Selpercatinib is a selective RET kinase inhibitor developed for cancers driven by RET gene fusions or activating RET mutations.
Pharmacology
RET is a receptor tyrosine kinase. Selpercatinib inhibits RET signaling and is designed to interfere with signaling caused by abnormal RET proteins. This molecular selectivity distinguishes it from conventional cytotoxic chemotherapy.
Pharmacokinetics
Current U.S. prescribing information reports approximately 96% protein binding in vitro. The apparent clearance is approximately 6 L/hour and the terminal half-life is approximately 32 hours after oral administration.
Metabolism
Selpercatinib is metabolized predominantly by CYP3A4. Following radiolabeled administration, most of the circulating radioactive drug components were represented by unchanged selpercatinib.
Excretion
Following administration of radiolabeled selpercatinib, approximately 69% of the administered dose was recovered in feces and 24% in urine.
Molecular targets
| Biological feature | Clinical relevance |
|---|---|
| RET kinase | Primary pharmacologic target |
| RET gene fusion | Relevant in NSCLC, thyroid and other solid tumors |
| RET mutation | Particularly important in medullary thyroid cancer |
| CYP3A4 | Major metabolic pathway |
| QT interval | Important pharmacodynamic safety consideration |
LIBRETTO-001
LIBRETTO-001 was a multicenter, open-label, phase I/II multicohort trial involving patients with RET-altered advanced or metastatic solid tumors. The pooled safety population included 796 patients.
LIBRETTO-431
LIBRETTO-431 was a randomized phase III trial evaluating first-line selpercatinib against platinum-based chemotherapy with or without pembrolizumab in previously untreated adults with advanced or metastatic RET fusion-positive nonsquamous NSCLC.
The trial reported median progression-free survival of 24.8 months for selpercatinib versus 11.2 months for the pembrolizumab-plus-chemotherapy group in the primary analysis population, with objective response rates of 84% and 65%, respectively.
LIBRETTO-531
In RET-mutant medullary thyroid cancer, LIBRETTO-531 compared selpercatinib with physician’s choice of cabozantinib or vandetanib. The published analysis reported substantially longer progression-free survival with selpercatinib.
LIBRETTO-432
In 2026, the LIBRETTO-432 study reported improved event-free survival for adjuvant selpercatinib compared with placebo in early-stage RET fusion-positive NSCLC. The clinical result is important, but regulatory authorization for any new indication must be distinguished from clinical-trial findings.
Evidence limitations
Clinical trial results describe populations studied under defined protocols. They do not guarantee an individual response or establish suitability for a particular patient.