Pharmacodynamics, clinical findings and approval status of current and emerging tyrosine-kinase inhibitors for pancreatic neuroendocrine tumors

ABSTRACT

Introduction: Pancreatic neuroendocrine tumors (panNETs) represent a rare group of malignancies. For decades, chemotherapy, somatostatin analogs and interferon represented the only systemic therapies; however, over the latest years, new options were registered, including Everolimus, Sunitinib (SUN), and Peptide Receptor Radionuclide Therapy.

Areas covered: This review discusses the role of tyrosine kinase inhibitors (TKIs) in advanced panNETs.

Expert opinion: TKIs showed an antiangiogenic and antiproliferative impact on advanced panNETs. Sunitinib is the only TKI currently available in clinical practice, having been approved on the basis of relevant results of a specific panNET phase III trial. New TKIs, such as Cabozantinib, Lenvatinib, Pazopanib, Surufatinib are still on investigation in panNETs. Although some phase II studies with the new TKIs yielded better PFS and RR compared with SUN, different study designs and tumor populations may have induced selection biases. However, it was reported that panNETs resistant to SUN could respond to a new TKI, indicating a possible further therapeutic line in this context. The global investigation plan of TKIs in panNETs is not homogeneous and it is difficult to understand what kind of development this can have in the near future for clinical practice.

KEYWORDS:

• Neuroendocrine tumors
• panNET
• sunitinib
• tyrosine kinase inhibitors

Article highlights

• Tyrosine kinase inhibitors represent a category of agents with anti-angiogenic and anti-proliferative effects

• Well-differentiated neuroendocrine tumors are more angiogenic than poorly differentiated neuroendocrine carcinomas

• Sunitinib is the only TKI currently available in clinical practice for pancreatic neuroendocrine tumors

• Date about lenvatinib, cabozantinib and pazopanib showed that panNETs can respond to new TKIs even when they progressed on sunitinib and/or everolimus.

• Only three TKIs are currently on phase III investigation in GEP NETs, such as surufatinib, cabozantinib, and axitinib, however, just surufatinib has been studied specifically in panNET.

This box summarizes key points contained in the article.

Declaration of interest

N Fazio has received advisory board and public speaking fees from Novartis, Ipsen, Pfizer, Merck Serono, Advanced Accelerator Applications and MSD.

M Del Re has received speaker’s bureau fees from Celgene, Janssen, and Sanofi, served as an advisory board participant for Astellas and Astra Zeneca, served as a consultant for Ipsen and Sanofi and has served as a speaker for Astellas, Astra Zeneca, Sanofi, Celgene, Novartis, Pfizer and Bio-Rad. F Spada has received travel grants from Novartis, Ipsen, Pfizer, and Merck Serono, project fees from Ipsen and Merck Serono and has served on an advisory board for Ipsen.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded