Selpercatinib as a first-line standard of care in advanced RET-mutant medullary thyroid cancer

The phase III LIBRETTO-531 trial was the first trial to directly compare selpercatinib with approved multikinase inhibitors (cabozantinib or vandetanib) as first-line therapy in patients with RET-mutant medullary thyroid cancer.  Treatment with selpercatinib resulted in superior progression-free survival, treatment failure–free survival, objective response rates and overall survival as compared with the multikinase inhibitors.

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that accounts for approximately 5% of all thyroid cancers. Mutations in the RET tyrosine kinase receptor are found in approximately all cases of hereditary MTC associated with the MEN type 2A and 2B syndromes, in 25-50% of all sporadic MTC and in up to 90% of advanced and metastatic cases. Previously, selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant MTC in the phase I/II LIBRETTO-001 trial, but its efficacy as compared with approved multikinase inhibitors remained unclear. The randomised study LIBRETTO-531 was designed to define the optimal first-line regimen for patients with advanced RET-mutant MTC.

Study design

LIBRETTO-531 is a phase III, randomised trial comparing selpercatinib (160 mg, BID) as first-line therapy with the physician’s choice of cabozantinib (140 mg, QD) or vandetanib (300 mg, QD) (control group) in patients with unresectable locally advanced or metastatic RET-mutant MTC. In order to be eligible, patients had to have progressive disease documented within 14 months before enrolment and no prior history of treatment with kinase inhibitors. The primary endpoint in the protocol-specified interim efficacy analysis was progression-free survival (PFS), as assessed by blinded independent central review (BICR). Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled endpoint that was to be tested only if PFS was significant. Among the other secondary endpoints were overall response and safety.

Results

In total, 291 patients were randomised to selpercatinib (N= 193) or treatment of physician’s choice (N= 98). At the time of the data cut-off, 175 patients in the selpercatinib arm were still on treatment. In the control arm, 40 patients were still on treatment and 58 patients discontinued treatment, of which 24 crossed over to selpercatinib. Baseline characteristics were well-balanced between study arms. At a median follow-up of 12 months, median PFS assessed by BICR was not reached in the selpercatinib group and was 16.8 months in the control group (HR[95%CI]: 0.280[0.165-0.475], p< 0.0001). A consistent PFS benefit was observed in all subgroups. Median treatment failure–free survival as assessed by BICR was not reached in the selpercatinib group and was 13.9 months in the control group (HR[95%CI]: 0.254[0.153- 0.423], p< 0.0001). The overall response rate was 69.4% for patients receiving selpercatinib and 38.8% for patients receiving cabozantinib or vandetanib, with complete response in respectively 11.9% and 4.1% of patients. Median duration of response was not reached in the selpercatinib arm and was 16.6 months in the control arm. At the time of the interim analysis, 94.8% of patients were alive on selpercatinib and 85.7% on control arm (HR[95%CI]: 0.374[0.147-0.949], p= 0.0312).

Treatment-emergent adverse events (TEAEs) of grade ≥3 were reported in 52.8% of patients under treatment with selpercatinib and in 76.3% of patients in the control arm. The most common TEAEs observed with selpercatinib were hypertension, dry mouth, and diarrhoea; and with control, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, and hypertension. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 79.2% for patients receiving cabozantinib and 72.0% for patients receiving vandetanib.  A permanent treatment discontinuation was reported in respectively 4.7% and 26.8% of patients in the selpercatinib and treatment of physician’s choice arms.

Conclusions

Selpercatinib, a selective RET inhibitor, demonstrated superior efficacy versus multikinase inhibitors in first-line patients with RET-mutant MTC. In addition, selpercatinib showed a favourable safety profile compared with multikinase inhibitors. These results highlight the importance of RET selectivity and timely implementation of biomarker testing for patients with metastatic MTC and support selpercatinib as the first-line standard of care for patients with advanced RET-mutant MTC.

Reference

Hadoux J, et al. Randomized phase III study of selpercatinib versus cabozantinib or vandetanib in advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer. Presented at ESMO 2023; Abstract LBA3.