origin is critical for clinical management, research has been dedicated to finding site and subtype-specific diagnostic markers.…”

Peptide receptor radionuclide therapy for neuroendocrine tumours: standardized and randomized, or personalized?

“…It sits amongst a growing number of therapeutic options, including pharmacological, hormonal [2] and liver-directed therapies, and surgical approaches. Pharmacological options include the mTOR inhibitor everolimus [3], the tyrosine kinase inhibitor sunitinib [4], and a variety of combination chemotherapy regimens, with promising results obtained with the combination of capecitabine and temozolomide in pancreatic NET in particular [5].…”

Targeting neuroendocrine tumor: mixing standard options with novel therapies

“…While chemotherapy remains frequently used in neuroendocrine tumors [1,2], sunitinib [3] and everolimus [4] have been more recently approved expanding treatment options for patients with advanced/metastatic pancreatic neuroendocrine tumors. Mixing standard options including surgery and chemotherapy with novel therapies has become a common challenge for physicians in charge of treatment for patients with neuroendocrine tumors.…”

“…At a cellular level, neuroendocrine tumor cell survival involves multiple signaling pathways among which the PI3k/AKT/mTOR pathway was shown to play a major role described by Cingarlini et al Based on preclinical data, everolimus has been tested in clinical trials and demonstrated striking activity prolonging progression-free survival in patients with advanced pancreatic neuroendocrine tumors [4]. Although not reaching the level of evidence required for approval, everolimus also showed activity in patients with non-pancreatic neuroendocrine tumors [9].…”