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LOXO-292 Demonstrates Promising Anti-Tumour Activity in RET-Altered Thyroid Cancer

The results from LIBRETTO-001 trial
29 Sep 2019
Cytotoxic Therapy;  Targeted Therapy
Endocrine Tumours

Patients with advanced RET fusion–positive thyroid cancer and RET-mutant medullary thyroid cancer (MTC) had high rates of response following treatment with selpercatinib (LOXO-292), which may provide a new treatment option for patients with RET-altered cancers, according to findings presented at the ESMO Congress 2019 in Barcelona, Spain.

Dr. Lori J. Wirth, Massachusetts General Hospital in Boston, USA, emphasized the need for new agents to treat patients with RET-altered cancers. Selpercatinib (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 in the LIBRETTO-001 trial (NCT03157128). Previously reported data from this trial formed the basis for the US Food and Drug Administration (FDA) Breakthrough Designation that was granted for selpercatinib (LOXO-292) in the treatment of RET fusion-positive non-small cell lung cancer (NSCLC), RET fusion-positive thyroid cancer, and RET-mutant MTC.

The global, phase I/II LIBRETTO-001 study enrolled patients with advanced RET fusion-positive cancers and RET-mutant MTC; phase I of the study determined the recommended phase II dose and phase II enrolled patients into 6 cohorts based on tumour 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 (OS), and safety.

At the ESMO 2019 Congress, Dr. Wirth presented the results from a cohort of 253 RET-altered thyroid cancer patients including 226 patients with RET-mutant MTC, and 27 patients with RET fusion-positive thyroid cancer.

Dr. Wirth presented results from the primary analysis set, which comprised the first 55 consecutively enrolled patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib. They received oral selpercatinib (LOXO-292) in 28-day cycles.

Selpercatinib (LOXO-292) showed promising activity in RET-mutant MTC and RET fusion-positive thyroid cancer

In this primary analysis set, patients with previously treated RET-mutant MTC demonstrated an ORR per investigator assessment of 56% (95% confidence interval [CI], 42-70%). Confirmation is pending for two of the partial responses (PR). The cohort of 31 patients with a response included 3 patients with a RET V804M/L gatekeeper mutation who achieved one complete response (CR) and 2 PR.

Wirth ESMO 2019 News

RET mutant-MTC PAS (n=55).

© Lori J. Wirth.

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

Calcitonin and CEA response, defined as ≥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 CEA 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 PRs awaiting confirmation).

Selpercatinib (LOXO-292) was well tolerated in a large safety data set

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, diarrhoea, hypertension, increased ALT, and increased AST. The adverse events were mostly grades 1 and 2. Treatment discontinuation due to a treatment-related adverse event occurred in nine patients (1.7%).

Discussant points

Enrique Grande of the MD Anderson Cancer Center, Madrid, Spain who discussed the study findings said that his learnings from the LIBRETTO-001 are that selpercatinib is active and safe in patients with advanced thyroid cancer harbouring RET mutations and fusions regardless of the histology. Furthermore, the findings confirm the need to perform a molecular testing in patients with advanced thyroid cancer as we have now RET inhibitors (selpercatinib and BLU-667), NTRK inhibitors (larotrectinib and entrectinib), BRAF inhibitors (vemurafenib and dabrafenib plus trametinib), mTOR inhibitors (everolimus), ALK inhibitors (crizotinib). In his humble opinion, there is enough evidence for approval of these targeted agents without the need of randomised trials although they are preferred.


This analysis of data from cohorts of patients with RET-altered thyroid cancer participating in the ongoing LIBRETTO-001 study demonstrated marked anti-tumour activity following treatment with selpercatinib (LOXO-292), which was well-tolerated.

Based on these findings, the investigators are planning to submit a new drug application with the FDA in late 2019.


This study was funded by Loxo Oncology. 


LBA93 – Wirth LJ, Sherman E, Drilon A, et al. Registrational Results of LOXO-292 in Patients with RET-Altered Thyroid Cancers.

Last update: 29 Sep 2019

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