The incidence of thyroid cancer has increased over the past decade, with medullary thyroid cancer representing 1–5% of all thyroid cancer cases (75% sporadic and 25% hereditary) and papillary thyroid cancer accounting for 80–85% of all differentiated thyroid cancer.1, 2, 3 Despite its low prevalence, medullary thyroid cancer accounts for almost 14% of all thyroid cancer-related deaths.4 Activating alterations in the RET proto-oncogene (RET), which encodes a transmembrane receptor tyrosine kinase (proto-oncogene tyrosine-protein kinase receptor RET), are known oncogenic drivers in both medullary thyroid cancer and differentiated thyroid cancer, and represent a promising therapeutic target.5, 6 Medullary thyroid cancer originates from parafollicular C cells and can be hereditary, associated with two subtypes of multiple endocrine neoplasia syndrome type 2 (MEN2; MEN2A and MEN2B), or sporadic.7 RET mutations occur in more than 95% of hereditary and approximately 50% of sporadic medullary thyroid cancer.8 In the hereditary form, these include extracellular domain mutations (most commonly at the C634 codon), which promote ligand-independent activation of RET, and kinase domain mutations (primarily M918T, A883F, or V804L/M), which promote RET autoactivation and consequent oncogenic signalling.9, 10 In the sporadic form, the M918T mutation accounts for more than 75% of the RET alterations and might be associated with a worse prognosis.11, 12 In differentiated thyroid cancer, which originates from follicular cells, RET fusions are present in approximately 10–20% of papillary thyroid cancer,8 and less common (<10%) in other thyroid cancer subtypes such as follicular, Hürthle-cell, poorly differentiated, and anaplastic.13, 14 Among patients with papillary thyroid cancer, the most common RET fusion partners are CCDC6 (59%) and NCOA4 (36%).10, 15
Research in context
Evidence before this study
We searched PubMed for studies published in English between Jan 1, 2015, and July 31, 2020, investigating targeted treatment of RET-altered thyroid cancer. Search terms included ”RET” plus ”thyroid” and were filtered for clinical trials. Of the 16 entries returned, there were no clinical trials specifically done in patients with RET-altered thyroid cancer. In clinical trials enrolling patients with medullary thyroid cancer not limited to RET-alterations, the response rate with the standard-of-care multikinase inhibitor cabozantinib was 32% and with vandetanib was 46%. Furthermore, in clinical trials of patients with radioiodine-refractory differentiated thyroid cancer, response rates with the standard-of-care multikinase inhibitor lenvatinib was 65% and with sorafenib was 12%. Although these multikinase inhibitors have shown clinical activity in the respective indications, rates of adverse events leading to dose reduction and treatment discontinuation were generally high owing to their broad activity against many kinases.
Added value of this study
To the best of our knowledge, ARROW is the first prospective study to investigate treatment of RET-altered solid tumours, including RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer, with pralsetinib. Our data show that pralsetinib has clinical activity in patients with RET-mutant medullary thyroid cancer, including in patients who were treatment naive or had previously received cabozantinib or vandetanib, or both, as well as in patients with previously treated RET fusion-positive thyroid cancer (response rates of 71%, 60%, and 89%, respectively). In patients with RET-altered thyroid cancer who received the recommended phase 2 dose of 400 mg once daily, pralsetinib was well tolerated with a predictable safety profile, and rates of dose reductions and treatment discontinuations because of treatment-related adverse events were low when compared with available multikinase inhibitors. Overall, pralsetinib had a manageable safety profile in patients with RET-altered thyroid cancer and provided meaningful clinical activity in patients irrespective of previous treatment history.
Implications of all the available evidence
Patients with RET-altered thyroid cancer have few safe and effective treatment options outside of standard of care available for tumours without targetable oncogenic drivers. Findings from our study show that RET-targeted treatment with pralsetinib has antitumour activity in RET-altered thyroid cancer and a manageable safety profile. The utility of RET-targeted therapies is also validated by outcomes with selpercatinib, another targeted RET inhibitor, which were reported following the data cutoff for the present study. Approval of both of these agents in the USA provides new treatment options in this patient population.
Multikinase inhibitors were in the past standard of care for advanced medullary thyroid cancer (cabozantinib and vandetanib) and radioiodine-refractory differentiated thyroid cancer (lenvatinib and sorafenib).16 Although these multikinase inhibitors have shown clinical activity in the respective indications,17, 18, 19, 20 they are associated with significant dermatological, cardiovascular, and gastrointestinal side-effects owing to their broad activity against many kinases, including vascular endothelial growth factor receptors.17, 18, 19, 20, 21 These toxicities frequently lead to dose reductions and discontinuations, which might affect the quality of life and outcomes of patients.17, 18, 19, 20, 21
Pralsetinib (formerly BLU-667, Blueprint Medicines) is an oral, once daily, selective RET inhibitor that potently targets RET-altered kinases, including V804L/M gatekeeper mutations associated with resistance to other tyrosine kinase inhibitors.22, 23 Here, we report on the safety and efficacy of pralsetinib in patients with RET-altered thyroid cancer from the registrational phase 1/2 study (ARROW), which formed the basis of approval in the USA for treatment of advanced or metastatic RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer.24