Treatment for Advanced Thyroid Cancer

Advanced stage IV thyroid cancer occurs in 1 of 100,000 individuals in the US population.¹ Approximately 15% of patients initially present with stage IV disease, and the incidence is higher among males than females (approximately 12% vs 5%, respectfully). Stage IV disease is more likely to occur with medullary thyroid cancer (MTC) versus papillary thyroid cancer (PTC).¹

The hierarchical treatment approach for advanced disease begins with surgery for locoregional disease in patients who may potentially be cured, followed by radioiodine treatment, external beam radiation therapy or thermal ablation, thyroid-stimulating hormone-suppressive thyroid hormone therapy, and systemic therapy with kinase inhibitors.² Among patients with only a few metastases or those with a high risk for local complications, localized thermal ablation should be used prior to systemic therapy. Systemic therapy with kinase inhibitors may be preferred versus external beam radiation because of the morbidity and poor efficacy associated with external beam radiation. Surgical therapy in incurable patients may be appropriate to prevent local complications. Stable, asymptomatic, local metastatic disease and stable, asymptomatic, noncentral nervous system distant metastatic disease may warrant a conservative approach of thyroid-stimulating hormone-suppressive thyroid hormone therapy.²

Kinase inhibitors are appropriate in the treatment of patients with radioiodine-refractory, metastatic, rapidly progressive, symptomatic, imminently threatening, and/or diffuse disease.² The tyrosine kinase inhibitors vandetanib (Caprelsa), lenvatinib (Lenvima), sorafenib (Nexavar), and cabozantinib (Cabometyx) are approved for the treatment of patients with advanced thyroid cancer that is refractory to radioiodine therapy.³ However, these drugs are relatively weak RET kinase inhibitors, and their clinical efficacy has been attributed more to their antiangiogenesis effects via vascular endothelial growth factor receptor pathway inhibition.⁴ Emerging therapies, such as the small-molecule inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto), are potent RET-specific kinase inhibitors that have demonstrated positive outcomes in clinical trials among patients with advanced cancer driven by RET alterations.

LIBRETTO-001 Clinical Trial

Selpercatinib was granted accelerated approval by the FDA for patients with advanced PTC whose disease is refractory to radioiodine therapy.⁵ It was studied in the LIBRETTO-001 clinical trial that included 38 patients with RET fusion–positive or metastatic thyroid cancer (non-MTC) and 306 patients with RET point mutation-positive advanced or metastatic MTC who received selpercatinib 20 mg to 240 mg twice daily in phase 1 and 160 mg in phase 2.⁶ The primary end point of the study was overall response rate (ORR) and median duration of response (DOR).

Among 19 patients with non-MTC who had received previous treatment with either sorafenib, lenvatinib, or both, the ORR was 79% (95% confidence interval [CI], 54-94) and the median DOR was 18.4 months (95% CI, 7.6-not estimable [NE]). Among the 8 patients who were naïve to systemic therapy, the ORR was 100% (95% CI, 63-100) and the median DOR had not been reached. In 88 patients with advanced or metastatic RET-mutant MTC who were naïve to cabozantinib or vandetanib treatment, the ORR was 73% (95% CI, 62-82) and the median DOR was 22 months (95% CI, NE-NE). Among the 55 patients who had been pretreated with cabozantinib and/or vandetanib, the ORR was 69% (95% CI, 55-81) and the median DOR had not been reached.⁶

The most common grade 1-2 toxicities included gastrointestinal adverse effects, hypertension, fatigue, edema, rash, headache, cough, and hemorrhage. Laboratory abnormalities for all grades include increases in aspartate aminotransferase (51%), alanine aminotransferase (45%), glucose (44%), creatinine (37%), alkaline phosphate (36%), total cholesterol (31%), potassium (24%), and total bilirubin (23%), and decreases in albumin (42%), calcium (41%), sodium (27%), magnesium (24%), glucose (22%), leukocytes (43%), and platelets (33%). The most common grade 3-4 adverse events were hypertension (18%), prolonged QT interval (4%), and diarrhea (3.4%).⁶

ARROW Clinical Trial

Pralsetinib is an investigational RET inhibitor that is being studied in an ongoing phase 1/2 clinical trial (NCT03037385) of patients with RET mutation–positive MTC or RET fusion–positive thyroid cancer who are receiving pralsetinib 400 mg daily.⁷ In treatment-naïve patients with RET mutation–positive MTC, the ORR is 74%; in those previously treated with cabozantinib or vandetanib, the ORR is 60%. Among 11 patients with RET fusion–positive thyroid cancer, the ORR was 91% (95% CI, 72-100).⁷ Pralsetinib was well-tolerated. The results from this study were recently reported at the American Society of Clinical Oncology 2020 annual meeting.

In summary, while there are no curative treatment options for patients with advanced disease, our developing understanding of the RET pathway and the development of therapies targeting this pathway, such as selpercatinib and pralsetinib, may improve outcomes for these patients.

References

1. Olson E, Wintheiser G, Wolfe KM, et al. Epidemiology of thyroid cancer: a review of the National Cancer Database, 2000-2013. Cureus. 2019;11:e4127.
2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26:1-133.
3. Lirov R, Worden FP, Cohen MS. The treatment of advanced thyroid cancer in the age of novel targeted therapies. Drugs. 2017;77:733-745.
4. Cabanillas ME, Ryder M, Jimenez C. Targeted therapy for advanced thyroid cancer: kinase inhibitors and beyond. Endocr Rev. 2019;40:1573-1604.
5. US Food and Drug Administration. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. May 22, 2020. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions. Accessed August 23, 2020.
6. Eli Lilly and Company. Retevmo (selpercatinib) oral therapy. www.retevmo.com/hcp. Accessed August 25, 2020.
7. Subbiah V, Hu MI, Gainor JF. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. J Clin Oncol. 2020;38(15_suppl). Abstract 109.