Advances in pharmacotherapy for advanced thyroid cancer of follicular origin (PTC, FTC). New approved drugs and future therapies

ABSTRACT

Introduction

The most common altered signaling found in aggressive iodine-refractory thyroid cancers derived from follicular cells (RAI-TC) are RTK, MAPK, PI3K, WNT, BRAF, RAS, RET, and TP53. Tyrosine Kinase Inhibitors (TKI) are multi-kinase inhibitors able to act against different pathways, that elicit an anti-neoplastic activity.

Areas covered

The aim of this paper is to review recent novel molecular therapies of RAI-TC. Recently, sorafenib and lenvatinib, have been approved for the treatment of aggressive RAI-TC. Other studies are evaluating vandetanib and selumetinib in RAI-TC. Furthermore, preliminary studies have evaluated dabrafenib, and vemurafenib in BRAF mutated RAI-TC patients to re-induce 131-iodine uptake. The interplay between cells of the immune system and cancer cells can be altered by immune checkpoints inhibitors. The expression of PDL1 in RAI-TC was related to tumor recurrence and poor survival. Several clinical trials are investigating a combination of different therapies, such as lenvatinib and pembrolizumab.

Expert opinion

Mechanisms of resistance to TKIs inhibitors can be of intrinsic or acquired origin. An acquired resistance to lenvatinib, or sorafenib can be due to upregulation of FGFR; therefore, anti-FGFR agents are evaluated. A new strategy is to combine TKIs with immunotherapy. Several studies are evaluating lenvatinib and pembrolizumab in RAI-TC patients.

KEYWORDS:

• Thyroid cancer
• tyrosine kinase inhibitors
• lenvatinib
• sorafenib
• immune therapy

Article highlights

• The most common-altered signaling via found in more aggressive types of RAI-TC are RTK, MAPK, PI3K, WNT, BRAF, RAS, RET, TP53.

• Tyrosine Kinase Inhibitors are multikinase inhibitors able to act against different pathways, that are involved in the growth and dissemination of the tumor (angiogenesis, invasiveness, local and distant spread).

• Recently sorafenib and lenvatinib (that improve PFS) have been approved for the treatment of aggressive RAI-TC.

• Preliminary studies have evaluated dabrafenib, and vemurafenib (selective BRAF inhibitors) in BRAF mutated TC patients to re-induce 131-iodine uptake.

• The interplay between cells of the immune system and cancer cells can be altered by immune checkpoints inhibitors (PD1, PDL-1, CTLA-4). The expression of PDL1 in TC was related to tumor recurrence and poor survival. Recent studies revealed a relatively poor response to immunotherapy with checkpoint inhibitors in DTC.

• A new strategy is to combine TKIs with immunotherapy. Several studies are evaluating lenvatinib and pembrolizumab in RAI-TC patients.

Declaration of Interest

The authors have no 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 manuscript has not been funded.