Endocrine Abstracts

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent an estimated 70% of NETs. GEP-NETs frequently develop metastatic disease with limited treatment options. For well-differentiated high grade 2 and 3 GEP-NETs, current therapies include peptide receptor radionuclide therapy (PRRT), somatostatin analogues, chemotherapy, cytoreduction, and molecular targeted therapies (everolimus, sunitinib). PRRT uses radiolabeled somatostatin analogues to selectively target somatostatin receptor expressing (SSTR+) tumor cells. The radiolabeled somatostatin analogue lutetium (¹⁷⁷Lu) edotreotide has shown promising efficacy and a favorable safety profile. Retrospective data in patients with metastatic GEP-NETs treated with two or more lutetium (¹⁷⁷Lu) edotreotide cycles demonstrated nearly 30 months progression-free survival (PFS). COMPOSE (NCT04919226), a prospective, randomized, controlled, open-label, multi-center Phase III study, aims to extend therapeutic options for patients with well-differentiated aggressive grade 2 and grade 3, SSTR+, GEP-NETs. Furthermore, functional imaging and genetic profiling analysis as part of COMPOSE plans to guide detection of specific traits in NET patients, to potentially improve treatment and surveillance strategies.

Trial design: COMPOSE evaluates efficacy, safety, and patient-reported outcomes of first- or second-line treatment with lutetium (¹⁷⁷Lu) edotreotide PRRT. At least 202 patients with SSTR+ disease will be randomized 1:1 to up to six cycles of lutetium (¹⁷⁷Lu) edotreotide, given at 6- to 8-week intervals, or to an active comparator (CAPTEM, FOLFOX or everolimus, according to investigator’s choice). PFS, the primary endpoint, will be assessed every 12 weeks until disease progression (RECIST v1.1) or death, whichever occurs earlier. Overall survival, assessed up to 2 years after disease progression, is a secondary outcome. In addition, baseline fluorodeoxyglucose and SSTR positron emission tomography imaging, full exome sequencing and gene expression analysis of tumor histology and longitudinal blood samples will be studied. DNA will be assessed to determine the impact of different types of mutations; mRNA will be assessed to confirm and quantify these assumptions and compare gene expression at different treatment phases. COMPOSE recruitment commenced in September 2021 and comprises of 40 study sites in the United States, Europe, India and Australia.

Conclusion: COMPOSE results are expected to inform about optimal treatment options for patients with well-differentiated aggressive grade 2 and grade 3 SSTR+ GEP-NETs. Moreover, the genetic profiling analysis may assist in developing predictive models that would integrate genetic data with functional and structural imaging, histopathology and phenotype information for implementation into clinical practice.