The U.S. Food and Drug Administration (FDA) has granted traditional approval to selpercatinib (Retevmo) for the treatment of adult and pediatric patients, aged 2 years and older, with advanced or metastatic medullary thyroid cancer (MTC) harboring a RET mutation. This approval marks a significant advancement in the treatment landscape for this patient population, providing a more effective and tolerable option compared to existing therapies.
The decision was primarily based on the results of the Phase 3 LIBRETTO-531 trial (NCT04211337), a randomized, multicenter, open-label study that compared selpercatinib to physician's choice of cabozantinib or vandetanib in patients with advanced RET-mutant MTC who had not previously been treated with kinase inhibitors. The trial enrolled 291 patients, randomizing them in a 2:1 ratio to receive either selpercatinib (160 mg twice daily) or cabozantinib (140 mg once daily) or vandetanib (300 mg once daily).
Superior Progression-Free Survival
The primary endpoint of the LIBRETTO-531 trial was progression-free survival (PFS), as determined by a blinded independent central review committee. Results demonstrated a significant improvement in PFS for patients treated with selpercatinib. Median PFS was not reached in the selpercatinib arm, while it was 16.8 months (95% CI: 12.2, 25.1) in the cabozantinib/vandetanib arm (HR, 0.280; 95% CI: 0.165, 0.475; p < 0.0001). This represents a 72% reduction in the risk of disease progression or death.
Improved Tolerability
In addition to superior efficacy, selpercatinib demonstrated a more favorable safety profile compared to cabozantinib and vandetanib. Patients in the selpercatinib arm reported less time with severe side effect bother than those receiving cabozantinib or vandetanib. The most common adverse reactions (≥25%) in patients treated with selpercatinib were hypertension, edema, dry mouth, fatigue, and diarrhea. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), decreased neutrophils, increased alkaline phosphatase (ALP), increased blood creatinine, decreased calcium, and increased aspartate aminotransferase (AST).
Implications for Clinical Practice
"These data from the LIBRETTO-531 trial confirm the importance of selectively targeting RET-driven cancers and suggest selpercatinib should be considered the preferred first-line treatment for people with advanced RET-mutant medullary thyroid cancer," said David Hyman, MD, chief medical officer at Loxo Oncology at Eli Lilly and Company.
The FDA noted that the recommended dose of selpercatinib for pediatric patients ranging in age from 2 to less than 12 years should be based on body surface area; however, for those aged 12 or older, the dose is based on weight. Selpercatinib is also approved to treat adults with locally advanced or metastatic non-small cell lung cancer with a RET gene fusion, as detected by an FDA-approved test; adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and have disease that is refractory to radioactive iodine (if radioactive iodine is appropriate); and adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, whose disease has progressed on or after systemic treatment or who have no satisfactory alternative treatment options.
