Thyroid Gland Medullary Carcinoma

P2, N=109, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Sep 2024

Further research is needed to validate the significance of these serum biomarkers in MTC and determine the effects of confounding factors on their levels. Clinicians should consider using these markers in MTC diagnosis, prognosis, and follow-up, particularly for patients with advanced disease.

P2, N=63, Active, not recruiting, National Cancer Institute (NCI)

Premedication with Entresto® results in a relevant stabilization of [177Lu]Lu-PP-FF11N and consecutively increases radiation doses in tumors and organs. Trial registration clinicaltrails.gov, NCT03647657. Registered 20 August 2018.

P1/2, N=589, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

The identification of RET SSVs in all MTCs, but rarely in other cancer types, demonstrates that these RET SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these RET SSVs play a pathogenic role in MTC.

P1, N=110, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Jun 2025 | Trial primary completion date: Apr 2026 --> Jun 2025

In this study, a structure-based dynamic pharmacophore-driven approach using E-pharmacophore modeling from molecular dynamics trajectories is proposed to select low energy favorable hypotheses, and ML-trained QSAR models to predict pIC50 values of compounds. For this aim, extensive small molecule libraries were screened using developed ligand-based models and potent compounds which are capable of inhibiting RET activation were proposed.

Sorafenib, lenvatinib, and cabozantinib are multikinase inhibitors approved for patients with metastatic RAI-refractory DTC, whereas vandetanib and cabozantinib are approved for patients with MTC. Management of thyroid carcinomas has evolved such that targeted therapies have become therapeutic options for patients with BRAF, RET, NTRK, ALK, and ROS1 alterations and even have reported efficacy in anaplastic thyroid carcinomas. In this article, we review the advances made over the years in the treatment of metastatic thyroid carcinoma and focus on the systemic therapies that have recently transformed the treatment landscape of advanced disease.

No abstract available

P3, N=427, Active, not recruiting, National Cancer Institute (NCI)

sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy.

P=N/A, N=500, Not yet recruiting, Aristotle University Of Thessaloniki

P=N/A, N=23, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Nov 2023 --> Mar 2024 | Trial primary completion date: Nov 2023 --> Mar 2024

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

Abnormal blood flow signal is of great significance in the diagnosis of LNM-MTC. Within the absence of ultrasonic characteristics, preoperative serum CT test can provide confidence for the diagnosis of MTC.

P2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Sep 2024 | Trial primary completion date: Jan 2024 --> Sep 2024

P=N/A, N=40, Not yet recruiting, Gloucestershire Hospitals NHS Foundation Trust | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=137, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jan 2024 --> Dec 2024

P2, N=334, Completed, UNICANCER | Active, not recruiting --> Completed

P=N/A, N=50, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Metastatic lymph nodes, liver, and bone metastases with varying degrees of uptake were detected on 18F-fluorodeoxyglucose (FDG) and 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT). 68Ga prostate-specific membrane antigen (PSMA) PET/CT was performed to explore whether the patient might have a chance for PSMA-targeted radionuclide therapy, and increased PSMA expression was noted in most of the metastatic lesions, even some of which have higher PSMA uptake than 18F-FDG and 68Ga-DOTATATE.

P=N/A, N=2030, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2023 --> Sep 2026 | Trial primary completion date: Sep 2023 --> Sep 2026

PDL1 CPS score did not correlate with medullary thyroid carcinoma IMTCGS grade. However, a subset of both low-grade and high-grade MTCs demonstrated PDL1 CPS scores ≥1 as estimated by two independent pathologists and could warrant further exploration in future studies as a potential therapeutic avenue for patients unresponsive to conventional TKI treatments.

P=N/A, N=20, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024

P1, N=18, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

As first in-label selective RET-Inhibitor, Selpercatinib showed promising efficacy in advanced MTC (first line) with RET mutations and rrDTC (second line) with RET fusions along with fewer side effects. Changes and new approaches for the treatment of ATC have been summarised in the current ATA guidelines.

The highest rate of bone metastases was found in patients with poorly differentiated, oncocytic, medullary, follicular, and papillary cancer, respectively. The results obtained in this study reveal the necessity and importance of bone metastasis evaluation in patients with thyroid cancer.

More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. This year we celebrate the 30th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.

Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.

However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.

A completion thyroidectomy was performed to remove the remaining thyroid tissue. Postoperatively, the patient is undergoing systemic surveillance.

For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma...Radioactive iodine treatment after surgery improves overall survival in patients at high risk of recurrence. Antiangiogenic multikinase inhibitors and targeted therapies to genetic mutations that give rise to thyroid cancer are increasingly used in the treatment of metastatic disease.

P2, N=21, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

P=N/A, N=21, Recruiting, Shanghai Jiao Tong University School of Medicine | Not yet recruiting --> Recruiting

The combination of PR and GAD2 increased both sensitivity and specificity. GAD2 immunohistochemistry is a highly useful diagnostic tool for the identification of pancreatic origin in case of neuroendocrine neoplasms with unknown site of origin.

In this population, 42% have received standard lenvatinib and 13% have received genotype-matched targeted therapy... In our real-world study, NGS testing revealed high rates of Tier I-II actionable genomic alterations in PTC (77%), MTC (81%), and ATC (31%). NGS-identified BRAF V600E mutations in ATC has a high rate of triggering matched targeted therapy. NGS identification of RET-mutated MTC facilitated use of RET inhibitors.

Nine patients received peptide receptor radiotherapy (PRRT) with Lu-177 with neoadjuvant capecitabine...Radiotherapy, TKI, and PRRT were given as a part of second-line or third-line therapy due to persistent disease and/or disease recurrence. The median PFS was better in female patients and in patients who had no residual lesions and stable disease after the primary modality of therapy.

No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates particular in patients with high PD-L1 expression. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as PD-1/PD-L1 and TMB, as predictors for response to immunotherapy. Furthermore, randomized prospective studies could provide more robust data on the efficacy and side effects of ICIs.

P1/2, N=875, Recruiting, Loxo Oncology, Inc. | Trial completion date: Sep 2024 --> Feb 2026 | Trial primary completion date: Mar 2024 --> Feb 2025

P1/2, N=50, Recruiting, Loxo Oncology, Inc. | Trial completion date: Jan 2025 --> May 2029 | Trial primary completion date: Aug 2024 --> Dec 2024