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Nature medicine
05, 2023;29 (5): 1092-1102.

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

Kelly C Goldsmith, Julie R Park, Kimberly Kayser, Jemily Malvar, Yueh-Yun Chi, Susan G Groshen, Judith G Villablanca, Kateryna Krytska, Lillian M Lai, Patricia T Acharya, Fariba Goodarzian, Bruce Pawel, Hiroyuki Shimada, Susan Ghazarian, Lisa States, Lynley Marshall, Louis Chesler, Meaghan Granger, Ami V Desai, Rajen Mody, Daniel A Morgenstern, Suzanne Shusterman, Margaret E Macy, Navin Pinto, Gudrun Schleiermacher, Kieuhoa Vo, Holger C Thurm, Joseph Chen, Marlon Liyanage, Gerson Peltz, Katherine K Matthay, Esther R Berko, John M Maris, Araz Marachelian, Yael P Mossé
Author Information
  1. Kelly C Goldsmith: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
  2. Julie R Park: Seattle Children's Hospital, Seattle, WA, USA.
  3. Kimberly Kayser: Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
  4. Jemily Malvar: Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  5. Yueh-Yun Chi: Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  6. Susan G Groshen: Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  7. Judith G Villablanca: Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  8. Kateryna Krytska: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  9. Lillian M Lai: Department of Radiology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.
  10. Patricia T Acharya: Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  11. Fariba Goodarzian: Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  12. Bruce Pawel: Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  13. Hiroyuki Shimada: Department of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
  14. Susan Ghazarian: Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  15. Lisa States: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  16. Lynley Marshall: The Royal Marsden Hospital, London, UK.
  17. Louis Chesler: The Royal Marsden Hospital, London, UK. ORCID
  18. Meaghan Granger: Cook Children's Medical Center, Fort Worth, TX, USA.
  19. Ami V Desai: Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Chicago, IL, USA.
  20. Rajen Mody: Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
  21. Daniel A Morgenstern: Division of Haematology and Oncology, Hospital for Sick Children, Toronto, ON, Canada. ORCID
  22. Suzanne Shusterman: Dana-Farber Cancer Institute, Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
  23. Margaret E Macy: University of Colorado Anschutz Medical Campus, Aurora, CO, USA. ORCID
  24. Navin Pinto: Seattle Children's Hospital, Seattle, WA, USA. ORCID
  25. Gudrun Schleiermacher: RTOP (Recherche Translationelle en Oncologie Pédiatrique), INSERM U830, Research Center, PSL Research University, Institut Curie, Paris, France. ORCID
  26. Kieuhoa Vo: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
  27. Holger C Thurm: Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA.
  28. Joseph Chen: Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA. ORCID
  29. Marlon Liyanage: Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA.
  30. Gerson Peltz: Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA.
  31. Katherine K Matthay: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
  32. Esther R Berko: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  33. John M Maris: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. ORCID
  34. Araz Marachelian: Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  35. Yael P Mossé: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. mosse@chop.edu. ORCID
PMID: 37012551 DOI: 10.1038/s41591-023-02297-5

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 .

Associated Data

ClinicalTrials.gov | NCT03107988

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Grants

  1. P01 CA217959/NCI NIH HHS
  2. R01 CA140198/NCI NIH HHS
  3. R35 CA220500/NCI NIH HHS

MeSH Term

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

Chemicals

3-Iodobenzylguanidine
Aminopyridines
Anaplastic Lymphoma Kinase
Lactams, Macrocyclic
lorlatinib
Protein Kinase Inhibitors
Clinical Trial, Phase I Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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