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Ref Type Journal Article
PMID (37012551)
Authors Goldsmith KC, Park JR, Kayser K, Malvar J, Chi YY, Groshen SG, Villablanca JG, Krytska K, Lai LM, Acharya PT, Goodarzian F, Pawel B, Shimada H, Ghazarian S, States L, Marshall L, Chesler L, Granger M, Desai AV, Mody R, Morgenstern DA, Shusterman S, Macy ME, Pinto N, Schleiermacher G, Vo K, Thurm HC, Chen J, Liyanage M, Peltz G, Matthay KK, Berko ER, Maris JM, Marachelian A, Mossé YP
Title Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.
Journal Vol Issue Date Pages Journal Short Title
Nature medicine 2023 Apr 03 1092-1102 Nat Med
URL
Abstract Text Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .

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