RET-y to rumble.

Top Line: RET is a receptor tyrosine-kinase that, when activated, contributes to malignancy. 

The Study: Germline mutations in RET lead to Multiple Endocrine Neoplasia (MEN) 2A and 2B and hereditary medullary thyroid carcinoma (MTC). In addition, over half of sporadic MTC cases also have alterations in RET. Multitargeted tyrosine kinase inhibitors (TKI) like cabozantinib are currently used for MTC, but both their non-selective toxicity and poor RET activity leave much to be desired. LIBRETTO-001 is a catch-all phase 1-2 trial using selpercatinib, a next-generation TKI highly-specific for RET, in patients with advanced malignancies harboring RET-alterations. This publication describes outcomes for 162 patients with either RET-mutated MTC or a RET-fusion(+) thyroid cancer of any histologic type. Among the 88 (54%) with RET-mutated MTC and no prior TKI treatment, the response rate was 73%, and the vast majority (92%) of those were still free from progression at one year. Among the 55 RET-mutated MTC patients with prior TKI therapy, response rate was 69%, with 82% free from progression at one year. Lastly, those with RET-fusion(+) thyroid cancers had a response rate of 79%, with 64% free from progression at one year. The main grade 3+ toxicities were hypertension and abnormal liver enzymes, though only 2% of patients discontinued therapy due to adverse events.

TBL: The first of its kind selective RET-targeted TKI selpercatinib shows encouraging rates and durations of response among patients with advanced RET-mutated or RET-fusion(+) thyroid cancer. | Wirth, N Engl J Med 2020