Selpercatinib treatment of RET-altered thyroid cancer resulted in high response and progression-free survival (PFS) rates with a tolerable safety profile, according to results of a phase 1-2 trial published in the New England Journal of Medicine.1

RET alterations are present among 70% of patients with in medullary thyroid cancers (MTC) and 10% of other thyroid cancers, but RET-specific inhibitors have not yet been evaluated in this population. Multitargeted kinase inhibitors are approved for the treatment of MTC, with response rates ranging from 12% to 65%. The purpose of this trial was to evaluate a RET-specific inhibitor among patients with RET-altered thyroid cancer.

The multicenter, open-label, phase 1/2 LIBRETTO-001 trial ( Identifier: NCT03157128) treated 162 patients with advanced or metastatic RET-altered thyroid cancer with selpercatinib. The phase 1 portion included dose escalation from 20 mg to 240 mg twice daily and the phase 2 portion used a dose of 160 mg twice daily. The primary endpoint was objective response rate (ORR) by independent review and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and safety.

Continue Reading

There were 3 efficacy analysis cohorts including 55 patients with RET-mutated disease previously treated with multikinase inhibitors, 88 patients with treatment-naive RET-mutated disease, and 19 patients with RET fusion–positive disease previously treated with multikinase inhibitors. The median patient age was 56 years (range, 15-88 years).

All patients in the RET-mutant arms had MTC, whereas patients in the RET-fusion arm had primarily papillary thyroid cancer followed by poorly differentiated, anaplastic, and other histologic types.

Response rates were high among all cohorts and occurred regardless of the RET alteration present. Among patients with RET-mutant MTC, treatment with selpercatinib resulted in an ORR of 69% (95% CI, 55%-81%) in the previously treated cohort and 73% (95% CI, 62%-82%) in the treatment-naive cohort. The ORR was 79% (95% CI, 54%-94%) among patients with previously treated RET fusion–positive disease.

The DOR could not be estimated for patients in the previously treated RET-mutant cohort. The median DOR was 22 months in the treatment-naive RET-mutant group and 18.4 months in the RET fusion group. The median follow-up ranged from 7.8 to 17.5 months.

PFS was also not able to be estimated for the previously treated RET-mutant group. The median PFS was 23.6 and 20.1 months in the treatment-naive RET-mutant and previously treated RET fusion groups, respectively. The median follow-up ranged from 11.1 to 16.7 months.

The most common grade 3/4 treatment-related adverse events (TRAEs) was hypertension (12%), elevated alanine aminotransferase (11%), and elevated aspartate aminotransferase (8%). There were 5 grade 5 events, which were considered unrelated to selpercatinib treatment. TRAEs led to a dose reduction among 30% of patients and treatment discontinuation among 2%.

The authors concluded that the results “showed marked and durable antitumor activity in patients with RET-mutant MTC with and without previous vandetanib or  cabozantinib treatment” and “promising activity was observed in a smaller group of patients with RET fusion–positive previously treated thyroid cancers of various histologic types.”


Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383:825-835. doi:10.1056/NEJMoa2005651