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

doi:10.1038/s41591-023-02297-5

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

Nat Med. 2023 May;29(5):1092-1102. doi: 10.1038/s41591-023-02297-5. Epub 2023 Apr 3.

Authors

Kelly C Goldsmith^{1

2}, Julie R Park^{3

4}, Kimberly Kayser⁵, Jemily Malvar⁶, Yueh-Yun Chi^{6

7}, Susan G Groshen⁷, Judith G Villablanca^{6

7}, Kateryna Krytska⁸, Lillian M Lai⁹, Patricia T Acharya^{7

10}, Fariba Goodarzian^{7

10}, Bruce Pawel^{7

11}, Hiroyuki Shimada¹², Susan Ghazarian⁶, Lisa States¹³, Lynley Marshall^{14

15}, Louis Chesler^{14

15}, Meaghan Granger¹⁶, Ami V Desai¹⁷, Rajen Mody¹⁸, Daniel A Morgenstern^{19

20}, Suzanne Shusterman²¹, Margaret E Macy^{22

23}, Navin Pinto^{3

4}, Gudrun Schleiermacher^{24

25}, Kieuhoa Vo²⁶, Holger C Thurm²⁷, Joseph Chen²⁷, Marlon Liyanage²⁷, Gerson Peltz²⁷, Katherine K Matthay²⁶, Esther R Berko^{8

28

29}, John M Maris^{8

13}, Araz Marachelian^{6

7}, Yael P Mossé^{30

31}

Affiliations

¹ Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
² Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
³ Seattle Children's Hospital, Seattle, WA, USA.
⁴ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁷ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸ Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Department of Radiology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.
¹⁰ Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹² Department of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ The Royal Marsden Hospital, London, UK.
¹⁵ The Institute of Cancer Research, London, UK.
¹⁶ Cook Children's Medical Center, Fort Worth, TX, USA.
¹⁷ Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Chicago, IL, USA.
¹⁸ Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Division of Haematology and Oncology, Hospital for Sick Children, Toronto, ON, Canada.
²⁰ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
²¹ Dana-Farber Cancer Institute, Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
²² University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²³ Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
²⁴ RTOP (Recherche Translationelle en Oncologie Pédiatrique), INSERM U830, Research Center, PSL Research University, Institut Curie, Paris, France.
²⁵ SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, Paris, France.
²⁶ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
²⁷ Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., New York, NY, USA.
²⁸ Division of Pediatric Hematology and Oncology, Schneider Children's Medical Center, Petach Tikva, Israel.
²⁹ Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³⁰ Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. mosse@chop.edu.
³¹ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. mosse@chop.edu.

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 .

Publication types

Clinical Trial, Phase I
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3-Iodobenzylguanidine / therapeutic use
Adolescent
Adult
Aminopyridines / therapeutic use
Anaplastic Lymphoma Kinase / genetics
Carcinoma, Non-Small-Cell Lung* / drug therapy
Child
Child, Preschool
Humans
Infant
Lactams, Macrocyclic / adverse effects
Lung Neoplasms* / drug therapy
Neoplasm Recurrence, Local / drug therapy
Neuroblastoma* / drug therapy
Neuroblastoma* / genetics
Protein Kinase Inhibitors / therapeutic use

Substances

3-Iodobenzylguanidine
Aminopyridines
Anaplastic Lymphoma Kinase
Lactams, Macrocyclic
lorlatinib
Protein Kinase Inhibitors

Associated data

ClinicalTrials.gov/NCT03107988

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding