Journal article
Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results
Nature medicine, Vol.29(5), pp.1092-1102
05/2023
DOI: 10.1038/s41591-023-02297-5
PMCID: PMC10202811
PMID: 37012551
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
I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m
/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/m
. 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 .
Details
- Title: Subtitle
- Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results
- Creators
- Kelly C Goldsmith - Emory University School of MedicineJulie R Park - University of Washington School of MedicineKimberly Kayser - Vanderbilt University Medical CenterJemily Malvar - Children's Hospital of Los AngelesYueh-Yun Chi - Keck School of Medicine, University of Southern California, Los Angeles, CA, USASusan G Groshen - Keck School of Medicine, University of Southern California, Los Angeles, CA, USAJudith G Villablanca - Keck School of Medicine, University of Southern California, Los Angeles, CA, USAKateryna Krytska - Children's Hospital of PhiladelphiaLillian M Lai - University of IowaPatricia T Acharya - Children's Hospital of Los AngelesFariba Goodarzian - Children's Hospital of Los AngelesBruce Pawel - Children's Hospital of Los AngelesHiroyuki Shimada - Stanford University School of MedicineSusan Ghazarian - Children's Hospital of Los AngelesLisa States - University of PennsylvaniaLynley Marshall - The Institute of Cancer Research, London, UKLouis Chesler - The Institute of Cancer Research, London, UKMeaghan Granger - Cook Children's Medical CenterAmi V Desai - University of ChicagoRajen Mody - University of MichiganDaniel A Morgenstern - University of TorontoSuzanne Shusterman - Dana-Farber Cancer Institute, Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USAMargaret E Macy - Center for Cancer and Blood DisordersNavin Pinto - University of Washington School of MedicineGudrun Schleiermacher - Institut CurieKieuhoa Vo - University of California - San Francisco School of MedicineHolger C Thurm - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USAJoseph Chen - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USAMarlon Liyanage - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USAGerson Peltz - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USAKatherine K Matthay - University of California - San Francisco School of MedicineEsther R Berko - Tel Aviv UniversityJohn M Maris - University of PennsylvaniaAraz Marachelian - Keck School of Medicine, University of Southern California, Los Angeles, CA, USAYael P Mossé - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.29(5), pp.1092-1102
- DOI
- 10.1038/s41591-023-02297-5
- PMID
- 37012551
- PMCID
- PMC10202811
- NLM abbreviation
- Nat Med
- eISSN
- 1546-170X
- Grant note
- R01CA140198 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R35CA220500 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P01CA217959 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
- Language
- English
- Electronic publication date
- 04/03/2023
- Date published
- 05/2023
- Academic Unit
- Radiology; Stead Family Department of Pediatrics
- Record Identifier
- 9984386253502771
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