As presented at the European Society for Medical Oncology (ESMO) Congress 2023 (Abstract LBA3) and reported in The New England Journal of Medicine by Hadoux et al, an interim analysis from the phase III LIBRETTO-531 trial has shown improved progression-free survival with selpercatinib vs physician’s choice of cabozantinib or vandetanib as first-line treatment  in patients with advanced RET-mutant medullary thyroid cancer.

Study Details

In the open-label trial, 291 patients from sites in 19 countries were randomly assigned 2:1 between February 2020 and March 2023 to receive selpercatinib at 160 mg twice daily (n = 193) or physician’s choice (n = 98) of cabozantinib at 140 mg once daily (n =71) or vandetanib at 300 mg once daily (n = 27). Eligible patients had progressive disease documented within 14 months before enrollment. Crossover to selpercatinib was permitted after disease progression in patients in the control group. The primary endpoint was progression-free survival on blinded independent central review.

Progression-Free Survival

Median follow-up was 12.5 months (95% confidence interval [CI] = 11.1–13.8 months) in the selpercatinib group and 11.0 months (95% CI = 7.7–16.6 months) in the control group. Median progression-free survival was not reached (95% CI = not evaluable to not evaluable) in the selpercatinib group vs 16.8 months (95% CI = 12.2–25.1 months) in the control group (hazard ratio [HR] = 0.28, 95% CI = 0.16–0.48, P < .001). Rates at 12 and 24 months were 86.8% vs 65.7% and 76.4% vs 37.2%, respectively.

Median treatment failure–free survival on blinded independent central review was not reached in the selpercatinib group (95% CI = not evaluable to not evaluable) vs 13.9 months in the control group (HR = 0.25, 95% CI = 0.15–0.42, P < .001). Rates at 12 months were 86.2% vs 62.1%. Objective response was achieved in 69.4% of patients in the selpercatinib group, including complete response in 11.9%, and in 38.8% of the control group, including complete response in 4.1%.

A total of 24 patients in the control group crossed over to selpercatinib upon disease progression. At a median follow-up of approximately 15 months, 94.8% of patients remained alive in the selpercatinib group vs 85.7% in the control group (HR = 0.37, 95% CI = 0.15–0.95).

Adverse Events

Grade ≥ 3 adverse events occurred in 52.8% of the selpercatinib group vs 76.3% of the control group. The most common adverse events in the selpercatinib group were hypertension (18.7%), increased alanine aminotransferase (10.4%), increased aspartate aminotransferase (4.7%), and prolonged QT interval (4.7%); the most common in the control group were hypertension (17.5%), mucosal inflammation (13.4%), and palmar-plantar erythrodysesthesia syndrome (9.3%).

Adverse events led to treatment discontinuation in 4.7% of those in the selpercatinib group and to discontinuation of cabozantinib or vandetanib in 26.8% of patients. Adverse events led to death in four patients (2.1%) in the selpercatinib group (due to COVID-19 infection, diabetic ketoacidosis, multiple organ dysfunction, and sudden death) and two patients (2.1%) in the control group (due to cholangitis and hemorrhage); the sudden death in the selpercatinib group was the only death in the trial considered potentially related to treatment.

The investigators concluded, “Selpercatinib treatment resulted in superior progression-free survival and treatment failure–free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer.”

Lori J. Wirth, MD, of the Cancer Center at Massachusetts General Hospital, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Loxo Oncology, a subsidiary of Eli Lilly. For full disclosures of the study authors, visit nejm.org.