Safety and efficacy of selpercatinib in pediatric patients with RET-altered solid tumors: Updated results from LIBRETTO-121.
Authors: Morgenstern Daniel A. , Casanova Michela , van Tilburg Cornelis Martinus , Ziegler David Simon , Campbell Martin , Watt Tanya Carens , Pappo Alberto S. , Laetsch Theodore Willis , Liu Dan , Liming Katherine , Kang Suhyun , Wright Jennifer , Kang Hyoung Jin 
Published: June 2024

10022 Background: Selpercatinib is a highly selective and potent CNS-penetrant oral RET inhibitor, approved for treatment of RET-driven thyroid cancer in adult and adolescent patients (pts), and lung or other solid tumors in adult pts. Here we present updated results from LIBRETTO-121, the first trial to assess the safety and efficacy of a selective RET inhibitor in pediatric and adolescent pts with RET-altered solid tumors. Methods: LIBRETTO-121 (NCT03899792) is a multicenter phase 1/2 trial in pts 0.5-21 yrs of age with advanced, RET-altered solid tumors. Enrollment began in June 2019 and is ongoing. To confirm the recommended phase 2 dose for selpercatinib, dosing started at 92 mg/m2 BID, expecting to result in equivalent exposure to 160 mg BID in adults.The primary objectives were to evaluate safety and dose limiting toxicities (DLTs) in phase 1 and determine the ORR per RECIST 1.1 by independent review in the phase 2 population. Results: At the data cut-off (January 13, 2023), 27 pts aged 2-20 yrs were treated with selpercatinib. Tumor types included RET-mutant medullary thyroid cancer (MTC, n = 14), RET fusion-positive papillary thyroid cancer (PTC, n = 10), or other (n = 3). The most common RET alterations were a M918T mutation (71.4% [10/14] of MTC pts) or NCOA4-RET fusion (50% [5/10] of PTC pts). Pediatric and adolescent patients treated at 92 mg/m2 (up to 160 mg BID) had a similar exposure as adults treated with 160 mg BID at steady state on cycle 1 day 8. Time on selpercatinib ranged from 0.4 to 40.8 mo and 22 pts remain on treatment. There were no treatment discontinuations due to DLTs or TEAEs; 2 pts (7.4%) experienced a dose reduction due to TEAEs (elevated ALT and reduced neutrophil count). The most common TEAEs observed (≥25% of pts) were diarrhea, headache, coronavirus infection, nausea, vomiting, elevated ALT, elevated AST and pyrexia. The most common TEAEs ≥ G3 included constipation, reduced neutrophil count, vomiting and weight gain, each occurring in 2 pts (7.4%). One pt (age 15 yrs) experienced a TEAE ≥ G3 of epiphysiolysis, a risk for selpercatinib in this population based on pre-clinical data. In pts with RECIST measurable disease at baseline, the ORR was 83.3% (10/12), while 1 pt had stable disease (SD) and 1 pt had progressive disease (PD). Among pts with measurable disease at baseline, PTC pts had an ORR of 100% (5/5), and MTC pts had an ORR of 83.3% (5/6), while 1 MTC pt had SD. No PTC or MTC pts had PD. Responses were durable, with a 24 mo DOR rate of 100% (95% CI: NE, NE). With a median follow up of 18 mo, the mPFS among all pts has not yet been reached, and the 24 mo rate of PFS was 92.4% (95% CI: 73.0% - 98.1%). Conclusions: Selpercatinib’s safety profile remains consistent with prior reports from adult trials. These results, including more robust efficacy and PK data, continue to support the use of selpercatinib in pediatric and adolescent pts with RET-altered solid tumors. Clinical trial information: NCT03899792 .