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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%).
This practice-changing study confirms a PFS benefit of selpercatinib over the previous standard of care (cabozantinib or vandetanib) in treatment-naive patients with advanced RET-mutant MTC. Of note, selpercatinib demonstrated a more favorable toxicity profile, with fewer dose-reductions and discontinuations. For advanced MTCs without RET mutations, MKIs remain the standard of care, although the relative benefit of cabozantinib versus vandetanib is not clear from subgroup analyses of pivotal phase 3 trials.
Hadoux J et al.
Title: Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer.
Source: N Engl J Med 2023 Oct 21; [e-pub]. (Abstract/FREE Full Text)