Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.
Date
2023-05-01ICR Author
Author
Goldsmith, KC
Park, JR
Kayser, K
Malvar, J
Chi, Y-Y
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
Type
Journal Article
Metadata
Show full item recordAbstract
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 .
Collections
Subject
Adult
Humans
3-Iodobenzylguanidine
Aminopyridines
Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung
Lactams, Macrocyclic
Lung Neoplasms
Neoplasm Recurrence, Local
Neuroblastoma
Protein Kinase Inhibitors
Child
Infant
Child, Preschool
Adolescent
Research team
Paediatric Tumour Biology
Language
eng
Date accepted
2023-03-09
License start date
2023-05-01
Citation
Nature Medicine, 2023, 29 (5), pp. 1092 - 1102
Publisher
NATURE PORTFOLIO