PMID- 37012551
OWN - NLM
STAT- MEDLINE
DCOM- 20230524
LR  - 20240328
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 29
IP  - 5
DP  - 2023 May
TI  - Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed 
      neuroblastoma: phase 1 trial results.
PG  - 1092-1102
LID - 10.1038/s41591-023-02297-5 [doi]
AB  - 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 .
CI  - (c) 2023. The Author(s).
FAU - Goldsmith, Kelly C
AU  - Goldsmith KC
AD  - Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 
      Atlanta, GA, USA.
AD  - Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
FAU - Park, Julie R
AU  - Park JR
AD  - Seattle Children's Hospital, Seattle, WA, USA.
AD  - Department of Pediatrics, University of Washington School of Medicine, Seattle, 
      WA, USA.
FAU - Kayser, Kimberly
AU  - Kayser K
AD  - Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical 
      Center, Nashville, TN, USA.
FAU - Malvar, Jemily
AU  - Malvar J
AD  - Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, 
      CA, USA.
FAU - Chi, Yueh-Yun
AU  - Chi YY
AD  - Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, 
      CA, USA.
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
FAU - Groshen, Susan G
AU  - Groshen SG
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
FAU - Villablanca, Judith G
AU  - Villablanca JG
AD  - Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, 
      CA, USA.
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
FAU - Krytska, Kateryna
AU  - Krytska K
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Lai, Lillian M
AU  - Lai LM
AD  - Department of Radiology, University of Iowa Hospital and Clinics, Iowa City, IA, 
      USA.
FAU - Acharya, Patricia T
AU  - Acharya PT
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
AD  - Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
FAU - Goodarzian, Fariba
AU  - Goodarzian F
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
AD  - Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
FAU - Pawel, Bruce
AU  - Pawel B
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
AD  - Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, 
      Los Angeles, CA, USA.
FAU - Shimada, Hiroyuki
AU  - Shimada H
AD  - Department of Pathology and Pediatrics, Stanford University School of Medicine, 
      Stanford, CA, USA.
FAU - Ghazarian, Susan
AU  - Ghazarian S
AD  - Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, 
      CA, USA.
FAU - States, Lisa
AU  - States L
AD  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA.
FAU - Marshall, Lynley
AU  - Marshall L
AD  - The Royal Marsden Hospital, London, UK.
AD  - The Institute of Cancer Research, London, UK.
FAU - Chesler, Louis
AU  - Chesler L
AUID- ORCID: 0000-0001-7842-2068
AD  - The Royal Marsden Hospital, London, UK.
AD  - The Institute of Cancer Research, London, UK.
FAU - Granger, Meaghan
AU  - Granger M
AD  - Cook Children's Medical Center, Fort Worth, TX, USA.
FAU - Desai, Ami V
AU  - Desai AV
AD  - Department of Pediatrics, Section of Hematology/Oncology/Stem Cell 
      Transplantation, University of Chicago, Chicago, IL, USA.
FAU - Mody, Rajen
AU  - Mody R
AD  - Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
FAU - Morgenstern, Daniel A
AU  - Morgenstern DA
AUID- ORCID: 0000-0002-4859-1108
AD  - Division of Haematology and Oncology, Hospital for Sick Children, Toronto, ON, 
      Canada.
AD  - Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
FAU - Shusterman, Suzanne
AU  - Shusterman S
AD  - Dana-Farber Cancer Institute, Boston Children's Cancer and Blood Disorders 
      Center, Harvard Medical School, Boston, MA, USA.
FAU - Macy, Margaret E
AU  - Macy ME
AUID- ORCID: 0000-0001-6446-9180
AD  - University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
AD  - Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, 
      USA.
FAU - Pinto, Navin
AU  - Pinto N
AUID- ORCID: 0000-0002-8775-6710
AD  - Seattle Children's Hospital, Seattle, WA, USA.
AD  - Department of Pediatrics, University of Washington School of Medicine, Seattle, 
      WA, USA.
FAU - Schleiermacher, Gudrun
AU  - Schleiermacher G
AUID- ORCID: 0000-0002-0133-5879
AD  - RTOP (Recherche Translationelle en Oncologie Pediatrique), INSERM U830, Research 
      Center, PSL Research University, Institut Curie, Paris, France.
AD  - SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents 
      and Young Adults with Cancer), Institut Curie, Paris, France.
FAU - Vo, Kieuhoa
AU  - Vo K
AD  - Department of Pediatrics, UCSF Benioff Children's Hospital, University of 
      California, San Francisco School of Medicine, San Francisco, CA, USA.
FAU - Thurm, Holger C
AU  - Thurm HC
AD  - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., 
      New York, NY, USA.
FAU - Chen, Joseph
AU  - Chen J
AUID- ORCID: 0000-0002-5998-7765
AD  - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., 
      New York, NY, USA.
FAU - Liyanage, Marlon
AU  - Liyanage M
AD  - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., 
      New York, NY, USA.
FAU - Peltz, Gerson
AU  - Peltz G
AD  - Global Product Development, Clinical Pharmacology, Pfizer Oncology, Pfizer, Inc., 
      New York, NY, USA.
