dc.contributor.author | Goldsmith, KC | |
dc.contributor.author | Park, JR | |
dc.contributor.author | Kayser, K | |
dc.contributor.author | Malvar, J | |
dc.contributor.author | Chi, Y-Y | |
dc.contributor.author | Groshen, SG | |
dc.contributor.author | Villablanca, JG | |
dc.contributor.author | Krytska, K | |
dc.contributor.author | Lai, LM | |
dc.contributor.author | Acharya, PT | |
dc.contributor.author | Goodarzian, F | |
dc.contributor.author | Pawel, B | |
dc.contributor.author | Shimada, H | |
dc.contributor.author | Ghazarian, S | |
dc.contributor.author | States, L | |
dc.contributor.author | Marshall, L | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Granger, M | |
dc.contributor.author | Desai, AV | |
dc.contributor.author | Mody, R | |
dc.contributor.author | Morgenstern, DA | |
dc.contributor.author | Shusterman, S | |
dc.contributor.author | Macy, ME | |
dc.contributor.author | Pinto, N | |
dc.contributor.author | Schleiermacher, G | |
dc.contributor.author | Vo, K | |
dc.contributor.author | Thurm, HC | |
dc.contributor.author | Chen, J | |
dc.contributor.author | Liyanage, M | |
dc.contributor.author | Peltz, G | |
dc.contributor.author | Matthay, KK | |
dc.contributor.author | Berko, ER | |
dc.contributor.author | Maris, JM | |
dc.contributor.author | Marachelian, A | |
dc.contributor.author | Mossé, YP | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-06-23T13:12:34Z | |
dc.date.available | 2023-06-23T13:12:34Z | |
dc.date.issued | 2023-05-01 | |
dc.identifier | 10.1038/s41591-023-02297-5 | |
dc.identifier.citation | Nature Medicine, 2023, 29 (5), pp. 1092 - 1102 | |
dc.identifier.issn | 1078-8956 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5855 | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.doi | 10.1038/s41591-023-02297-5 | |
dc.description.abstract | 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 . | |
dc.format | Print-Electronic | |
dc.format.extent | 1092 - 1102 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.ispartof | Nature Medicine | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Adult | |
dc.subject | Humans | |
dc.subject | 3-Iodobenzylguanidine | |
dc.subject | Aminopyridines | |
dc.subject | Anaplastic Lymphoma Kinase | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Lactams, Macrocyclic | |
dc.subject | Lung Neoplasms | |
dc.subject | Neoplasm Recurrence, Local | |
dc.subject | Neuroblastoma | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Child | |
dc.subject | Infant | |
dc.subject | Child, Preschool | |
dc.subject | Adolescent | |
dc.title | Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-03-09 | |
dc.date.updated | 2023-06-23T13:12:02Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41591-023-02297-5 | |
rioxxterms.licenseref.startdate | 2023-05-01 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37012551 | |
pubs.issue | 5 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41591-023-02297-5 | |
pubs.volume | 29 | |
icr.researchteam | Paediatric Tumour Biology | |
dc.contributor.icrauthor | Chesler, Louis | |
icr.provenance | Deposited by Mr Arek Surman (impersonating Prof Kevin Harrington) on 2023-06-23. Deposit type is initial. No. of files: 1. Files: Lorlatinib with or without chemotherapy in ALK-driven refractoryrelapsed neuroblastoma phase 1 trial results.pdf | |