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

Autor: Goldsmith KC; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA., Park JR; Seattle Children's Hospital, Seattle, WA, USA.; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA., Kayser K; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA., Malvar J; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Chi YY; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Groshen SG; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Villablanca JG; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Krytska K; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Lai LM; Department of Radiology, University of Iowa Hospital and Clinics, Iowa City, IA, USA., Acharya PT; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA., Goodarzian F; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA., Pawel B; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA., Shimada H; Department of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Ghazarian S; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., States L; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Marshall L; The Royal Marsden Hospital, London, UK.; The Institute of Cancer Research, London, UK., Chesler L; The Royal Marsden Hospital, London, UK.; The Institute of Cancer Research, London, UK., Granger M; Cook Children's Medical Center, Fort Worth, TX, USA., Desai AV; Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Chicago, IL, USA., Mody R; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA., Morgenstern DA; Division of Haematology and Oncology, Hospital for Sick Children, Toronto, ON, Canada.; Department of Paediatrics, University of Toronto, Toronto, ON, Canada., Shusterman S; Dana-Farber Cancer Institute, Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA., Macy ME; University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA., Pinto N; Seattle Children's Hospital, Seattle, WA, USA.; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA., Schleiermacher G; RTOP (Recherche Translationelle en Oncologie Pédiatrique), INSERM U830, Research Center, PSL Research University, Institut Curie, Paris, France.; SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, Paris, France., Vo K; Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA., Thurm HC; Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA., Chen J; Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA., Liyanage M; Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA., Peltz G; Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA., Matthay KK; Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA., Berko ER; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Pediatric Hematology and Oncology, Schneider Children's Medical Center, Petach Tikva, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Maris JM; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Marachelian A; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Mossé YP; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. mosse@chop.edu.; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. mosse@chop.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 May; Vol. 29 (5), pp. 1092-1102. Date of Electronic Publication: 2023 Apr 03.
DOI: 10.1038/s41591-023-02297-5
Abstrakt: 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 123 I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m 2 /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 2 . 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 .
(© 2023. The Author(s).)
Databáze: MEDLINE
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