Dataset Information

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer.

ABSTRACT:

Purpose

Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC).

Methods

A total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy.

Results

8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0-57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1-3.

Conclusion

The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.

SUBMITTER: Koehler VF

PROVIDER: S-EPMC10590332 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer.

Koehler Viktoria Florentine VF Achterfeld Josefine J Sandner Natalie N Koch Christine C Wiegmann Jonas Paul JP Ivanyi Philipp P Käsmann Lukas L Pusch Renate R Wolf Dominik D Chirica Mihaela M Knösel Thomas T Demes Melanie-Christin MC Kumbrink Joerg J Vogl Thomas J TJ Meyer Gesine G Spitzweg Christine C Bojunga Joerg J Kroiss Matthias M

Journal of cancer research and clinical oncology 20230807 15

<h4>Purpose</h4>Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for ...[more]

PMID: 37548775

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Project description:BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Project description:Lenvatinib is a small oral molecule able to inhibit three of the extracellular and intracellular molecules involved in the modulation of angiogenesis and lymphangiogenesis: vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, and platelet-derived growth factor receptor alpha. Since it is also able to inhibit the REarranged during Transfection oncogene and the protooncogene c-KIT, this drug can also be used to control tumor cell proliferation. The maximum tolerated dose, as demonstrated in Phase I studies, is 25 mg daily. The drug is rapidly absorbed with maximum concentrations achieved within 3 and 5 hours after administration in fasting and nonfasting treated patients, respectively. The most common adverse events, reported in Phase I study and confirmed in the subsequent Phase II and III studies, are hypertension, proteinuria, and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In Phase I studies, efficacy of lenvatinib in solid tumors was demonstrated, and these encouraging results have led to the development of a Phase II study using lenvatinib in advance radioiodine-refractory differentiated thyroid cancer (DTCs) patients. Since an overall response rate of 50% was reported, this study also confirmed the efficacy of lenvatinib in DTCs patients with an acceptable toxicity profile. Recently, a Phase III study in patients with DTCs (SELECT study) demonstrated the lenvatinib efficacy in prolonging progression-free survival with respect to the placebo (18.3 vs 3.6 months; P<0.001). Although there was no statistically significant difference in the overall survival of the entire group, this result was observed when the analysis was restricted to both the follicular histotype and the group of senior patients (>65 years). The study confirmed that the most common side effects of this drug are hypertension, diarrhea, decreased appetite, weight loss, nausea, and proteinuria. In this review, we report the results of the main studies on lenvatinib efficacy in patients with advanced and progressive thyroid cancer, mainly in DTCs but also in medullary and anaplastic thyroid cancer. We also compared the efficacy of lenvatinib with that of other tyrosine kinase inhibitors, mainly sorafenib, already tested in the same type of patient population.

Dataset Information

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer.

Purpose

Methods

Results

Conclusion

Publications

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer.

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