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ABSTRACT
Introduction
The most frequent radioactive (RAI) refractory thyroid cancers are papillary thyroid carcinoma, followed by poorly differentiated thyroid carcinoma. They are rare and lethal. In recent years, significant therapeutic progress has been achieved.
Areas covered
This paper offers insights on refractoriness to RAI treatment and the optimization of treatment initiation and treatment choice. Clinical trials performed with anti-angiogenic kinase inhibitors and with targeted inhibitors in patients with BRAF, RAS mutation or RET, TRK or ALK fusion are discussed.
Expert opinion
These treatments provide high response rates. Anti-angiogenic kinase inhibitors improve median progression-free-survival; however, their benefit in terms of overall survival has been shown in only few subsets of patients. Treatment sequencing is challenging; in the absence of targetable abnormality, lenvatinib should be used as first-line treatment. Options for second-line treatment include lenvatinib (if not given at first line), cabozantinib or the addition of an anti-checkpoint antibody. In patients with a targetable abnormality, specific inhibitors, might be used as first-line treatment and lenvatinib as second line or vice-versa. Further studies are needed, based on documented genomic and immunologic characteristics of the tumor to assess the potential role of combination and redifferentiation therapy.
Article highlights
Several treatment modalities are currently available for the rare patients with refractory thyroid cancer with extended disease and demonstrated tumor progression.
Genomic and immunologic studies of tumor characteristics are needed to guide treatment decisions.
The key prospective randomized trials of anti-angiogenic kinase inhibitors are the placebo randomized trials with sorafenib, lenvatinib, and cabozantinib.
In the presence of targetable somatic abnormality, phase I-II trials have shown the efficacy of selpercatinib and pralsetinib in case of RET rearrangement, and of larotrectinib and entrectinib in case of NTRK rearrangement.
In the presence of BRAF mutation, besides anti-BRAF treatment, redifferentiation with a short course of anti-BRAF and anti-MEK, followed by the administration of a radioactive iodine treatment produced promising results.
Immunotherapy as a single agent may not be sufficient but added to an anti VEGR treatment is under study
Most patients will progress, and the choice of second line treatment depends on the first line that was given, and the presence of targeted abnormalities.
Declaration of interest
E. Baudin sits on the advisory boards for Ipsen, Novartis, and Pfizer and has received research grants from Novartis, Pfizer and HRA.
S Leboulleux sits on the advisory boards for Ipsen, EISAI, Bayer and Lilly.
L Lamartina sits on the advisory boards for EISAI and Bayer.
J Hadoux sits on the advisory boards for Ipsen, EISAI, AAA and Lilly.
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