1. Selpercatinib, a highly selective RET kinase inhibitor, was effective in antitumor activity against medullary thyroid cancer.
2. Selpercatinib caused low-grade toxic effects in patients being treated for medullary thyroid cancer.
Evidence Rating Level: 2 (Good)
Study Rundown: The RET proto-oncogene encodes a transmembrane receptor tyrosine kinase. Mutations in the RET gene result in hereditary multiple endocrine neoplasia 2A and 2B resulting in medullary thyroid cancer. Currently, multitargeted kinase inhibitors such as vandetanib and cabozantinib have been approved to treat medullary thyroid cancer. However, their use is limited due to their lack of specificity to RET and toxic effects. As such, this study determined the safety and efficacy of selpercatinib, a highly selective RET kinase inhibitor, in RET-mutated thyroid cancer. The results of this study demonstrated that selpercatinib was effective for antitumor activity in medullary thyroid cancer. One key limitation of this study was the length of follow-up, as long-term follow-up of the participants treated with selpercatinib would be necessary to define the durability of the therapeutic’s efficacy. Nonetheless, this study was strengthened by the novel use of a RET specific inhibitor to treat RET-mutated thyroid cancer.
Click to read the study. published today in NEJM
Relevant Reading: Radiation exposure, young age, and female gender are associated with high prevalence of RET/PTC1 and RET/PTC3 in papillary thyroid cancer: a meta-analysis
In-Depth [prospective cohort]: This prospective cohort study enrolled 162 participants in a multicenter study at 65 centers in 12 countries. Participants included in the study were at least 12 years of age and had received a diagnosis of advanced or metastatic solid tumor. Participants without a RET alteration, either fusion or mutation, were excluded from this study. The participants were given selpercatinib, orally, in 28-day cycles until there was disease progression, unacceptable toxic side effects or withdrawal of consent. The participants enrolled in the Phase 1 dose escalation trial received selpercatinib dosing from 20 milligram (mg), once daily to 240 mg, twice daily. The participants enrolled in Phase 2 received selpercatinib dosing of 160 mg, twice daily. The primary endpoint was an objective response, which was defined as a complete or partial response as determined by an independent review committee of radiologists. Among the 55 patients with RET-mutant medullary thyroid cancer, 69% of the participants had an objective response (95% confidence interval [CI], 55 to 81). Specifically, 5 participants (9%) had a completed response and 33 participants (33%) had a partial response. Furthermore, selpercatinib efficacy was observed regardless of the number of previous multitargeted kinase inhibitors used by the participants (percentage of participants with a response, 67% with vandetanib only, 69% with cabozantinib only, and 71% with both). The biochemical response for calcitonin was present in 91% of the participants (95% CI, 80 to 97) and in 66% of the participants (95% CI, 52 to 79) for the carcinoembryonic antigen (CEA) level. Finally, the most common adverse events from selpercatinib treatment were hypertension (21% of participants), increased alanine aminotransferase levels (11%), increased aspartate aminotransferase level (9%), and hyponatremia (8%). Grade 3 tumor lysis developed in one participant diagnosed with medullary thyroid cancer, and 30% of the participants had a dose reduction because of treatment-related adverse events. Taken together, selpercatinib was shown to be an effective treatment for antitumor activity for patients diagnosed with RET-mutated medullary thyroid cancer with low-grade toxic side effects.
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