Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study

Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHN; usually myeloid) are often present, leading to poor survival. We report on the oral, highly selective, potent KIT D816V inhibitor avapritinib (200-mg once-daily starting dose) with >4 years follow-up from the fully enrolled PATHFINDER (NCT03580655) study. Endpoints included overall response rate (ORR; primary), duration of response (DOR), progression-free survival (PFS), overall survival (OS), changes in objective biomarkers of disease, and safety (all secondary). Of 107 patients with AdvSM (including 71 [66%] with SM-AHN; overall population median follow-up: 49 months), 83 were response evaluable. ORR was 73% (95% confidence interval [95% CI], 63%-83%). Median DOR was 58 months, PFS 51 months, and OS 62 months. Disease progression occurred in 21/107 patients, predominantly in SM-AHN and largely driven by the AHN. Reductions in objective biomarkers of disease were observed. Most frequent (≥30% patients) treatment-emergent adverse events (TEAEs) (any grade; grade ≥3) were thrombocytopenia (58%; 31%); periorbital edema (57%; 6%), anemia (54%; 33%), peripheral edema (48%; 2%), and diarrhea (36%; 5%). Adverse events of special interest were cognitive effects (34%; 8%) and intracranial bleeds (4%, 2%). Eleven (10%) patients experienced TEAEs leading to death, of which 1 was deemed related to avapritinib by the principal investigator. With 4-year follow-up, avapritinib-treated patients with AdvSM experienced deep and durable responses and a favorable benefit-risk profile.

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Journal
Blood Advances
Published
2026-01-28
DOI
https://doi.org/10.1182/bloodadvances.2025017519
Primary Topic
Mast cells and histamine
Type
article
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article

Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study

Stephen T. Oh, Javier I. Munoz-Gonzalez, J. Gotlib, Prithviraj Bose et al.
Blood Advances
Mast cells and histamine
article

Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study

Stephen T. Oh, Javier I. Munoz-Gonzalez, J. Gotlib, Prithviraj Bose, Andrzej Mital, Ilda Bidollari, Joseph G. Jurcic, Johannes Lübke, M. Triggiani, Elizabeth A. Griffiths, Ingunn Dybedal, Abdulraheem Yacoub, A Ivan, Roberta Zanotti, Michael Deininger, Hui‐Min Lin, Matthew Butler, Saša Dimitrijević, C. Bulai Livideanu, Uwe Platzbecker, Elizabeth Hexner, Jens P. Panse, Kristen M. Pettit, Andreas Reiter, Alessandro M. Vannucchi, Svetlana N. Rylova, Stephanie G Lee, Daniel J. DeAngelo, Celalettin Ustun, Ruben A Mesa, Deepti H. Radia, Amro Elshoury, Olivier Hermine, Tracy I. George
article en

Abstract

Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHN; usually myeloid) are often present, leading to poor survival. We report on the oral, highly selective, potent KIT D816V inhibitor avapritinib (200-mg once-daily starting dose) with >4 years follow-up from the fully enrolled PATHFINDER (NCT03580655) study. Endpoints included overall response rate (ORR; primary), duration of response (DOR), progression-free survival (PFS), overall survival (OS), changes in objective biomarkers of disease, and safety (all secondary). Of 107 patients with AdvSM (including 71 [66%] with SM-AHN; overall population median follow-up: 49 months), 83 were response evaluable. ORR was 73% (95% confidence interval [95% CI], 63%-83%). Median DOR was 58 months, PFS 51 months, and OS 62 months. Disease progression occurred in 21/107 patients, predominantly in SM-AHN and largely driven by the AHN. Reductions in objective biomarkers of disease were observed. Most frequent (≥30% patients) treatment-emergent adverse events (TEAEs) (any grade; grade ≥3) were thrombocytopenia (58%; 31%); periorbital edema (57%; 6%), anemia (54%; 33%), peripheral edema (48%; 2%), and diarrhea (36%; 5%). Adverse events of special interest were cognitive effects (34%; 8%) and intracranial bleeds (4%, 2%). Eleven (10%) patients experienced TEAEs leading to death, of which 1 was deemed related to avapritinib by the principal investigator. With 4-year follow-up, avapritinib-treated patients with AdvSM experienced deep and durable responses and a favorable benefit-risk profile.

Blood Advances
University of Verona (IT), Oslo University Hospital (NO), Atrium Health Wake Forest Baptist (US), Rush University Medical Center (US), Roswell Park Comprehensive Cancer Center (US), St. Michael's Hospital (CA), University of Salerno (IT), The University of Texas MD Anderson Cancer Center (US), Inserm (FR), University of Toronto (CA), Guy's and St Thomas' NHS Foundation Trust (GB), Heidelberg University (DE), University of Michigan (US), University Hospital Heidelberg (DE), Institut Necker Enfants Malades (FR), Düsseldorf University Hospital (DE), ARUP Laboratories (United States) (US), Integrated Oncology (United States) (US), Hospital Virgen del Valle (ES), Assistance Publique – Hôpitaux de Paris (FR), Blueprint Medicines (United States) (US), Jewish Hospital (US), Parker Institute for Cancer Immunotherapy (US), Michigan United (US), Azienda Ospedaliero-Universitaria Careggi (IT), Versiti Blood Center of Wisconsin (US), Dana-Farber Cancer Institute (US), Hôpital Larrey (FR), University of Kansas Medical Center (US), University Medical Centre Mannheim (DE), Indiana Hemophilia and Thrombosis Center (US), Institut des Maladies Génétiques Imagine (FR), Heinrich Heine University Düsseldorf (DE), The University of Texas at San Antonio (US), Gdańsk Medical University (PL), Medical University of Vienna (AT), Columbia University (US), RWTH Aachen University (DE), Leipzig University (DE), Stanford University (US)
Amgen, Aplastic Anemia and MDS International Foundation, Mastocytosis Society, Eli Lilly and Company, Pfizer, Gilead Sciences, Alexion Pharmaceuticals, Celgene, Incyte, Seagen, Astellas Pharma, Servier, Swedish Orphan Biovitrum, Scheme for Promotion of Academic and Research Collaboration, Daiichi Sankyo Europe
Openalex Percentile: Top 74%
Mast cells and histamine
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