FDA Approves Selpercatinib for RET Fusion–Positive Medullary Thyroid Cancer

FDA

The FDA has granted traditional approval to selpercatinib (Retevmo) for adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.¹

In May 2020, the regulatory agency granted accelerated approval to selpercatinib for several indications, including adult and pediatric patients aged 12 years of age or older with advanced or metastatic RET-positive medullary thyroid cancer who require systemic treatment.² In May 2024, the agent was awarded another accelerated approval for use in pediatric patients aged 2 years of age and older with advanced or metastatic medullary thyroid cancer harboring a RET mutation who require systemic treatment, advanced or metastatic thyroid cancer harboring a RET gene fusion who need systemic therapy, and who are refractory to radioactive iodine, and select patients with locally advanced or metastatic solid tumors and a RET gene fusion.³

Today's decision was supported by data from the phase 3 LIBRETTO-531 trial (NCT04211337), which showed that the agent (n = 193) improved progression-free survival (PFS) vs physician's choice of cabozantinib (Cabometyx) or vandetanib (Caprelsa; n = 98; HR, 0.280; 95% CI, 0.165-0.475; P < .0001).

The median PFS with selpercatinib was not reached (NR; 95% CI, not evaluable [NE]-NE) compared with 16.8 months (95% CI, 12.2-25.1) with cabozantinib or vandetanib, translating to a 72% reduction in the risk of disease progression or death.⁴ The 12-month PFS rate by blinded independent central review (BICR) with selpercatinib was 86.8% (95% CI, 79.8%-91.6%) vs 65.7% (95% CI, 51.9%-76.4%) with a control agent.

Looking at LIBRETTO-531: Eligibility, Treatment, Objectives

The study enrolled patients with pathologically confirmed, unresectable, locally advanced or metastatic medullary thyroid cancer who had no prior exposure to kinase inhibitors. They needed to be at least 12 years old, had radiologic progressive disease by RECIST 1.1 criteria, and a prospectively identified pathogenic RET alteration. They were also required to have an ECOG performance status ranging from 0 to 2, acceptable organ function, and normal electrolyte levels.

Study participants were randomly assigned 2:1 to receive 160 mg of selpercatinib twice daily, or physician's choice of cabozantinib once daily at 140 mg or vandetanib at 300 mg once daily. They were stratified based on RET mutation (M918T vs other) and intended treatment in the control arm (cabozantinb vs vandetanib). They received treatment until progressive disease, intolerable toxicity, withdrawn consent, or death.

PFS by RECIST 1.1 criteria and BICR served as the trial's primary end point. Secondary end points included treatment failure-free survival (TFFS) by BICR and investigator, investigator-assessed PFS, overall survival (OS) by BICR and investigator assessment, and safety.

Additional Efficacy Findings

The investigator-assessed PFS in the respective arms was NR and 13.9 months (95% CI, 11.1-22.1), respectively (HR, 0.19; 95% CI, 0.11-0.32); respective investigator-assessed PFS rates at 12 months were 91.3% (95% CI, 85.4%-94.9%) and 56.9% (95% CI, 43.7%-68.1%).

The median TFFS with selpercatinib was NR vs 13.9 months (95% CI, 11.3-25.1) with a control agent (HR, 0.25; 95% CI, 0.15-0.42; P < .001). The 12-month TFFS rates in the respective arms were 86.2% (95% CI, 79.1%-91.0%) and 62.1% (95% CI, 48.9%-72.8%).

Overall response rates in the selpercatinib and control arms were 69.4% (95% CI, 62.4%-75.8%) and 38.8% (95% CI, 29.1%-49.2%), respectively. At an approximate median follow-up of 15 months, 18 deaths had occurred; 94.8% and 85.7% of those in the investigative and control arms, respectively, were alive (HR, 0.37; 95% CI, 0.15-0.95). Estimated 18-month OS rates in the respective arms were 95.5% (95% CI, 90.1%-98.0%) and 92.8% (95% CI, 83.0%-97.1%).

A Spotlight on Safety

The most common toxicities observed in at least 25% of patients included hypertension, edema, dry mouth, fatigue, and diarrhea.¹ The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased alanine aminotransferase, decreased neutrophils, increased alkaline phosphatase, increased blood creatinine, decreased calcium, and increased aspartate aminotransferase.

References

1. FDA approves selpercatinib for RET fusion-positive medullary thyroid cancer. FDA. September 27, 2024. Accessed September 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-ret-fusion-positive-medullary-thyroid-cancer
2. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. May 8, 2020. Accessed September 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions
3. FDA grants accelerated approval to selpercatinib for pediatric patients two years and older with RET-altered metastatic thyroid cancer or solid tumors. FDA. May 29, 2024. Accessed September 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selpercatinib-pediatric-patients-two-years-and-older-ret-altered
4. Hadoux J, Elisei R, Brose MS, et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389(20):1851-1861. doi:10.1056/NEJMoa2309719