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Daniel J. DeAngelo, Email: daniel_deangelo@dfci.harvard.edu

A list of study investigators and the study RAC is provided in the Methods. B.G.M. was the medical monitor of the study. H.-M.L. led the generation of data analyses. D.J.D., M.W.D. and J.G. contributed equally as senior authors. All authors were involved in data interpretation and in the writing, revision and critical review of the manuscript. All authors have approved the submitted version and are accountable for their contributions and the integrity of the work.

This study was funded by Blueprint Medicines Corporation. The authors thank the patients, their families and all investigators involved in this study. P.B. is supported by the National Cancer Institute (National Institutes of Health (NIH), no. P30 CA016672). J.G. is supported by an internal grant from the Stanford Cancer Institute Clinical Innovation Fund. E.O.H. is supported by the National Cancer Institute (NIH, nos. 1UE5CA246744-01 and P01-CA214278-03), the National Center for Advancing Translational Sciences (NIH no. NIH-NCATS UL1TR001878) and the National Heart, Lung and Blood Institute (NIH no. R01-HL-148014-01A1). Pathology assessment was supported by K. Karner, K. Moser and A. Rets (all ARUP Laboratories, University of Utah). Data management support was provided by C. Langford (Stanford Cancer Institute). Medical writing support was provided by Danielle Russell, PhD and Jeremy Kennard, PhD (both of Paragon, Knutsford, UK), supported by Blueprint Medicines Corporation in accordance with Good Publication Practice (GPP3) guidelines (https://www.ismpp.org/gpp3). The sponsor was involved in the study design and collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions and data interpretation lies with the authors.

The authors declare the following competing interests: D.J.D. has served as a consultant for Amgen, Agios, Autolus, Blueprint Medicines Corporation, Forty-Seven, Incyte Corporation, Jazz, Novartis, Pfizer, Shire and Takeda, and received research funding from AbbVie, GlycoMimetics and Novartis. D.H.R. is a paid consultant for and has received research support from Blueprint Medicines Corporation, is a member of the RACs for the EXPLORER and PATHFINDER studies and has received honoraria from Novartis for educational events and consultancy. T.I.G. is a paid consultant and has served as a study steering group member for Blueprint Medicines Corporation, and is employed by ARUP Laboratories/University of Utah, which received funding from Blueprint Medicines Corporation. W.A.R. has received research funding from Blueprint Medicines Corporation. A.T.Q. has no competing interests to declare. M.W.D. received research support from Blueprint Medicines Corporation and Novartis. P.B. has received research honoraria/consulting fees from Blueprint Medicines Corporation, Incyte Corporation, Celgene Corporation (now BMS), CTI BioPharma, Kartos Therapeutics and Sierra Oncology, and research support from Blueprint Medicines Corporation, Celgene Corporation (now BMS), Kartos Therapeutics, Incyte Corporation, Constellation Pharmaceuticals, CTI BioPharma, Astellas Pharmaceuticals, Pfizer, Inc., NS Pharma and Promedior. E.O.H. has received research support and has served on a Data and Safety Monitoring Board for Blueprint Medicines Corporation, has received research support from Novartis Pharmaceuticals and Tmunity Therapeutics, and serves on the hematology exam committee for the American Board of Internal Medicine. E.F.W. has received research support for conduct of clinical studies from Blueprint Medicines Corporation, Samus Therapeutics and Incyte Corporation. H.-P.H. has served as a consultant for Novartis and Blueprint Medicines Corporation. M.T., O.S.-K. and E.K.E. are shareholders and former employees of Blueprint Medicines Corporation. H-M.L. and B.G.M. are both current employees and shareholders of Blueprint Medicines Corporation. S.V. declares research support for the conduct of clinical studies from Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma, AbbVie, Blueprint Medicines Corporation, Novartis, Sierra Oncology, PharmaEssentia, Constellation Pharmaceuticals, Ital Pharma, Protagonist and Kartos Therapeutics. M.W.D. is a paid consultant for Fusion Pharma, Takeda, Medscape, Novartis, Incyte, Sangamo, SPARC, Pfizer and DisperSol, has received research support from Blueprint Medicines Corporation and SPARC, and has served on study management committees for clinical studies sponsored by Pfizer, Takeda and Blueprint Medicines Corporation. J.G. is a paid consultant for, and has received research funding from, Blueprint Medicines Corporation, Deciphera, Incyte and Kartos Therapeutics, and has served as chair of the RAC for Blueprint Medicines Corporation’ phase 1 EXPLORER study, and for the phase 2 PATHFINDER study, and as co-chair for the Deciphera Study Steering Committee for ripretinib in AdvSM and chair of the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.



  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

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Journal Title:



Volume 27, Number 12


, Pages 2183-+

Type of Work:

Article | Final Publisher PDF


Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

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© The Author(s) 2021

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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