Efficacy of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is frequently driven by alterations in RET. The multi-kinase inhibitors (MKIs) vandetanib and cabozantinib — the current standard-of-care for advanced MTC — were approved over a decade ago based on a progression-free survival (PFS) benefit over placebo in phase 3 randomized clinical trials. Recently, the highly selective RET inhibitors selpercatinib and pralsetinib were approved for advanced RET-mutant MTC based on encouraging activity in phase 1–2 trials, with overall response rates of 60% to 70% in RET-mutant MTCs (N Engl J Med 2020; 383:825; Lancet Diabetes Endocrinol 2021; 9:491).

In this industry-funded, phase 3, randomized, controlled trial, researchers compared the efficacy of selpercatinib to physician's choice of MKI in treatment-naive patients with advanced RET-mutant MTC who had disease progression within 14 months before enrollment. A total of 291 patients were randomized 2:1 to selpercatinib (160 mg twice daily; n=193) or either cabozantinib (140 mg daily; n=73) or vandetanib (300 mg daily; n=25).

At a median follow-up of 12 months, median PFS assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months in the control group (hazard ratio, 0.28; 95% CI, 0.16–0.48; P<0.001). A significant PFS benefit was observed with selpercatinib regardless of age, sex, or RET mutation (M918T versus others). The overall response rate was 69.4% in the selpercatinib group compared with 38.8% in the control group. The selpercatinib group had lower incidence of adverse events leading to dose reduction (38.9% vs. 77.3%) and treatment discontinuation (4.7% vs. 26.8%).