Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

Abstract

Background: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.

Conclusions: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Figure 1.. Waterfall plots of the maximum change in tumor size in (A) vandetanib and/or cabozantinib pretreated RET-mutant MTC patients, (B) vandetanib/cabozantinib naïve RET-mutant MTC patients, and (C) RET fusion-positive thyroid cancer patients per investigator assessments.

For each patient, the best (minimum) percent change from baseline in the sum of diameters for all target lesions is represented by a vertical bar. Data for 4 patients not shown in vandetanib and/or cabozantinib pretreated RET-mutant MTC group: 2 discontinued prior to any post-baseline imaging assessments, and 2 did not have measurable disease at baseline. Data for 4 patients not shown in vandetanib/cabozantinib naïve RET-mutant MTC group: 2 patients discontinued prior to any post-baseline imaging assessments and 2 did not have measurable disease at baseline. RET fusion-positive thyroid cancer patients; Data for 2 patients not shown in RET fusion-positive thyroid cancer group: 1 did not have measurable disease at baseline, and 1 deemed not evaluable on study by the investigator.

Figure 2:

Kaplan-Meier plots of (A) duration of response among 34 patients with a response and (B) progression-free survival in all 55 patients in the vandetanib and/or cabozantinib pretreated RET-mutant MTC group according to investigator assessments.