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.

TRK fusions, involving the genes NTRK1, NTRK2, and NTRK3, occur in a broad range of malignancies, including TC and SGC. Larotrectinib is the first selective pan-TRK inhibitor in development, and has demonstrated an overall response rate (ORR) across various TRK-fusion solid tumors of 76% by investigator assessment (Hyman et al, JCO 2017) and an ORR of 75% by independent radiology review. Here we summarize the activity and safety of larotrectinib in advanced TRK-fusion TC and SGC. 19 patients (age 15-75 years) with TRK-fusion TC (n = 7) or SGC (n = 12) were treated with oral larotrectinib (4 in the adult phase 1 study, 2 in the SCOUT global pediatric phase 1/2 study, and 15 in the NAVIGATE global phase 2 study). TRK fusions were identified by local testing. 16 patients received the dose equivalent of 100mg BID on a continuous 28d schedule; 1 patient each was treated with 150 mg BID, 100 mg QD, or 75 mg QD. 17 patients had measurable disease (5 TC and 12 SGC); efficacy was assessed by investigator (INV) and independent review (IRC) using RECIST v1.1. TC histologies included 6 differentiated (follicular and papillary), and 1 anaplastic. SGC histologies included 6 acinar/mammary analogue secretory carcinoma (MASC), 1 adenoid cystic, 1 adenocarcinoma, 1 mucoepidermoid, 1 sarcomatoid, and 2 NOS. In the 19 patients treated, 4 different fusion constructs were identified with 84% being ETV6-NTRK3 positive. Patients had received a median of 3 prior lines of therapy, including surgery (19), external beam radiation (14), I-131 (4), chemotherapy (8) and tyrosine kinase inhibitors (3). For the 17 patients with measurable disease, larotrectinib treatment resulted in an ORR of 88% by both INV and IRC (3CRs, 12PR, 2PD). ORR for TC was 100% (5/5PR) and ORR for SGC was 83 % (3CR/7PR) by both INV and IRC. Responses occurred within the first 2 months in 87% of patients. At the time of data cut off, treatment is ongoing in 89% of patients, with median follow-up of 10 months. Only 4 patients experienced a grade ≥3 treatment related AE. TRK inhibition with larotrectinib yields durable high response rates, including CRs, in adolescents and adults with recurrent TRK fusion TC and SGC, regardless of histology. Prolonged larotrectinib therapy is associated with minimal toxicity. Genomic profiling with assays capable of identifying TRK fusions should be strongly considered in patients with recurrent TC and SGC when determining systemic treatment options.