The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer and a number of other ...commercially available drugs that have been studied for this indication. Although most of the US Food and Drug Administration (FDA)-approved drugs are antiangiogenic multikinase inhibitors-vandetanib, cabozantinib, sorafenib, lenvatinib-there are two FDA indications that are mutation specific-dabrafenib/trametinib for BRAF-mutated anaplastic thyroid cancer and larotrectinib for NTRK-fusion thyroid cancer. Furthermore, other mutation-specific drugs, immunotherapies, and novel strategies for advanced thyroid cancer are under investigation. Understanding the molecular basis of thyroid cancer, the drugs of interest for treatment of advanced thyroid cancer, and how these drugs can be administered safely and in the appropriate clinical scenario are the topics of this review.
Thyroid cancer Cabanillas, Maria E, Dr; McFadden, David G, MD; Durante, Cosimo, MD
Lancet,
12/2016, Letnik:
388, Številka:
10061
Journal Article
Recenzirano
Odprti dostop
Summary Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. ...Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer—medullary and anaplastic—are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease.
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers Wirth, Lori J; Sherman, Eric; Robinson, Bruce ...
New England journal of medicine/The New England journal of medicine,
08/2020, Letnik:
383, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Medullary thyroid cancer often develops in patients with somatic or germline mutations in
RET
. Selpercatinib is a novel RET inhibitor. In a phase 1–2 trial, a response to selpercatinib occurred in ...38 of 55 previously treated patients (69%) and in 64 of 88 previously untreated patients (73%). Toxic effects were mainly low grade.
Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors 1–4, RET, KIT, and platelet-derived growth factor receptor-α. ...Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.
Highlights • We review advanced thyroid cancer (TC) etiology and signaling pathway mutations. • We review the mechanism of action and role of tyrosine kinase inhibitors (TKIs). • Lenvatinib, a ...multitargeted TKI, has broad antitumor and antiangiogenic activity. • We review phase III radioactive iodine-refractory differentiated TC results. • Lenvatinib shows superior progression-free survival and overall response rate.
Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the ...molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer.
Tumours can arise from thyroid follicular cells if they acquire driver mutations that constitutively activate the MAPK signalling pathway. In addition, a limited set of additional mutations in key ...genes drive tumour progression towards more aggressive and less differentiated disease. Unprecedented insights into thyroid tumour biology have come from the breadth of thyroid tumour sequencing data from patients and the wide range of mutation-specific mechanisms identified in experimental models, in combination with the genomic simplicity of thyroid cancers. This knowledge is gradually being translated into refined strategies to stratify, manage and treat patients with thyroid cancer. This Review summarizes the biological underpinnings of the genetic alterations involved in thyroid cancer initiation and progression. We also provide a rationale for and discuss specific examples of how to implement genomic information to inform both recommended and investigational approaches to improve thyroid cancer prognosis, redifferentiation strategies and targeted therapies.
A Review of Thyroid Cancer—Reply Boucai, Laura; Zafereo, Mark; Cabanillas, Maria E
JAMA : the journal of the American Medical Association,
06/2024, Letnik:
331, Številka:
21
Journal Article
Summary Background About half of patients with papillary thyroid cancer have tumours with activating BRAFV600E mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF -positive ...melanoma, showed clinical benefit in three patients with BRAFV600E -positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAFV600E -positive papillary thyroid cancer. Methods We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAFV600E mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov , number NCT01286753. Findings Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2–26·0) in cohort 1 and 12·0 months (6·7–20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2–59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven 27% in cohort 1, five 20% in cohort 2), lymphopenia (two 8% in each cohort), and increased γ-glutamyltransferase (one 4% in cohort 1, three 12% in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. Interpretation Vemurafenib showed antitumour activity in patients with progressive, BRAFV600E -positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. Funding F Hoffmann-La Roche.
Thyroid Cancer: A Review Boucai, Laura; Zafereo, Mark; Cabanillas, Maria E
JAMA : the journal of the American Medical Association,
02/2024, Letnik:
331, Številka:
5
Journal Article
Recenzirano
IMPORTANCE: Approximately 43 720 new cases of thyroid carcinoma are expected to be diagnosed in 2023 in the US. Five-year relative survival is approximately 98.5%. This review summarizes current ...evidence regarding pathophysiology, diagnosis, and management of early-stage and advanced thyroid cancer. OBSERVATIONS: Papillary thyroid cancer accounts for approximately 84% of all thyroid cancers. Papillary, follicular (≈4%), and oncocytic (≈2%) forms arise from thyroid follicular cells and are termed well-differentiated thyroid cancer. Aggressive forms of follicular cell-derived thyroid cancer are poorly differentiated thyroid cancer (≈5%) and anaplastic thyroid cancer (≈1%). Medullary thyroid cancer (≈4%) arises from parafollicular C cells. Most cases of well-differentiated thyroid cancer are asymptomatic and detected during physical examination or incidentally found on diagnostic imaging studies. For microcarcinomas (≤1 cm), observation without surgical resection can be considered. For tumors larger than 1 cm with or without lymph node metastases, surgery with or without radioactive iodine is curative in most cases. Surgical resection is the preferred approach for patients with recurrent locoregional disease. 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. CONCLUSIONS: Approximately 44 000 new cases of thyroid cancer are diagnosed each year in the US, with a 5-year relative survival of 98.5%. Surgery is curative in most cases of well-differentiated thyroid cancer. 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.
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