Pediatric Patients With RET-Altered Tumors Experience Tumor Responses With Selpercatinib


Evidence of preliminary activity was noted with the use of the RET inhibitor selpercatinib in pediatric patients with solid tumors harboring RET alterations.

Data from the ongoing phase 1/2 LIBRETTO-121 trial (NCT03899792) that were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated antitumor activity of selpercatinib (Retevmo) in pediatric patients with RET-altered solid tumors.1

Among 8 patients with measurable disease, the objective response rate (ORR) was 50% (95% CI, 16%-84%). Four patients had partial responses (PRs), 2 patients had stable disease (SD), 1 patient had progressive disease (PD), and 1 patient was not evaluable, translating to a clinical benefit rate of 75% (95% CI, 35%-97%).

“These data provide further evidence that selpercatinib is effective in pediatric patients with RET-mutant medullary thyroid cancer [MTC] and RET fusion–positive thyroid cancer. These patients should be universally screened for RET alterations,” lead study author Daniel A. Morgenstern, MBBChir, PhD, director of the New Agent and Innovative Therapy Program and Therapeutic MIBG Program, co-director of the Neuroblastoma Program in Haematology/Oncology at SickKids, and medical director of the Oncology and BMT/CT Clinical Trials Support Unit, said in a virtual presentation of the data.

RET fusions are the most common actionable alteration in children with papillary thyroid cancer (PTC), and the majority of children with MTC have germline RET mutations associated with MEN2 syndrome.

Selpercatinib is a highly selective and potent RET inhibitor with central nervous system (CNS) activity that is approved for the treatment of adult patients with metastatic RET fusion–positive non–small cell lung cancer, adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant MTC who require systemic therapy, and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory.2

The favorable efficacy and safety profile of the agent in adult patients set the stage for its evaluation in a pediatric population.

To that end, investigators conducted a multicenter, phase 1/2 study of selpercatinib in pediatric patients at least 6 months of age to 21 years of age with advanced, RET-altered solid or CNS tumors. Patients in the European Union and Canada had to have been at least 12 years of age to have been eligible for enrollment.

In the phase 1 dose-escalation/confirmation portion of the study, patients received a starting dose of 92 mg/m2 of selpercatinib twice daily, which is equivalent to the recommended adult dose of 160 mg twice daily.

The phase 2 expansion portion of the study consisted of 4 cohorts, which enrolled patients with RET fusion–positive solid tumors with measurable disease (cohort 1), RET-mutant MTC with measurable disease (cohort 2), RET fusion–positive CNS tumors with measurable disease (cohort 3), and patients ineligible for cohorts 1 through 3 with a RET alteration (cohort 4).

The maximum tolerated dose/recommended phase 2 dose (RP2D) and ORR served as the primary end points of the phase 1 and phase 2 portions of the study, respectively. The RP2D was confirmed separately for patients under the age of 2 and 2 years of age and older.

As of the data cutoff on March 30, 2021, 12 patients had been enrolled. Patients were a median age of 14 years (range, 2-20). Six male and 6 female patients were each enrolled. The majority of patients (n = 9) had metastatic disease at study entry, prior treatment—surgery (n = 9), radiotherapy (n = 4), and systemic therapy (n = 3)—and a Karnofsky/Lansky performance status of 100 (n = 7). Three patients with locally advanced disease were also enrolled.

The majority of patients had a diagnosis of MTC (n = 8), followed by PTC (n = 2), rhabdomyosarcoma (n = 1), and osteosarcoma (n = 1). Both of the sarcoma cases had a variant of unknown significance in RET.

The response data indicated that the 1 patient with osteosarcoma had PD, but all the other patients with thyroid cancers and RET aberrations had SD or PR.

RET alterations in pediatric cancers beyond MTC and thyroid cancer are rare, and as expected, no responses were observed for RET variants of unknown significance,” said Morgenstern.

Additional results demonstrated that the median progression-free survival was not reached at a median follow-up of 8 months from the first dose of selpercatinib. The median duration of response was not reached at a median follow-up of 5 months from the initial response, and all 4 PRs are ongoing.

“The important message is that, of the patients on study, the vast majority––9 of the 12––remain on therapy,” said Morgenstern.

Notably, all 8 patients with MTC experienced biochemical response by way of a reduction in calcitonin and variable reductions in carcinoembryonic antigen, regardless of their radiologic response.

Regarding safety, no dose-limiting toxicities were reported at the starting dose of selpercatinib, which became the RP2D. In the expansion cohorts, 1 patient discontinued treatment because of PD, 1 because of patient non-compliance, and 1 because of treatment-unrelated adverse effects (AEs).

“Overall, this drug was very well tolerated with minimal toxicity, consistent with the adult experience. The most common AEs were diarrhea, hyperphosphatemia, nausea, and abnormal liver enzymes,” said Morganstern.

An analysis demonstrated comparable results with the pharmacokinetics of selpercatinib exposures at day 8 from the first 3 patients enrolled onto the study vs those from the LIBRETTO-001 trial (n = 222) and a pediatric compassionate use program (n = 4).

“Although the data points for the pediatric patients are rather sparse, the important message here is that overall exposures in the pediatric population are broadly similar to that in adults, supporting use of this dose going forward in the expansion cohorts,” concluded Morgenstern.


1. Morgenstern D, Mascarenhas L, Campbell M, et al. Oral selpercatinib in pediatric patients with advanced RET-altered solid or primary CNS tumors: preliminary results from the phase 1/2 LIBRETTO-121 trial. J Clin Oncol. 2021;39(suppl 15):10009. doi:10.1200/JCO.2021.39.15_suppl.10009

2. Retevmo prescribing information. FDA. Revised May 2020. Accessed June 6, 2021.

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