Efficacy/Safety Evaluation of Selpercatinib in RET-Driven MTC Ongoing in LIBRETTO-531

LIBRETTO-531 succeeds LIBRETTO-001 to continue the study of selpercatinib in patients with multikinase inhibitor therapy-naive RET-mutant advanced medullary thyroid cancer.

Selpercatinib (LOXO-292), a selective and potent RET inhibitor, is now under evaluation for the treatment of RET-mutant medullary thyroid cancer (MTC) in a phase 3 clinical trial (LIBRETTO-531; NCT04211337) in which the agent is compared with physician’s choice of either cabozantinib (Cabometyx) or vandetanib (Caprelsa).1

With RET gene alteration being common in MTC, there is a need for treatment options for this population, and according to research, current therapies are not ideal for many patients with MTC due to toxicity and tumor resistance. Evidence of robust anti-tumor activity has been shown with selpercatinib in patients with advanced RET-mutant MTC who are naïve to treatment with multikinase inhibitors in the phase 1/2 LIBRETTO-001 clinical trial.2

In LIBRETTO, 143 patients were evaluated in the integrated analysis set. The objective response rate (ORR) observed was 69.2% among patients treated with selpercatinib and the treatment was well-tolerated in the patient population. The most common treatment-emergent adverse events (TEAEs) included dry mouth, diarrhea, hypertension, fatigue, and constipation. These TEAEs were predominantly low grade.3

“What’s next with selpercatinib in the patient population of RET-altered thyroid cancers is more selpercatinib. Most patients originally enrolled on LIBRETTO-001 had responses to therapy and remain in response at this time, so 1 critical question is what will the median progression-free survival be? What will the median duration of response be? It's good that we don't know the answer to that question because so far, we have not yet met those medians despite the length of time that we've had in follow-up thus far,” said Lori Wirth, MD, an associate professor of medicine at Harvard Medical School and Medical Director of the Center for Head and Neck Cancers at Massachusetts General Hospital, in an interview with Targeted Oncology™.

LIBRETTO-531 is designed to further analyze the safety and efficacy of selpercatinib in patients with RET-mutant MTC. The study follows a multicenter, randomized, open-label design with a target enrollment of 400 patients. The patients are randomized 2:1 to receive either selpercatinib 160 mg twice daily or the physician’s choice of cabozantinib 140 mg once daily or vandetanib 300 mg once daily.1,2

Patients with MKI-naïve advanced RET-mutant MTC will be stratified by RET mutation type and intended treatment if randomized to the control arm. The primary end point of the study is treatment failure-free survival assessed by a blinded independent review committee. The secondary end points of the study include progression-free survival, ORR, duration of response, overall survival, second disease progression or death from any cause, comparative tolerability, and the percentage of patients with RET-positive specimens.

To be included in the study, patients must be at least 18 years of age with histologically or cytologically RET-altered disease that has radiographic progression per RECIST v1.1. Patients must also have an ECOG performance status of 0 to 2, and adequate hematologic, hepatic, and renal function.1

The study excludes patients with oncogenic drivers in MTC that may cause resistance to selpercatinib. Patients with symptomatic central nervous system metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression are ineligible for the study along with patients who have clinically significant active cardiovascular disease, active infections, active hemorrhage or another malignancy diagnosed within 2 years of the study.

LIBRETTO-531 will be conducted at 158 sites worldwide. Investigators, like Wirth, are hoping that the study will answer important clinical questions. “One important question in thyroid cancer is how we can best take advantage of this good drug. Particularly with MTC when patients can be relatively asymptomatic, or RET fusion-positive advanced thyroid cancer when patients can be relatively asymptomatic? Sometimes we hold off as long as possible when starting a multikinase inhibitor therapy because of the balance of efficacy and side effect profile that you have to deal with, but when the efficacy is really good, and the side effect profile isn't as troublesome, should we be using these drugs earlier in the course of disease rather than holding off for as long as possible? I think that's a really important question,” Wirth said.


1. A study of selpercatinib (LY3527723) in participants with RET-mutant medullary thyroid cancer (LIBRETTO-531). Clinicaltrials.gov. Accessed January 24, 2022. https://bit.ly/3g9dTtr

2. Hernando J, Tarasova V, Hu M, et al. 1927TiP LIBRETTO-531: Selpercatinib in patients with treatment (Tx)-naïve RET-mutant medullary thyroid cancer (MTC). Ann Oncol. 2022;31(suppl 4): S1091. doi: 10.1016/j.annonc.2020.08.1415

3. Sherman EJ, Wirth LJ, Shah MH, et al. Selpercatinib efficacy and safety in patients with RET-altered thyroid cancer: A clinical trial update. J Clin Oncol. 2021;39(15):6073-6073. doi: 10.1200/JCO.2021.39.15_suppl.6073