PMID- 33453089
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20221202
IS  - 1549-490X (Electronic)
IS  - 1083-7159 (Print)
IS  - 1083-7159 (Linking)
VI  - 26
IP  - 4
DP  - 2021 Apr
TI  - Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following 
      at Least Three Prior Lines of Therapy.
PG  - e639-e649
LID - 10.1002/onco.13674 [doi]
AB  - BACKGROUND: Most gastrointestinal stromal tumors (GIST) driven by KIT or 
      platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance 
      to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, 
      single-arm, dose escalation and expansion study designed to evaluate safety and 
      antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and 
      PDGFRA, in patients with unresectable or metastatic GIST. MATERIALS AND METHODS: 
      Eligible patients were 18 years or older with histologically or cytologically 
      confirmed unresectable GIST and Eastern Cooperative Oncology Group performance 
      status </=2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary 
      endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg 
      once daily and overall response rate (ORR) in patients in the safety population 
      with three or more previous lines of TKI therapy. RESULTS: As of November 16, 
      2018, in the safety population (n = 204), the most common adverse events (AEs) 
      were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive 
      effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients 
      discontinued due to treatment-related AEs, most frequently confusion, 
      encephalopathy, and fatigue. ORR in response-evaluable patients with GIST 
      harboring KIT or non-D842V PDGFRA mutations and with at least three prior 
      therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median 
      duration of response was 10.2 months (95% CI, 7.2-10.2), and median 
      progression-free survival was 3.7 months (95% CI, 2.8-4.6). CONCLUSION: 
      Avapritinib has manageable toxicity with meaningful clinical activity as 
      fourth-line or later treatment in some patients with GIST with KIT or PDGFRA 
      mutations. IMPLICATIONS FOR PRACTICE: In the NAVIGATOR trial, avapritinib, an 
      inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, 
      provided durable responses in a proportion of patients with advanced 
      gastrointestinal stromal tumors (GIST) who had received three or more prior 
      therapies. Avapritinib had a tolerable safety profile, with cognitive adverse 
      events manageable with dose interruptions and modification in most cases. These 
      findings indicate that avapritinib can elicit durable treatment responses in some 
      patients with heavily pretreated GIST, for whom limited treatment options exist.
CI  - (c) 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf 
      of AlphaMed Press.
FAU - George, Suzanne
AU  - George S
AUID- ORCID: 0000-0002-1284-8493
AD  - Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
FAU - Jones, Robin L
AU  - Jones RL
AD  - Royal Marsden Hospital and Institute of Cancer Research, London, UK.
FAU - Bauer, Sebastian
AU  - Bauer S
AD  - Department of Medical Oncology, West German Cancer Center, University of 
      Duisburg-Essen, Essen, Germany.
FAU - Kang, Yoon-Koo
AU  - Kang YK
AD  - Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
FAU - Schoffski, Patrick
AU  - Schoffski P
AD  - University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
FAU - Eskens, Ferry
AU  - Eskens F
AD  - Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
FAU - Mir, Olivier
AU  - Mir O
AD  - Institut Gustave Roussy, Villejuif, France.
FAU - Cassier, Phillipe A
AU  - Cassier PA
AD  - Centre Leon Berard, Lyon, France.
FAU - Serrano, Cesar
AU  - Serrano C
AD  - Vall d'Hebron Institute of Oncology, Barcelona, Spain.
FAU - Tap, William D
AU  - Tap WD
AD  - Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New 
      York, New York, USA.
FAU - Trent, Jonathan
AU  - Trent J
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
FAU - Rutkowski, Piotr
AU  - Rutkowski P
AD  - Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
FAU - Patel, Shreyaskumar
AU  - Patel S
AD  - MD Anderson Cancer Center, Houston, Texas, USA.
FAU - Chawla, Sant P
AU  - Chawla SP
AD  - Sarcoma Oncology Center, Santa Monica, California, USA.
FAU - Meiri, Eval
AU  - Meiri E
AD  - Cancer Treatment Center of America, Atlanta, Georgia, USA.
FAU - Gordon, Michael
AU  - Gordon M
AD  - HonorHealth Research Institute, Scottsdale, Arizona, USA.
FAU - Zhou, Teresa
AU  - Zhou T
AD  - Blueprint Medicines Corporation, Cambridge, Massachusetts, USA.
FAU - Roche, Maria
AU  - Roche M
AD  - Blueprint Medicines Corporation, Cambridge, Massachusetts, USA.
FAU - Heinrich, Micahel C
AU  - Heinrich MC
AD  - Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, 
      Oregon, USA.
FAU - von Mehren, Margaret
AU  - von Mehren M
AD  - Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA240139/CA/NCI NIH HHS/United States
GR  - I01 BX005358/BX/BLRD VA/United States
GR  - I01 BX000338/BX/BLRD VA/United States
GR  - R21 CA263400/CA/NCI NIH HHS/United States
GR  - UL1 TR002369/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20210201
PL  - England
TA  - Oncologist
JT  - The oncologist
JID - 9607837
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrroles)
RN  - 0 (Triazines)
RN  - 513P80B4YJ (avapritinib)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
SB  - IM
MH  - *Antineoplastic Agents/adverse effects
MH  - *Gastrointestinal Stromal Tumors/drug therapy/genetics
MH  - Humans
MH  - Mutation
MH  - Proto-Oncogene Proteins c-kit/genetics
MH  - Pyrazoles/therapeutic use
MH  - Pyrroles/therapeutic use
MH  - Triazines/therapeutic use
PMC - PMC8018324
OTO - NOTNLM
OT  - Avapritinib
OT  - Clinical trial
OT  - Gastrointestinal stromal tumors
OT  - KIT
OT  - Platelet-derived growth factor receptors
OT  - Protein-tyrosine kinases
COIS- Disclosures of potential conflicts of interest may be found at the end of this 
      article.
EDAT- 2021/01/17 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/04/01
CRDT- 2021/01/16 12:07
PHST- 2020/09/25 00:00 [received]
PHST- 2021/01/05 00:00 [accepted]
PHST- 2021/01/17 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2021/01/16 12:07 [entrez]
PHST- 2021/04/01 00:00 [pmc-release]
AID - ONCO13674 [pii]
AID - 10.1002/onco.13674 [doi]
PST - ppublish
SO  - Oncologist. 2021 Apr;26(4):e639-e649. doi: 10.1002/onco.13674. Epub 2021 Feb 1.