FAU - Matthay, Katherine K
AU  - Matthay KK
AD  - Department of Pediatrics, UCSF Benioff Children's Hospital, University of 
      California, San Francisco School of Medicine, San Francisco, CA, USA.
FAU - Berko, Esther R
AU  - Berko ER
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
AD  - Division of Pediatric Hematology and Oncology, Schneider Children's Medical 
      Center, Petach Tikva, Israel.
AD  - Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Maris, John M
AU  - Maris JM
AUID- ORCID: 0000-0002-8088-7929
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
AD  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA.
FAU - Marachelian, Araz
AU  - Marachelian A
AD  - Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, 
      CA, USA.
AD  - Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
FAU - Mosse, Yael P
AU  - Mosse YP
AUID- ORCID: 0000-0002-3463-0399
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA. mosse@chop.edu.
AD  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA. mosse@chop.edu.
LA  - eng
SI  - ClinicalTrials.gov/NCT03107988
GR  - P01 CA217959/CA/NCI NIH HHS/United States
GR  - R01 CA140198/CA/NCI NIH HHS/United States
GR  - R35 CA220500/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230403
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 35MRW7B4AD (3-Iodobenzylguanidine)
RN  - 0 (Aminopyridines)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - 0 (Lactams, Macrocyclic)
RN  - OSP71S83EU (lorlatinib)
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
MH  - Adult
MH  - Humans
MH  - 3-Iodobenzylguanidine/therapeutic use
MH  - Aminopyridines/therapeutic use
MH  - Anaplastic Lymphoma Kinase/genetics
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - Lactams, Macrocyclic/adverse effects
MH  - *Lung Neoplasms/drug therapy
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - *Neuroblastoma/drug therapy/genetics
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Child
MH  - Infant
MH  - Child, Preschool
MH  - Adolescent
PMC - PMC10202811
COIS- The authors declare the following competing interests. Y.P.M. is the principal 
      investigator of the NANT phase 1 trial of lorlatinib and is a consultant for 
      Pfizer. Y.P.M. has previously received research funding from Pfizer and Novartis. 
      Y.P.M. has also served as a consultant for Lilly, Auron Therapeutics and Jumo 
      Health. Y.P.M. serves as a member of the Data and Safety Monitoring Committee for 
      the ASCO TAPUR study and receives honoraria for this role. H.T. is an employee of 
      Pfizer and holds Pfizer stock. J.S. was an employee of Pfizer during the conduct 
      and analysis of this work, currently owns Pfizer stock and is currently employed 
      by Roche-Genentech. M.L. is a postdoctoral fellow with funding supported by 
      Pfizer. G.P., at the time of study, was employed by Pfizer and held company 
      stock. A.M. and NANT clinical research operations received funding from Pfizer in 
      support of this study. K.C.G. has been an uncompensated consultant to Y-mAbs 
      Therapeutics. L.M. has been a consultant or advisor for Bayer, Bristol Myers 
      Squibb, Illumina and Tesaro and served as an EDMC member on studies run by Eisai 
      and Merck. A.D. has stock ownership in Pfizer and Viatris and has acted as a paid 
      consultant or advisor for Merck, Ology Medical Education, Y-mAbs Therapeutics and 
      GlaxoSmithKline. D.A.M. has been a consultant or advisory board member to Y-mAbs 
      Therapeutics, Clarity Pharmaceuticals, RayzeBio and Oncoheroes Biosciences. G.S. 
      has received research funding from Bristol Myers Squibb, MSDavenir, Roche and 
      Pfizer for research projects distinct from this trial. K.M. is a consultant with 
      Y-mabs Therapeutics and RayzeBio. R.M. is on the Data and Safety Monitoring 
      Committee for Y-Mabs Therapeutics and Jubilant Draximage. M.M. has stock in 
      Johnson & Johnson, GE Healthcare and Varian Medical Systems. M.M. has been a 
      consultant or advisory board memebr to Y-mAbs Therapeutics and has received 
      research funding from Bayer, Ignyta, Roche, Lilly, Merck, Oncternal Therapeutics, 
      AbbVie, Jubilant Draxlmage and Actuate Therapeutics. The remaining authors 
      declare no competing interests.
EDAT- 2023/04/04 06:00
MHDA- 2023/05/24 06:42
PMCR- 2023/04/03
CRDT- 2023/04/03 23:31
PHST- 2022/10/26 00:00 [received]
PHST- 2023/03/09 00:00 [accepted]
PHST- 2023/05/24 06:42 [medline]
PHST- 2023/04/04 06:00 [pubmed]
PHST- 2023/04/03 23:31 [entrez]
PHST- 2023/04/03 00:00 [pmc-release]
AID - 10.1038/s41591-023-02297-5 [pii]
AID - 2297 [pii]
AID - 10.1038/s41591-023-02297-5 [doi]
PST - ppublish
SO  - Nat Med. 2023 May;29(5):1092-1102. doi: 10.1038/s41591-023-02297-5. Epub 2023 Apr 
      3.