First-Line Selpercatinib: New Standard of Care for RET-Positive Medullary Thyroid Cancer?

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First-line treatment with selpercatinib achieved a statistically significant improvement in progression-free survival and overall response rate vs treatment with cabozantinib or vandetanib in patients with multikinase inhibitor–naive, RET-mutant advanced or metastatic medullary thyroid cancer.1

At a median follow-up of 12 months, the median progression-free survival was not reached with selpercatinib vs 16.8 months in the control arm (either cabozantinib or vandetanib), for a 72% reduction in the risk of disease progression or death (P < .0001). These interim results of the phase III LIBRETTO-531 trial were presented at the European Society for Medical Oncology (ESMO) Congress 2023 and published simultaneously in TheNewEngland Journal of Medicine.2

“Selpercatinib, a potent selective RET inhibitor, provides prolonged progression-free survival, prolonged treatment failure–free survival, higher overall response rate, and a favorable safety profile as compared with multikinase inhibitors for the first-line treatment of patients with RET-mutant medullary thyroid carcinoma,” said lead study author Julien Hadoux, MD, PhD, of Gustave Roussy, Villejuif, France. “These results highlight the importance of RET selectivity and timely implementation of biomarker testing for patients with metastatic medullary thyroid cancer and support selpercatinib as a new first-line standard of care for patients with advanced RET-mutant medullary thyroid cancer.”

Julien Hadoux, MD, PhD

Julien Hadoux, MD, PhD

These findings apply to patients with a rare thyroid cancer but point to the importance of genomic testing for a targetable and actionable mutation. Indeed, medullary thyroid cancer accounts for about 5% of all thyroid tumors. RET mutations occur in almost 100% of hereditary medullary thyroid cancers, 25% to 50% of all sporadic medullary thyroid cancers, and up to 80% to 90% of all advanced/metastatic medullary thyroid cancers.

The multikinase inhibitors cabozantinib and vandetanib are standard front-line treatment options for advanced medullary thyroid cancer, but they are not specifically selective for RET inhibition and are associated with toxicity. To date, the RET kinase inhibitor selpercatinib has been globally approved for the treatment of metastatic medullary thyroid cancer in either the first-line (United States) or second-line setting (Europe).

Study Details

The phase III LIBRETTO-531 trial was designed to identify the optimal first-line regimen for patients with advanced RET-mutant medullary thyroid cancer. Eligible patients had unresectable locally advanced or metastatic RET-mutant medullary thyroid cancer that progressed within 14 months prior to enrollment. Patients were naive to treatment with a kinase inhibitor.

A total of 291 patients with advanced RET-mutant medullary thyroid cancer were randomly assigned 2:1 to receive first-line treatment with selpercatinib at 160 mg twice daily (n = 193) or physician’s choice of cabozantinib at 140 mg daily or vandetanib at 300 mg daily (n = 98). Patients were enrolled between February 2020 and March 2023 at 176 centers across 19 countries.

Stratification factors were mutational status and investigator’s choice of treatment on the control arm. Crossover to selpercatinib was allowed after centrally confirmed disease progression.

The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors by blinded independent committee review. Secondary endpoints included treatment failure–free survival according to blinded independent committee review and investigator, investigator-assessed progression-free survival, overall survival by blinded independent committee review and investigator assessment, and safety.

A total of 18 patients discontinued selpercatinib compared with 58 patients who discontinued cabozantinib or vandetanib. Of the 58 patients, 24 crossed over to the selpercatinib arm.

Baseline characteristics were comparable between the two treatment arms. The median patient age was around 55 years, and about 25% were aged 65 or older. About two-thirds were male, and 68.7% were White. A total 62.5% of patients had a RET M918T mutation. The median time from diagnosis to study enrollment was 42.7 months in the selpercatinib arm and 61.6 months in the control arm.

Key Results

The progression-free survival benefit of selpercatinib was also seen according to investigator assessment, improving progression-free survival by 72% (P < .0001). Improved progression-free survival with selpercatinib was observed across all prespecified subgroups, in particular, those with a RET co-mutation in addition to M918T.

At a median follow-up of 15 months, 8 deaths occurred on the selpercatinib arm vs 10 on the control arm; 94.8% and 85.7% of patients on each arm were alive at the time of the ESMO Congress, respectively. Survival data are still immature. Of the 24 patients who crossed over to receive selpercatinib, 19 remained on treatment as of the data cutoff date.

Treatment failure–free survival was significantly improved with selpercatinib vs control treatment according to both blinded independent committee review and investigator assessment (P < .0001).

Overall response rate was 69.4% with selpercatinib vs 38.8% in the control group. The complete response rate was 11.9% with selpercatinib vs 4.1% in the control group. The median duration of response was not reached with selpercatinib compared with 16.6 months with cabozantinib or vandetanib.

Selpercatinib was associated with fewer treatment-related adverse events than either cabozantinib or vandetinib. The rate of grade 3 or higher treatment-related adverse events was 52.8% with selpercatinib and 76.3% with cabozantinib or vandetanib.

Dose reductions because of adverse events were reported in 38.9%, 79.2%, and 71.0% of patients given selpercatinib, cabozantinib, and vandetanib, respectively. Treatment discontinuations as a result of adverse events occurred in 4.7% and 26.8% of patients, respectively. There were four deaths from adverse events in the selpercatinib arm and two deaths from adverse events on the control arm. 

DISCLOSURE: Dr. Hadoux has received honoraria for speaker engagements, advisory roles, or funding of continuous medical education from Eli Lilly, AAA, Ipsen, Roche, PharmaMar, and Eisai; and has received research grants from Novartis.


1. Hadoux J, et al: ESMO Congress 2023. Abstract LBA3. Presented October 21, 2023.

2. Hadoux J, et al: N Engl J Med. October 21, 2023 (early release online).

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