Oral selpercatinib in pediatric patients (pts) with advanced RET-altered solid or primary CNS tumors: Preliminary results from the phase 1/2 LIBRETTO-121 trial.
Authors: Morgenstern Daniel A. , Mascarenhas Leo , Campbell Martin , Ziegler David S. , Nysom Karsten , Casanova Michela , Pappo Alberto S. , Albert Catherine Michelle , Xia Meng , Barker Scott S. , Wright Jennifer , Laetsch Theodore Willis 
Published: June 2021

10009 Background: Activating RET alterations are oncogenic drivers of select pediatric and adult cancers. Selpercatinib is a first-in-class, highly selective and potent, CNS active RET kinase inhibitor. The manageable toxicity profile and durable anti-tumor activity in RET-altered cancers demonstrated in the LIBRETTO-001 phase 1/2 trial led to global approvals of selpercatinib in adults and adolescents with thyroid cancer and adults with NSCLC. Methods: LIBRETTO-121 (JZJJ) is a multicenter phase 1/2 trial in pts 0.5-21 years (yrs) of age with advanced, RET-altered solid or CNS tumors. Enrollment began in June 2019 and is ongoing. Selpercatinib is administered orally as capsule or liquid suspension BID continuously. Dosing started at the adult recommended phase 2 dose (RP2D) equivalent, 92mg/m2 BID, to confirm RP2D in pts ≤2 yrs and > 2 yrs. The phase 1 primary objective is to evaluate safety and dose limiting toxicities (DLTs). The phase 2 primary objective is to determine overall response rate by RECIST 1.1 or RANO by independent review. Results: As of 2-Oct-2020, 11 pts (6 male) aged 2–20 yrs (medullary thyroid cancer, n = 8; papillary thyroid cancer, n = 2; osteosarcoma, n = 1) had been treated (phase 1, n = 4; phase 2, n = 7). At baseline, 7 pts had measurable disease. RET alterations included fusions (n = 2), activating mutations (n = 8) and mutation with unknown clinical significance (n = 1). Prior therapies included surgery (n = 8), chemotherapy (n = 1), vandetanib (n = 1) and radiotherapy (n = 3), while 3 pts were previously untreated. Time on selpercatinib ranged from 0.9-13.4 months and 9 pts remain on treatment. One pt experienced a dose reduction and 2 pts experienced dose interruptions due to treatment-emergent adverse events (TEAEs) (elevated alanine aminotransferase [ALT] and bilirubin). There were no DLTs and no TEAEs that led to discontinuation of selpercatinib. TEAEs in > 15% of pts included elevated alkaline phosphatase (ALP), constipation, headache, elevated aspartate aminotransferase (AST), diarrhea, hyperphosphatemia, hypoalbuminemia, hypothyroidism, nausea, pyrexia, urinary tract infection, vomiting and weight gain. Drug-related TEAEs in > 15% of pts included elevated AST, elevated ALP, hyperphosphatemia and hypothyroidism. One pt reported TEAEs ≥ grade (G) 3 (elevated ALT, G3 and AST, G3) related to selpercatinib. Best response was unconfirmed partial responses in 4 pts, stable disease in 6 pts (two lasting ≥16 weeks) and progressive disease in 1 pt. Conclusions: These findings appear consistent with the adult trial results, showing preliminary evidence of safety and efficacy of selpercatinib in pediatric pts with RET-altered solid tumors. The phase 1 portion in pts ≤2 yrs and phase 2 portion at RP2D of 92mg/m2 BID for pts > 2 yrs are ongoing. Clinical trial information: NCT03899792.