Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate-grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical trial

Abstract

IntroductionFinding the optimal management strategy for patients with advanced, metastatic neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas is a work in progress. Sunitinib and everolimus are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic low-grade or intermediate-grade pancreatic NETs. However, mutation-targeted therapy with sunitinib or everolimus has not been studied in this patient population.Methods and analysisThis prospective, open-label phase II clinical trial was designed to determine if mutation-targeting therapy with sunitinib or everolimus for patients with advanced low-grade or intermediate-grade NETs is more effective than historically expected results with progression-free survival (PFS) as the primary end point. Patients ≥18 years of age with progressive, low-grade or intermediate-grade locally advanced or metastatic NETs are eligible for this study. Patients will undergo tumour biopsy (if they are not a surgical candidate) for tumour genotyping. Patients will be assigned to sunitininb or everolimus based on somatic/germline mutations profile. Patients who have disease progression on either sunitinib or everolimus will crossover to the other drug. Treatment will continue until disease progression, unacceptable toxicity, or consent to withdrawal. Using the proposed criteria, 44 patients will be accrued within each treatment group during a 48-month period (a total of 88 patients for the 2 treatments), and followed for up to an additional 12 months (a total of 60 months from entry of the first patient) to achieve 80% power in order to test whether there is an improvement in PFS compared to historically expected results, with a 0.10 α level one-sided significance test.Ethics and disseminationThe study protocol was approved by the institutional review board of the National Cancer Institute (NCI-IRB Number 15C0040; iRIS Reference Number 339636). The results will be published in a peer-reviewed journal and shared with the worldwide medical community.Trial registration numberNCT02315625.

Sequential Everolimus and Sunitinib Treatment in Pancreatic Metastatic Well-Differentiated Neuroendocrine Tumours Resistant to Prior Treatments

“…Although robust conclusions regarding the ideal sequence of treatment cannot be derived from this study, it is probable that previous treatments could affect first-line treatment and the efficacy of the sequential treatment. It is expected that the on-going characterization of the molecular profiling of pNETs will make possible the selection of the sequence of the most appropriate agent [16] . pNETs are in their great majority slowly growing tumours and generally more indolent than adenocarcinomas; however, once these tumours progress beyond surgical resectability, they are essentially incurable [17] .…”

“…This is particularly important given that the survival of patients with advanced NETs appears to be different based on the driver mutation(s) present in the tumour. An ongoing study includes the analysis of the involved cell signalling pathways for the treatment of patients with advanced metastatic gastrointestinal NETs and pNETs with currently approved MTT agents according to the mutations present (sunitinib for MEN1 / PDGFR / KIT / FLT3 mutations or everolimus for NF1 / PTEN / PI3K / AKT / mTOR / VHL / TP53 mutations) [16] .…”

“…The majority of pNETs is non-functional, and they are frequently diagnosed at a late stage in the presence of metastatic disease [1][2][3] . One of the largest series of patients with pNETs showed that those presenting with unresectable or metastatic disease exhibit a worse prognosis with a median overall survival (OS) of 17 months (95% confidence interval [CI], [14][15][16][17][18][19] compared to those with localized disease that exert a median OS of 100 months (95% CI, 68-148) [2] . However, during the last years the median survival of patients with metastatic pNETs has improved substantially, reaching 41.7 months following the introduction of newer chemotherapeutic agents [4] .…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…In an ongoing phase 2 trial in GEP-NET, patients will be assigned to a targeted therapy based on a mutation profile determined in tumor tissue either retrieved at surgery or from a biopsy. Patients will be treated with sunitinib (for mutations in MEN1/PDGFR/cKIT/FLT3) or everolimus (for mutations in NF1/PTEN/PI3K/AKT/mTOR/VHL/TP53) (Neychev et al 2015). This mutation-targeted therapy will elucidate if a more specific therapy stratification based on biomarkers will be associated with a more durable response.…”

Summary of emerging personalized medicine in neuroendocrine tumors: are we on track?

“…Those with multiple of the above mutations or those with no mutations will be assigned to receive sunitinib. Patients will crossover to the other drug upon first progression (69).…”