TOPLINE:

Selpercatinib, a first-in-class, potent RET kinase inhibitor with central nervous system activity, shows sustained, significant improvements in progression-free survival (PFS) and overall survival (OS) in the frontline treatment of patients with RET fusion systemic treatment-naive thyroid cancer in the 5-year final analysis of the LIBRETTO-001 trial.

The drug’s safety remained tolerable, despite the longer-term duration of treatment.

METHODOLOGY:

• In the phase 1-2 LIBRETTO-001 trial, 24 patients with RET fusion systemic treatment-naive thyroid cancer, after radioactive iodine (where appropriate), were treated in a phase 1 dose escalation trial of oral selpercatinib, ranging from 20 gm once daily to 240 mg twice daily.
• During the phase 2 dose expansion, patients received selpercatinib orally 160 mg twice daily. The median age was 60.5 years, and 58.3% were men. The Eastern Cooperative Oncology Group performance status score was 0 in 58% of patients, 1 in 37% of patients, and 2 in 4% of patients.
• The primary endpoint was an objective response rate (ORR) by RECIST 1.1, with secondary endpoints including duration of response (DoR), PFS, and safety.

TAKEAWAY:

• For the primary endpoint, the ORR was 95.8% based on an independent review committee, with 20.8% having a complete response, 75% having a partial response, 4.2% having stable disease, and 0 having progressive disease.
• The 5-year estimated DoR was 63.5%, with a median follow-up of 54.8 months.
• The 5-year estimated PFS was 70.7% with a median follow-up of 58.6 months.
• The 5-year estimated OS was 75.7%.
• No new safety signals were identified compared with prior analyses of the trial.
• While 10 patients required dose modifications, there were no patient discontinuations due to treatment-emergent adverse events.

IN PRACTICE:

“With longer follow-up, selpercatinib continues to demonstrate durable responses and strong 5-year rates of PFS and OS in patients with treatment-naive RET fusion-positive thyroid cancer, further highlighting selpercatinib as the standard of care for the first-line treatment in this population,” said the first author of the study while presenting the findings.

“These results support early and comprehensive genomic testing and use of selpercatinib as first-line therapy in patients with RET-driven cancers,” she said.

SOURCE:

The study was led by Lori Wirth, MD, of Massachusetts General Hospital in Boston. The results were presented at the American Thyroid Association (ATA) 2025 Meeting in Scottsdale, Arizona.

LIMITATIONS:

Wirth noted that data are not available regarding drug holidays in patients who do have complete responses; however, “because patients generally tolerate selpercatinib so well, there isn’t really a need to consider stopping therapy,” she said.

DISCLOSURES:

The study was funded by Loxo Oncology, a subsidiary of Eli Lilly and Company. Wirth did not have any disclosures listed in the abstract.