Selpercatinib Shows Durable Responses in Pediatric Solid Tumors

Selpercatinib (Retevmo), a selective oral RET inhibitor, demonstrated durable antitumor activity and a manageable safety profile in pediatric and adolescent patients with RET-altered solid tumors, according to findings from the phase 1/2 LIBRETTO-121 study (NCT03899792) published in the Journal of Clinical Oncology.¹

As of November 8, 2024, the objective response rate (ORR) was 53% among 36 patients aged 2 to 20 years. The 24-month duration of response (DOR) rate was 100%.

The FDA granted traditional approval to selpercatinib in adult and pediatric patients with RET fusion–positive tumors, following accelerated approval in May 2024 for pediatric patients 2 years and older and in September 2022 for adult patients.² The pediatric indication was supported by findings from LIBRETTO-121.

LIBRETTO-121 Efficacy Findings

LIBRETTO-121 was a multicenter phase 1/2 trial evaluating selpercatinib in patients aged 0.5 to 21 years with advanced, RET-altered solid tumors. Earlier findings from LIBRETTO-121 showed encouraging antitumor activity with selpercatinib in pediatric patients with RET-altered cancers.

The primary end point of phase 2 was ORR, assessed by an independent review committee according to RECIST version 1.1.

Among the 36 patients, 15 had RET-altered medullary thyroid cancer (MTC), 15 had RET fusion–positive papillary thyroid cancer (PTC), and 6 had other tumor types.

The ORR was 60% (9 of 15; 95% CI, 32%-84%) in patients with MTC and 53% (n = 8/15; 95% CI, 27%-79%) in those with PTC. No progression events were reported among participants with PTC.

Responses varied by tumor type and RET alteration. Two of 3 patients with RET fusions in nonthyroid tumors responded, whereas none of 3 patients with RET point mutations in non-MTC tumors responded. The authors noted that the role of these mutations in driving the cancers remained unclear.¹

Safety and Clinical Implications

Selpercatinib was generally well tolerated. Common treatment-emergent adverse events included diarrhea, nausea, elevated aspartate aminotransferase and alanine aminotransferase, fever, abdominal pain, headache, cough, and vomiting. No patients discontinued treatment because of treatment-related adverse events, and no new adverse drug reactions were identified.

The authors highlighted epiphysiolysis, involving displacement at a growth plate, as an adolescent-specific adverse drug reaction requiring monitoring. Further follow-up is needed to understand potential long-term effects of kinase inhibitor treatment in pediatric patients.

The findings support measurable testing to identify actionable RET alterations in pediatric cancers. Although selpercatinib appeared to offer an alternative to multikinase inhibitors such as cabozantinib (Cabometyx) and vandetanib (Caprelsa), the authors cautioned that cross-trial comparisons are limited because earlier studies did not exclusively evaluate RET-driven cancers.

Study limitations included the small number of patients across multiple tumor types and uncertainty about the optimal treatment duration for pediatric patients who achieve complete responses. The appropriate dose for children younger than 2 years also remains

unconfirmed.¹

An ongoing trial (NCT06458036) is evaluating selpercatinib with radioactive iodine in patients with RET fusion–positive PTC.³

REFERENCES

1. Selpercatinib in pediatric and adolescent patients with RET-altered solid tumors: safety and efficacy results from the phase I/II LIBRETTO-121 study. J Clinical Oncology.0, JCO-25-03013. doi:10.1200/JCO-25-03013

2. FDA grants traditional approval to selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. News release. FDA. July 14, 2026. Accessed October 16, 2026. https://tinyurl.com/ym3hr6pj

3. Selpercatinib Pre-RAI in Patients With RET Fusion Thyroid Cancer (RAISE) (RAISE). ClinicalTrials.gov. Updated July 24, 2026. Accessed October 19, 2026. https://clinicaltrials.gov/study/NCT06458036