Leyden, Simone

TPS660 Background: Deeper comprehension of gastroenteropancreatic neuroendocrine tumor (GEP-NET) characteristics has led to development of therapeutic interventions such as targeted radionuclide therapies (TRT). In the prospective, randomized, controlled, open-label, multi-center, Phase III COMPOSE trial, the radiolabeled somatostatin analogue 177Lu-edotreotide will be compared to approved standard of care with everolimus, CAPTEM or FOLFOX in patients with well-differentiated aggressive grade 2 and 3 (Ki-67 index 15−55%), somatostatin receptor positive GEP-NETS. While TRT is advantageous, a key unmet need is to identify additional markers intended to guide patient selection for TRT. This is highly relevant as TRT is a therapy of growing interest likely to be broadly available for patients with variable phenotypes. Profiling analysis as part of COMPOSE plans to analyze the genetic signature of GEP-NETS through full exome sequencing and gene expression analysis of tumor histology and longitudinal blood samples. This analysis may guide detection of pathogenic mutations in NET patients, to potentially inform treatment and surveillance strategies. Methods: Whole exome analysis of tumor-suppressor- and proto-oncogenes included in several pan-cancer panels, upstream and downstream regulators, and novel candidate genes, will be studied. Following patient consent, historical tumor biopsy and blood samples will undergo genetic analysis. Genetic profiling analysis inclusion will not impact trial involvement or disease management. 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. Samples will be analyzed in a central pathology laboratory. The aim of this analysis is to develop software that would integrate genetic data with structural and functional imaging, histopathology and phenotype information for implementation into clinical practice. Clinical trial information: NCT04919226 .

TPS514 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which represent approximately 70% of NETs, frequently develop metastatic disease with limited treatment options. Current standard therapies for well-differentiated high grade 2 and grade 3 GEP-NETs include cytoreductive procedures, somatostatin analogues, molecular targeted therapies (everolimus or sunitinib), chemotherapy and peptide receptor radionuclide therapy (PRRT), with no specified sequence of use. PRRT may stabilize disease and induce objective tumor responses. This treatment uses radiolabeled somatostatin analogues to selectively target somatostatin receptor expressing (SSTR+) tumor cells. 177 Lu-edotreotide is an innovative radiolabeled somatostatin analogue with a favorable safety profile and promising efficacy. Retrospective data in metastatic GEP-NETs treated with two or more 177 Lu-edotreotide cycles demonstrated a progression free survival (PFS) of at least 30 months. The currently recruiting Phase III COMPETE trial compares the efficacy and safety of 177 Lu-edotreotide, versus everolimus, in grade 1 and grade 2 GEP-NETs. Methods: COMPOSE (NCT04919226) is a prospective, randomized, controlled, open-label, multi-center Phase III study, in patients with well-differentiated high grade 2 and grade 3 (Ki-67 index 15−55%), SSTR+, GEP-NETs. This trial is to evaluate the efficacy, safety and patient-reported outcomes of first- or second-line treatment with 177 Lu-edotreotide PRRT compared to best standard of care. It aims to randomize 202 patients 1:1 to a defined number of cycles of 177 Lu-edotreotide or an active comparator (either chemotherapy [CAPTEM or FOLFOX] or everolimus, according to investigator´s choice). The primary endpoint is PFS, assessed every 12 weeks until disease progression (RECIST v1.1), or death, whichever occurs earlier. Secondary outcomes include overall survival, assessed up to 2 years after disease progression. Study recruitment for COMPOSE commenced in September 2021. It is expected that COMPOSE will inform optimal treatment options for patients with well-differentiated high grade 2 and grade 3 SSTR+ GEP-NETs, including for first-line therapy. Clinical trial information: NCT04919226.