Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results

• Type of Material: Article
• Authors: Kelly Goldsmith, Emory University; Julie R Park, Seattle Children’s Hospita; Kimberly Kayser, Vanderbilt University; Jemily Malvar, Children’s Hospital Los Angeles; Yueh-Yun Chi, Children’s Hospital Los Angeles; Susan G Groshen, University of Southern California; Judith G Villablanca, Children’s Hospital Los Angeles; Kateryna Krytska, Childrens Hospital of Philadelphia; Lillian M Lai, University of Iowa Hospital and Clinics; Patricia T Acharya, University of Southern California; Fariba Goodarzian, University of Southern California; Bruce Pawel, University of Southern California; Hiroyuki Shimada, Stanford University; Susan Ghazarian, Children’s Hospital Los Angeles; Lisa States, University of Pennsylvania; Lynley Marshall, The Royal Marsden Hospital; Louis Chesler, The Royal Marsden Hospital; Meaghan Granger, Cook Children’s Medical Center; Ami V Desai, University of Chicago; Rajen Mody, University of Michigan; Daniel A Morgenstern, Hospital for Sick Children; Suzanne Shusterman, Harvard Medical School; Margaret E Macy, University of Colorado Anschutz Medical Campus; Navin Pinto, Seattle Children’s Hospital; Gudrun Schleiermacher, PSL Research University; Kieuhoa Vo, University of California San Francisco; Holger C Thurm, Pfizer Inc; Joseph Chen, Pfizer Inc; Marlon Liyanage, Pfizer Inc; Gerson Peltz, Pfizer Inc; Katherine K Matthay, University of California San Francisco; Esther R Berko, Childrens Hospital of Philadelphia; John M Maris, Childrens Hospital of Philadelphia; Araz Marachelian, Childrens Hosp Los Angeles; Yael P Mosse, Childrens Hospital of Philadelphia
• Language: English
• Date: 2023-04-03
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41591-023-02297-5
• Title of Journal or Parent Work: NATURE MEDICINE
• Volume: 29
• Issue: 5
• Start Page: 1092
• End Page: 1102
• Keywords: SINGLE-ARM; Science & Technology; OPEN-LABEL; LYMPHOMA; MULTICENTER; KINASE; Medicine, Research & Experimental; Life Sciences & Biomedicine; CRIZOTINIB; Cell Biology; Biochemistry & Molecular Biology; ACTIVATING MUTATIONS; Research & Experimental Medicine; PF-06463922; CELL LUNG-CANCER; TELOMERE MAINTENANCE MECHANISMS
• Research Categories: Health Sciences, Oncology; Health Sciences, Mental Health; Health Sciences, Radiology

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.