Selpercatinib outperforms cabozantinib and vandetanib in RET-mutant medullary thyroid cancer

November 2023 Cancer trials Andrea Enguita

Selpercatinib, a highly selective, potent RET inhibitor, previously showed efficacy in patients with advanced RET-mutant medullary thyroid cancer. However, its efficacy compared with approved multikinase inhibitors is unclear. Recently published in The New England Journal of Medicine, the results of LIBRETTO-001 showed that selpercatinib treatment leads to superior progression-free and treatment failure-free survival in patients with RET-mutant medullary thyroid cancer, compared to cabozantinib and vandetanib.

Medullary thyroid cancer is primarily driven by alterations in the RET proto-oncogene. Vandetanib and cabozantinib are two multikinase inhibitors approved for the treatment of symptomatic or progressive unresectable, locally advanced or metastatic medullary thyroid cancer. Although these two multikinase inhibitors are effective, their use can be challenging due to suboptimal RET inhibition, toxic effects related to the inhibition of non-RET kinases, long pharmacologic half-lives that complicate management, and resistance due to the emergence of the gatekeeper mutant RET V804X.

Selpercatinib is a first-in-class, highly selective, potent, and brain-penetrant RET kinase inhibitor that has shown marked and durable efficacy in non-randomised studies in patients with RET-activated cancers. This study compared selpercatinib with vandetanib or cabozantinib in patients with progressive, locally advanced or metastatic RET-mutant medullary thyroid cancer who had not received treatment with kinase inhibitors.


The phase 3 LIBRETTO-001 trial enrolled patients (≥12 years) with unresectable, locally advanced or metastatic medullary thyroid cancer and no history of treatment with kinase inhibitors. In total, 291 patients were randomly assigned (2:1) to receive selpercatinib (160 mg twice daily, n=193) or the treating physician’s choice (PC) of cabozantinib (140 mg once daily, n=73) or vandetanib (300 mg once daily, n=25), all administered orally. Crossover to selpercatinib was permitted among patients in the control group after disease progression. The primary endpoint was progression-free survival (PFS). Treatment failure-free survival, overall response rate (ORR) and safety were secondary endpoints.

Study findings

After a median follow-up of 12 months, selpercatinib demonstrated a significant progression-free survival benefit over PC (HR[95%CI]: 0.28[ 0.16-0.48]; p<0.001). The median PFS was not reached in the selpercatinib group, compared to 16.8 months in the PC group. Similarly, median treatment failure-free survival was not reached in the selpercatinib group, whereas it was 13.9 months in the control group (HR[95%CI]: 0.25[0.15-0.42]; p<0.001). At the 12-month mark, treatment failure-free survival rates were reported at 86.2% vs. 62.1% in the selpercatinib and PC groups, respectively. ORR was reported at 69.4% in the selpercatinib group and 38.8% in the control group. Adverse events (AEs) led to a dose reduction in 38.9% vs. 77.3% of patients in the selpercatinib and control arms, respectively, and to treatment discontinuation in 4.7% vs. 26.8%. Grade ≥3 AEs were less common with selpercatinib (52.8% vs. 76.3% in the PC arm). The most common grade ≥3 AEs in the selpercatinib arm were hypertension (18.7%), increased alanine aminotransferase (10.4%) and aspartate aminotransferase (4.7%) levels and prolonged QT interval as documented on an electrocardiogram (4.7%). In the control group, the most common grade ≥3 AEs were hypertension (17.5%), mucosal inflammation (13.4%), and palmar–plantar erythrodysesthesia syndrome (9.3%).

These findings from the LIBRETTO-531 trial confirmed that selpercatinib is more efficient than the multikinase inhibitors cabozantinib and vandetanib in the treatment of advanced RET-mutant medullary thyroid cancer. These results also underscore the importance of timely biomarker testing to identify actionable RET mutations, guiding optimal first-line therapy for all patients with advanced medullary thyroid cancer.


Hadoux J, Elisei R, Brose MS, et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. N Engl J Med. 2023; 389:1851-61.