Combination Systemic Therapies in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): A Comprehensive Review of Clinical Trials and Prospective Studies

SIMPLE SUMMARY: This comprehensive review explores evolving systemic combination regimens for advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with evidence provided by clinical trials and prospective studies. Phase 1 and 2 trials predominated, with few phase 3 trials impacting clinical practice. Results showed variability in anti-tumor activity of combination regimens, with some showing promising outcomes. Among others, treatments with a peptide receptor radionuclide therapy backbone displayed favorable results and warrant further investigation. In contrast, immune-checkpoint inhibitor-based combinations had limited applicability in this patient population. More extensive trials are needed to determine optimal treatment strategies. ABSTRACT: There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs.