Recent advances in tyrosine kinase inhibitors VEGFR 1-3 for the treatment of advanced metastatic melanoma

ABSTRACT

Introduction

Increasing evidence from preclinical and clinical studies suggests the role of vascular endothelial growth factor (VEGF) signaling in melanoma progression, response to therapy, and overall survival. Moreover, the discovery of the potential involvement of the VEGF pathway in resistance to immunotherapy has led to new clinical trials with VEGFR inhibitors.

Areas covered

We have reviewed recent literature, mainly published within the last 5 years, on VEGFR-targeted treatments for advanced melanoma, including mucosal, acral, and uveal melanoma. The VEGFR inhibitors were used as a single therapy or combined with either immunotherapy or chemotherapy, and they were employed in treatment for KIT-mutated cutaneous melanoma and for patients with brain metastases.

Expert opinion

Trials involving monotherapy have been unsuccessful in demonstrating meaningful efficacy. Despite some activity, the combination of VEGFR-targeting tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICI) in patients with ICI-resistant melanoma, the combination did not significantly improve outcomes compared to anti-PD-1 monotherapy in the first-line settings. On the contrary, some patients with mucosal, acral or KIT-mutant melanoma may benefit from TKI-based therapies. Further studies focused on biomarker discovery and randomized trials are necessary to better understand the role of VEGFR1–3 as a therapeutic target in melanoma.

KEYWORDS:

• VEGFR
• melanoma
• TKI
• lenvatinib
• axitinib
• apatinib
• cabozantinib

Article highlights

• The combination of VEGFR-targeting tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICI) has some activity in patients with ICI-resistant melanoma.

• The combination did not significantly improve outcomes compared to anti-PD-1 monotherapy in the first-line settings.

• Some patients with rare melanoma subtypes (mucosal, acral or KIT-mutant melanoma) may benefit from TKI-based therapies.

Declaration of interest

Piotr Rutkowski has received honoraria for lectures and Advisroty Boards outside of the scope of this paper from MSD, BMS, Novartis, Pierre Fabre, Merck, Sanofi, Pfizer, Genesis and Medison. 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.