PMID- 37115514
OWN - NLM
STAT- MEDLINE
DCOM- 20231005
LR  - 20240429
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 25
IP  - 10
DP  - 2023 Oct 3
TI  - Long-term safety and efficacy of selumetinib in children with neurofibromatosis 
      type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.
PG  - 1883-1894
LID - 10.1093/neuonc/noad086 [doi]
AB  - BACKGROUND: Selumetinib shrank inoperable symptomatic plexiform neurofibromas 
      (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical 
      benefit for many in our previously published phase 1/2 clinical trials (SPRINT, 
      NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of 
      participants were still receiving treatment. This report presents up to 5 years 
      of additional safety and efficacy data from these studies. METHODS: This 
      manuscript includes data from the phase 1 and phase 2, stratum 1 study which 
      included participants with clinically significant PN-related morbidity. 
      Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety 
      and efficacy data through February 27, 2021 are included. PN response assessed by 
      volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) 
      >/=20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants 
      completed patient-reported outcome measures assessing tumor pain intensity 
      (Numeric Rating Scale-11) and interference of pain in daily life (pain 
      interference index). RESULTS: For the 74 children (median age 10.3 years; range 
      3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment 
      was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) 
      lasting >/= 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain 
      interference (n = 18, P = .0059) showed durable improvement from baseline to 48 
      cycles. No new safety signals were identified; however, some developed known 
      selumetinib-related adverse events (AEs) for the first time after several years 
      of treatment. CONCLUSIONS: With up to 5 years of additional selumetinib 
      treatment, most children with NF1-related PN had durable tumor shrinkage and 
      sustained improvement in pain beyond that previously reported at 1 year. No new 
      safety signals were identified; however, ongoing monitoring for known 
      selumetinib-related AEs is needed while treatment continues.
CI  - Published by Oxford University Press on behalf of the Society for Neuro-Oncology 
      2023.
FAU - Gross, Andrea M
AU  - Gross AM
AUID- ORCID: 0000-0003-1646-4531
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Dombi, Eva
AU  - Dombi E
AUID- ORCID: 0000-0002-5323-6995
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Wolters, Pamela L
AU  - Wolters PL
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Baldwin, Andrea
AU  - Baldwin A
AD  - Leidos, Clinical Research Directorate (CRD), Frederick National Laboratory for 
      Cancer Research, Frederick, Maryland, USA.
FAU - Dufek, Anne
AU  - Dufek A
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Herrera, Kailey
AU  - Herrera K
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Martin, Staci
AU  - Martin S
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Derdak, Joanne
AU  - Derdak J
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Heisey, Kara S
AU  - Heisey KS
AD  - Leidos, Clinical Research Directorate (CRD), Frederick National Laboratory for 
      Cancer Research, Frederick, Maryland, USA.
FAU - Whitcomb, Patricia M
AU  - Whitcomb PM
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
FAU - Steinberg, Seth M
AU  - Steinberg SM
AUID- ORCID: 0000-0002-8280-551X
AD  - Biostatistics and Data Management Section, Center for Cancer Research, National 
      Cancer Institute, Bethesda, Maryland 20892, USA.
FAU - Venzon, David J
AU  - Venzon DJ
AD  - Biostatistics and Data Management Section, Center for Cancer Research, National 
      Cancer Institute, Bethesda, Maryland 20892, USA.
FAU - Fisher, Michael J
AU  - Fisher MJ
AD  - Children's Hospital of Philadelphia, Section of Neuro-Oncology, Philadelphia, 
      Pennsylvania, USA.
FAU - Kim, AeRang
AU  - Kim A
AUID- ORCID: 0000-0002-7813-5568
AD  - Children's National Hospital, Center for Cancer and Blood Disorders, Washington, 
      District of Columbia, USA.
FAU - Bornhorst, Miriam
AU  - Bornhorst M
AUID- ORCID: 0000-0002-7595-7726
AD  - Children's National Hospital, Center for Cancer and Blood Disorders, Washington, 
      District of Columbia, USA.
FAU - Weiss, Brian D
AU  - Weiss BD
AD  - Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
FAU - Blakeley, Jaishri O
AU  - Blakeley JO
AUID- ORCID: 0000-0002-1049-0993
AD  - Johns Hopkins University, Division of Neurology, Baltimore, Maryland, USA.
FAU - Smith, Malcolm A
AU  - Smith MA
AD  - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, 
      USA.
FAU - Widemann, Brigitte C
AU  - Widemann BC
AUID- ORCID: 0000-0002-9198-7175
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01362803
GR  - U54 CA196519/CA/NCI NIH HHS/United States
GR  - RC/CCR NIH HHS/United States
GR  - U54 CA196519-04/NH/NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (AZD 6244)
RN  - 0 (Benzimidazoles)
SB  - IM
MH  - Child
MH  - Humans
MH  - *Neurofibromatosis 1/complications/drug therapy
MH  - *Neurofibroma, Plexiform/drug therapy/pathology
MH  - Benzimidazoles/adverse effects
MH  - Pain
PMC - PMC10547508
OTO - NOTNLM
OT  - MEK Inhibitors
OT  - Neurofibromatosis type 1
OT  - Plexiform Neurofibromas
COIS- Dr. Michael J Fisher and Dr. Jaishri O Blakeley have been paid advisors for 
      Springworks Therapeutics. The authors report no other financial conflicts of 
      interest. Dr. Miriam Bornhorst has been a paid advisor for Alexion, AstraZeneca 
      Rare Disease.
EDAT- 2023/04/28 12:42
MHDA- 2023/10/05 06:43
PMCR- 2024/04/28
CRDT- 2023/04/28 11:15
PHST- 2023/10/05 06:43 [medline]
PHST- 2023/04/28 12:42 [pubmed]
PHST- 2023/04/28 11:15 [entrez]
PHST- 2024/04/28 00:00 [pmc-release]
AID - 7146403 [pii]
AID - noad086 [pii]
AID - 10.1093/neuonc/noad086 [doi]
PST - ppublish
SO  - Neuro Oncol. 2023 Oct 3;25(10):1883-1894. doi: 10.1093/neuonc/noad086.