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      Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond

      review-article
      Author(s): 1 , 2 , 1
      Publication date (Electronic):
      Journal: Endocrine Reviews
      Publisher: Endocrine Society

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          Abstract

          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.

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          Thyroid cancer

          Maria Cabanillas, David McFadden, Cosimo Durante (2016)
          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.
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            Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.

            Samuel A Wells, Bruce Robinson, Robert Gagel … (2012)
            There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).
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              Cabozantinib in progressive medullary thyroid cancer.

              Rossella Elisei, Martin Schlumberger, Stefan Müller … (2013)
              Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Endocr Rev
                Journal ID (iso-abbrev): Endocr. Rev
                Journal ID (publisher-id): edrv
                Title: Endocrine Reviews
                Publisher: Endocrine Society (Washington, DC )
                ISSN (Print): 0163-769X
                ISSN (Electronic): 1945-7189
                Publication date Collection: December 2019
                Publication date (Electronic): 19 July 2019
                Publication date PMC-release: 19 July 2020
                Volume: 40
                Issue: 6
                Pages: 1573-1604
                Affiliations
                [1 ] Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center , Houston, Texas
                [2 ] Department of Endocrinology and Medical Oncology, Mayo Clinic , Rochester, Minnesota
                Author notes
                Correspondence and Reprint Requests: Maria E. Cabanillas, MD, Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: mcabani@ 123456mdanderson.org .
                Author information
                http://orcid.org/0000-0002-5124-1811
                Article
                Accession ID: PMC7341904 Pmcid ID: PMC7341904 Pmc-uid ID: 7341904 Publisher ID: 201900007
                DOI: 10.1210/er.2019-00007
                PMC ID: 7341904
                PubMed ID: 31322645
                SO-VID: 50003971-de8f-49b7-928c-ba067df9ec62
                Copyright © Copyright © 2019 Endocrine Society
                History
                Date received : 22 January 2019
                Date accepted : 11 July 2019
                Page count
                Pages: 32
                Funding
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Categories
                Subject: Reviews
                Subject: Thyroid

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