ESMO 2019: LIBRETTO-001 Trial of Selpercatinib in RET Fusion–Positive Thyroid Cancer

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Patients with advanced RET fusion–positive thyroid cancer and RET-mutant medullary thyroid cancer had high rates of response following treatment with selpercatinib, according to findings from the phase I/II LIBRETTO-001 trial presented by Wirth et al at the European Society for Medical Oncology (ESMO) 2019 Congress (Abstract LBA93).

Lori J. Wirth, MD

Lori J. Wirth, MD

First study author Lori J. Wirth, MD, of Massachusetts General Hospital, emphasized the need for new agents to treat patients with RET-altered cancers. Selpercatinib (previously known as LOXO-292) is an oral and selective investigational new agent that is being evaluated for the treatment of patients with cancers that harbor alterations in the RET kinase. Previously reported data from this trial formed the basis for the U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation that was granted for selpercatinib  in the treatment of RET fusion–positive non–small cell lung cancer, RET fusion–positive thyroid cancer, and RET-mutant medullary thyroid cancer.


The global study enrolled patients with advanced RET fusion–positive cancers and RET-mutant medullary thyroid cancer; phase I of the study determined the recommended phase II dose, and phase II enrolled patients into six cohorts based on tumor type, RET alteration, and prior therapy.

The primary endpoint of the study was the objective response rate (ORR), and the secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival, and safety.

At the ESMO Congress, Dr. Wirth presented the results from a cohort of 253 patients with RET-altered thyroid cancer, including 226 patients with RET-mutant medullary thyroid cancer and 27 patients with RET fusion–positive thyroid cancer.

Results were presented from the primary analysis set, which comprised the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had received prior cabozantinib and/or vandetanib. They received oral selpercatinib in 28-day cycles.


In this primary analysis set, patients with previously treated RET-mutant medullary thyroid cancer demonstrated an ORR per investigator assessment of 56% (95% confidence interval [CI] = 42%–70%). Confirmation is pending for two of the partial responses. The cohort of 31 patients with a response included three patients with a RET V804M/L gatekeeper mutation (one complete response and two partial responses).

At median follow-up of 10.6 months, 6 DoR events occurred; the median DoR has not been reached (95% CI = 11.1 months–not estimable).


  • Patients with previously treated RET-mutant medullary thyroid cancer demonstrated an ORR per investigator assessment of 56%.
  • In a cohort of patients with evaluable RET fusion–positive thyroid cancer, the ORR was 62%.

Calcitonin and carcinoembryonic antigen response, defined as a ≥ 50% decrease that lasted for ≥ 4 weeks, were observed in the majority of patients. Among the biochemical-evaluable patients, the calcitonin response was 49 of 54 patients (91%) and the carcinoembryonic antigen response was 34 of 53 patients (64%).

Results from a cohort of 26 patients with evaluable RET fusion–positive thyroid cancer were also presented. Among these patients, the ORR was 62% (95% CI = 41%–80%); 16 patients showed a response (including two partial responses awaiting confirmation).

The safety data set included all 531 patients with various cancer types that were treated. Five treatment-emergent adverse events occurred in ≥ 15% of patients, including dry mouth, diarrhea, hypertension, increased ALT, and increased AST. The adverse events were mostly grade 1 and 2. Treatment discontinuation due to a treatment-related adverse event occurred in nine patients (1.7%).


Enrique Grande, MD, PhD, of MD Anderson Cancer Center, Madrid, commented these findings show that selpercatinib is active and safe in patients with advanced thyroid cancer harboring RET mutations and fusions, regardless of the histology. Furthermore, the findings confirm the need to perform molecular testing in patients with advanced thyroid cancer.

Disclosure: LIBRETTO-001 was funded by Loxo Oncology. For full disclosures of the study authors, visit

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