Endocrine Abstracts

Background: Neuroendocrine tumours (NET) are rare cancers arising from cells of the neuroendocrine system and frequently present with advanced disease. They are characterised by the presence of somatostatin receptors (SSTR) on the tumour surface. The presence of SSTR are associated with the inhibition of NET proliferation and have formed the basis of peptide receptor radionuclide therapy (PRRT), such as Lutathera. PRRT relies on SSTR tumour expression and patients without this biomarker do not benefit from Lutathera. ASTX727 is an oral fixed-dose combination of cedazuridine plus decitabine. Cedazuridine is a cytidine deaminase (CDA) inhibitor and decitabine is a nucleoside hypomethylating agent (HMA) known to induce demethylation through deoxyribonucleic acid (DNA) methyltransferase inhibition. ASTX727 may induce demethylation to increase expression of SSTRs on NETs. Therefore, pre-treatment with ASTX727 may allow patients previously unsuitable for Lutathera to gain benefit from treatment.

Methods: LANTana will recruit patients with a biopsy-proven NET without tumoural uptake or uptake less than liver on [⁶⁸Ga]DOTA-TATE imaging. Twenty-seven eligible participants will be recruited and are firstly administered 1st cycle ASTX727. Subsequently, they are assessed for SSTR expression (via [⁶⁸Ga]DOTA-TATE PET & tumour biopsy) and if proven, will progress to receive a further ASTX727 cycle and Lutathera. Lutathera will then continue every 2 months for 4 cycles until disease progression, patient withdrawal or completion of one year of treatment. The primary objective of the trials is to determine whether pre-treatment with ASTX727 results in re-expression of SSTR2 using [⁶⁸Ga]DOTA-TATE to image epigenetic modification of the SSTR2 locus, allowing subsequent treatment with Lutathera. Secondary objectives include tolerability of combination therapy and assessment of response to treatment. Exploratory outcomes include SSTR2 expression and methylation of its locus in tumours in conjunction with baseline PET uptake parameters. Response will be assessed by computed tomography imaging or magnetic resonance imaging (MRI).

Discussion: The trial is designed to provide prospective evidence on the efficacy and tolerability of epigenetic modification pre-treatment with ASTX727 in patients who were previously not eligible for PPRT. Outcomes will aim to improve prognosis in an otherwise poor-prognostic cohort and inform use of this imaging methodology to assess epigenetic modification.