LBA3 Randomized Phase III Study of Selpercatinib Versus Cabozantinib or Vandetanib in Advanced, Kinase Inhibitor-Naïve, RET-mutant Medullary Thyroid Cancer

Selpercatinib is a highly selective and potent RET inhibitor approved for treatment of advanced RET-mutant medullary thyroid carcinoma (MTC) but has not been directly compared with approved multikinase inhibitors (MKI). LIBRETTO-531 (NCT04211337) is a randomized phase 3 study comparing first-line selpercatinib versus physician’s choice of cabozantinib or vandetanib. Eligible patients had kinase inhibitor-naïve progressive disease documented in the 14 months prior to enrollment. The pre-planned interim efficacy analysis occurred after 59 progression-free survival (PFS) events. The primary endpoint was blinded independent central review (BICR)-assessed PFS. In total, 291 patients were randomized. Baseline characteristics were well-balanced between study arms. At a median follow-up of 12 months, median PFS by BICR was not reached with selpercatinib remaining inestimable (95% CI: NE, NE) and was 16.8 months (95% CI: 12.2, 25.1) with control (HR: 0.280, 95% CI: 0.165, 0.475; P<.0001); by investigator assessment the HR was 0.187 (95% CI: 0.109, 0.321; P<.0001). BICR overall response rate (ORR) was 69.4% (95% CI: 62.4, 75.8) with selpercatinib compared to 38.8% (95% CI: 29.1, 49.2) with control (odds ratio 3.7, 95% CI, 2.2, 6.3; P<0.0001). At a median follow-up of 15 months, overall survival (OS) was better with selpercatinib (HR: 0.374, 95% CI: 0.147, 0.949). The most common treatment-emergent adverse events observed with selpercatinib were hypertension, dry mouth, and diarrhea; and with control, diarrhea, palmar-plantar erythrodysaesthesia syndrome, and hypertension. In total, 38.9% of patients treated with selpercatinib had a dose reduction (versus 77.3% in control) and 4.7% discontinued treatment due to an adverse event (versus 26.8% in control). The study met the interim analysis criteria of efficacy. First-line selpercatinib delivered markedly prolonged PFS, improved ORR, and better OS compared with MKI. This study highlights the importance of selectivity in targeting RET-mutant MTC. Selpercatinib should be considered the preferred first-line standard of care for patients with advanced RET-mutant MTC.