The LIBRETTO-531 study

LIBRETTO-531, a phase 3 trial, was designed to establish the optimal first-line regimen for advanced RET-mutant MTC. Experts are deliberating the necessity of a large-scale global phase 3 study, especially given the promising outcomes observed in the phase 1 study, which may suffice for rare cancer types with robust biomarker data.

Results presented at ESMO2023 confirm that selpercatinib enhances Objective Response Rate (ORR), Progression-Free Survival (PFS), and Time to Treatment Failure (TFFS) in MTC patients with RET mutations. Predicting the overall impact on Overall Survival (OS) is challenging due to patient crossover. In cases where selpercatinib fails to elicit a response, cabozantinib or vadetanib represent the only viable alternatives. Although second-generation RET inhibitors exist, none have proven effective against initial RET inhibitor resistance. They might, however, influence newly developing mutations.

The future course of action remains uncertain. Presently, selpercatinib serves as the first-line treatment, with a shift to multikinase inhibitors, excluding cabozantinib or vadetanib, upon progression.

Rapid RET testing poses a challenge, necessitating clear protocols. Both germline and somatic testing are advisable. Notably, MTC patients rarely have a family history (less than 25%), making it imperative to test all newly diagnosed patients for germinal mutations. When testing for somatic mutations, utilizing a recent biopsy instead of the original one is recommended. The time gap of a decade or more between the original diagnosis and systemic therapy could lead to deterioration in the original biopsy. Additionally, disease progression is associated with increased mutations. While primary tumors exhibit RET mutations in 25-50% of cases, advanced stages manifest mutations in over 80-90%. Therefore, testing new material is crucial to capture the mutation’s evolutionary trajectory.

A pivotal biomarker is RET mutations in liquid biopsies, which brings promising developments to the forefront.

Reference:

Hadoux J. – Randomized phase III study of selpercatinib versus cabozantinib or vandetanib in advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer. ESMO 2023 – #LBA3