Impact of multikinase inhibitors in reshaping the treatment of advanced gastroenteropancreatic neuroendocrine tumors

Abstract

Neuroendocrine tumors (NETs) pose a considerable challenge due to their increasing incidence and frequently late-stage diagnosis. The arrival of multikinase inhibitors (MKIs) into clinical practice has brought notable progress in the management of advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This review aims at exploring the impact of MKIs in reshaping the treatment landscape for advanced GEP-NETs. Current approaches in managing advanced GEP-NETs are discussed, including somatostatin analogs, surgery, peptide receptor radionuclide therapy, and approved systemic treatments such as everolimus or sunitinib. The limitations and challenges faced in treating these tumors remain significant. Here, we review the clinical evidence supporting the use of everolimus as a targeted therapy, which has demonstrated improved progression-free survival (PFS), and the need for alternative therapies. Discussions focus on the clinical effectiveness and the emerging role of both established and novel MKIs in the treatment of GEP-NETs, including recent evidence from the CABINET trial and other emerging agents such as surufatinib, axitinib, pazopanib, and lenvatinib. We explore the clinical evidence that showcases sunitinib's and other MKIs' effectiveness in prolonging PFS compared to placebo in advanced GEP-NETs. Recently, MKIs have shown to have a significant impact for the treatment of advanced GEP-NETs. There remain several unmet needs that must be addressed, particularly regarding optimal treatment sequencing and the development of predictive biomarkers. Ongoing research and the use of current and emerging MKIs hold great potential to advance the treatment landscape for advanced GEP-NETs significantly.

Keywords: everolimus; neuroendocrine tumor (NET); peptide receptor radionuclide therapy (PRRT); predictive biomarker; sunitinib; survival; targeted therapy; treatment sequence.

Figure 1

Potential molecular targets in NET and SSA crosstalk of sunitinib and everolimus. Adapted from Carmona-Bayonas et al. (2017). VEGFR, vascular endothelial growth factor; PDGFR, platelet-derived growth factor receptor; SSTR, somatostatin receptor; SSA, somatostatin analogs; MAPK, mitogen-activated protein kinase; Akt, protein kinase B (PKB), also known as Akt; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homolog; JAK-2, Janus kinase 2.