Selpercatinib improves outcomes in RET-mutant medullary thyroid cancer
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Key takeaways:
- Selpercatinib prolonged PFS and treatment failure-free survival compared with two approved therapies.
- A higher percentage of patients assigned to the control arm discontinued treatment due to adverse events.
MADRID — Selpercatinib improved outcomes compared with cabozantinib or vandetanib for treatment of RET-mutant medullary thyroid cancer, according to randomized phase 3 study results presented at ESMO Congress.
Patients assigned selpercatinib (Retevmo, Eli Lilly & Co.) achieved longer PFS and treatment failure-free survival.
“The results support selpercatinib as the first-line standard of care for patients with advanced RET-mutant medullary thyroid cancer,” Julien Hadoux, MD, PhD, medical oncologist at Gustave Roussy in France, said during a presentation. “The results also highlight the importance of RET selectivity and timely implementation of biomarker testing for patients with metastatic medullary thyroid cancer.”
Selpercatinib — a kinase inhibitor — received FDA approval last year for treatment of adults with locally advanced or metastatic RET fusion-positive non-small cell lung cancer as detected by an FDA-approved test.
RET mutations occur in approximately 25% to 50% of sporadic medullary thyroid cancers and more than 90% of hereditary medullary thyroid cancers.
Selpercatinib exhibited efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1/phase 2 trial; however, the agent’s effectiveness in comparison with other FDA-approved multikinase inhibitors has not been established, according to study background.
Hadoux and colleagues conducted the LIBRETTO-531 trial to compare first-line selpercatinib with physician’s choice of cabozantinib (Cabometyx, Exelixis) or vandetanib (Caprelsa, Sanofi) to define the optimal first-line regimen for this population. Cabozantinib and vandetanib are approved first-line options for this patient population.
The analysis included 291 patients, all of whom had progressive disease documented within 14 months prior to enrollment. Researchers randomly assigned them 2:1 to selpercatinib or one of the approved agents.
Patients assigned cabozantinib or vandetanib who developed disease progression could cross over to selpercatinib.
PFS per blinded independent central review served as the primary endpoint. Treatment failure-free survival — defined as time from randomization to first occurrence of progressive disease, discontinuation due to treatment-related adverse event or death — assessed by blinded independent central review, overall response and safety served as secondary endpoints.
After median follow-up of 12 months, results showed improved median PFS in the selpercatinib group (not reached vs. 16.8 months; HR = 0.28; 95% CI, 0.16-0.48). The PFS benefit appeared consistent across all subgroups, Hadoux said.
A higher percentage of patients assigned selpercatinib remained progression free at 12 months (86.8% vs. 65.7%).
Other efficacy outcomes also favored selpercatinib, including median treatment failure-free survival (not reached vs. 13.9 months; HR = 0.25; 95% CI, 0.15-0.42), 12-month treatment failure-free survival (86.2% vs. 62.1%) and overall response rate (69.4% vs. 38.8%).
OS data remained immature; however, at the time of interim analysis, results favored selpercatinib (HR = 0.37; 95% CI, 0.14-0.94).
A higher percentage of patients assigned cabozantinib or vandetanib required either dose reduction (79.2% vs. 38.9%) or treatment discontinuation (26.8% vs. 4.7%) due to adverse events.
Perspective
Back to TopLaura D. Locati, MD
Vandetanib and cabozantinib were designed to tackle several tyrosine kinase receptors, including RET and VEGFR. Toxicity — particularly the off-target effects — are one of the main concerns for the use of these agents in clinical practice due to the high rate of dose reduction and treatment interruption.
Selpercatinib is the new standard for RET-positive, progressive medullary thyroid cancer. The agent significantly reduced the risk for disease progression by 72% compared with multi-tyrosine kinase inhibitors, and it is associated with remarkable overall and complete response rates. OS data are still immature but already suggest a beneficial effect, though longer follow-up is needed. The toxicity profiles also favored selpercatinib.
One of the main criticisms for use of multi-tyrosine kinase inhibitors in thyroid cancer is a lack of positive data on OS. In this study, we have some positive signals from selpercatinib, but we need longer follow-up to see any difference in the OS curves.
Multi-tyrosine kinase inhibitors are a treatment option for patients with medullary thyroid cancer beyond selpercatinib, but the activity of these agents in that setting remains an open issue.
A somatic RET test is mandatory for all patients with advanced or metastatic medullary thyroid cancer, and it is very important to increase awareness about this test among patients and physicians.
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Hadoux J, et al. Abstract LBA3. Presented at: European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid.
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