Redifferentiating Effect of Larotrectinib in <i>NTRK</i>-Rearranged Advanced Radioactive-Iodine Refractory Thyroid Cancer

Groussin, Lionel; Theodon, Helene; Bessiène, Laura; Bricaire, Léopoldine; Bonnet-Serrano, Fidéline; Cochand‐Priollet, Béatrix; Leroy, Karen; Garinet, Simon; Pasmant, Éric; Zerbit, Jérémie; Seban, Romain-David; Goldwasser, François; Clerc, Jérôme; Huillard, Olivier

doi:10.1089/thy.2021.0524

Cited by 26 publications

(13 citation statements)

References 19 publications

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“…Other studies have been carried out by using different drugs including BRAF V600E , TRK, and RET inhibitors in selected patients according to their genomic tests ( 58 , 99 – 101 ).…”

Section: Rai-r Development and Redifferentiation Strategiesmentioning

confidence: 99%

Molecular features of aggressive thyroid cancer

et al. 2022

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Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking 131I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAFV600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies.

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“…Other studies have been carried out by using different drugs including BRAF V600E , TRK, and RET inhibitors in selected patients according to their genomic tests ( 58 , 99 – 101 ).…”

Section: Rai-r Development and Redifferentiation Strategiesmentioning

confidence: 99%

Molecular features of aggressive thyroid cancer

et al. 2022

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“…This trial is aiming at treating patients with short-term lenvatinib treatment with potential subsequent I-131 therapy after identification of a redifferentiation effect. Toxicities of this treatment combination of therapy are not thoroughly investigated, although no cumulative toxicity has been described in comparable trials sequentially combining both selective and multitarget TKIs and I-131 therapy [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. We expect that this treatment combination potentially will avoid severe toxicities that are observed in long-term lenvatinib treatment.…”

Section: Discussionmentioning

confidence: 99%

“…These studies showed that after short-term therapy of approximately 4 weeks with these TKIs, renewed or enhanced RAI uptake was observed in 35–67% of RAI-refractory patients. Subsequently, I-131 therapy was initiated in 35–71% of all patients [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial

et al. 2022

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Background: Management of patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a challenge as I-131 therapy is deemed ineffective while standard-of-care systemic therapy with tyrosine kinase inhibitor (TKI) lenvatinib is associated with frequent toxicities leading to dose reductions and withdrawal. A potential new treatment approach is to use TKIs as redifferentiation agent to restore RAI uptake to an extent that I-131 therapy is warranted. Prior studies show that short-term treatment with other TKIs restores RAI uptake in 50–60% of radioiodine-refractory DTC patients, but this concept has not been investigated for lenvatinib. Furthermore, the optimal duration of treatment with TKIs for maximal redifferentiation has not been explored. Methods and Design: A total of 12 patients with RAI-refractory DTC with an indication for lenvatinib will undergo I-124 PET/CT to quantify RAI uptake. This process is repeated after 6 and 12 weeks post-initiating lenvatinib after which the prospective dose estimate to target lesions and organs at risk will be determined. Patients will subsequently stop lenvatinib and undergo I-131 treatment if it is deemed effective and safe by predefined norms. The I-124 PET/CT measurements after 6 and 12 weeks of the first six patients are compared and the optimal timepoint will be determined for the remaining patients. In all I-131 treated patients post-therapy SPECT/CT dosimetry verification will be performed. During follow-up, clinical response will be evaluated using serum thyroglobulin levels and F-18 FDG PET/CT imaging for 6 months. It is hypothesized that at least 40% of patients will show meaningful renewed RAI uptake after short-term lenvatinib treatment. Discussion: Shorter treatment duration of lenvatinib treatment is preferred because of frequent toxicity-related dose reductions and drug withdrawals in long-term lenvatinib treatment. Short-term treatment with lenvatinib with subsequent I-131 therapy poses a potential new management approach for these patients. Since treatment duration is reduced and I-131 therapy is more tolerable for most patients, this potentially leads to less toxicity and higher quality of life. Identifying RAI-refractory DTC patients who redifferentiate after lenvatinib therapy is therefore crucial. Trial Registration: ClinicalTrials.gov, NTC04858867.

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“…However, a recently completed phase III clinical trial showed that the addition of selumetinib to adjuvant RAI did not significantly improve the complete remission rate in DTC patients with metastatic disease (Ho et al 2022). Finally, redifferentiation of NTRK-rearranged, RAIresistant thyroid tumors was possible with larotrectinib (Groussin et al 2022), and selpercatinib restored iodine uptake in almost all metastases in a patient with a RET rearrangement/fusion as a sole mutation (Groussin et al 2021). While these results are encouraging, they were obtained from case studies.…”

Section: :11mentioning

confidence: 97%

Molecular mechanisms of resistance to kinase inhibitors in thyroid cancers

Hofmann

Kunnimalaiyaan

Wang

et al. 2022

Endocrine-Related Cancer

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Protein kinases play critical roles in cell survival, proliferation and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome drug resistance. Understanding how cancer cells respond to drugs and identifying novel molecular targets for therapy still represents a major challenge for the treatment of these patients.

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Redifferentiating Effect of Larotrectinib in NTRK-Rearranged Advanced Radioactive-Iodine Refractory Thyroid Cancer

Cited by 26 publications

References 19 publications

Molecular features of aggressive thyroid cancer

Molecular features of aggressive thyroid cancer

Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial

Molecular mechanisms of resistance to kinase inhibitors in thyroid cancers

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