On May 29, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the RET inhibitor selpercatinib (Retevmo) for pediatric patients aged 2 years and older with the following:
- Advanced or metastatic medullary thyroid cancer with a RET mutation, as detected by an FDA-approved test, who require systemic therapy
- Advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine–refractory (if treatment with radioactive iodine is appropriate)
- Locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, whose disease has progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.
This is the first FDA approval of a targeted therapy for pediatric patients under 12 years old with RET alterations. Selpercatinib was previously granted accelerated approval for the thyroid cancer indications in adults and pediatric patients aged 12 years and older. It was also previously granted accelerated approval for the solid tumor indication in adults.
LIBRETTO-121
The efficacy of selpercatinib in pediatric and young adult patients was evaluated in LIBRETTO-121 (ClinicalTrials.gov identifier NCT03899792), an international, single-arm, multicohort trial. Patients received selpercatinib at 92 mg/m2 orally twice daily until disease progression, unacceptable toxicity, or other reason for treatment discontinuation. The primary efficacy population included 25 patients aged 2 to 20 years with locally advanced or metastatic RET-activated solid tumors that were nonresponsive to available therapies or with no standard systemic curative therapy available.
The major efficacy outcome measures of LIBRETTO-121 were confirmed overall response rate and duration of response. The confirmed overall response rate (per Response Evaluation Criteria in Solid Tumors version 1.1), as determined by blinded independent review committee, was 48% (95% confidence interval [CI] = 28%–69%). The median duration of response was not reached (95% CI = not evaluable to not evaluable), with 92% of responders remaining in response at 12 months. Durable responses were observed in pediatric and young adult patients with RET-mutant medullary thyroid cancer (n = 14; overall response rate = 43%, 95% CI = 18%–71%) and RET fusion–positive thyroid cancer (n = 10; overall response rate = 60%, 95% CI = 26%–88%).
The most common adverse reactions (occurring in ≥ 25% of patients who received selpercatinib) were musculoskeletal pain, diarrhea, headache, nausea, vomiting, SARS–CoV-2 infection, abdominal pain, fatigue, pyrexia, and hemorrhage. The most common grade 3 or 4 laboratory abnormalities (occurring in ≥ 5% of patients) were decreased calcium, decreased hemoglobin, and decreased neutrophils.
The recommended selpercatinib dose for pediatric patients aged 2 to less than 12 years old is based on body surface area. It is based on weight for patients aged 12 years or older. See the prescribing information for specific dosing information.
LIBRETTO-121 was conducted as part of a pediatric Written Request under the Best Pharmaceuticals for Children Act. This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The application was granted Priority Review and Orphan Drug designation.
