Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study
Year: 2026
Type: article
Abstract: ABSTRACT: Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHNs; 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 study. End points 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, 63-83). Median DOR was 58 months; PFS, 51 months, and OS, 62 months. Disease progression occurred in 21 of 107 patients (20%), 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, patients with AdvSM treated with avapritinib experienced deep and durable responses and a favorable benefit-risk profile. This trial was registered at www.ClinicalTrials.gov as #NCT03580655.
Source: Blood Advances
Authors: Jason Gotlib, Andreas Reiter, Deepti H. Radia, Iván Álvarez-Twose, Michael W. Deininger, Tracy I. George, Jens Panse, Andrzej Mital, Kristen M. Pettit, Alessandro M. Vannucchi, Uwe Platzbecker, Olivier Hermine, Amro Elshoury, Cristina Bulai Livideanu, Ruben Mesa, Celalettin Ustun, Massimo Triggiani, Ingunn Dybedal, Joseph G. Jurcic, Roberta Zanotti, Stephen T. Oh, Abdulraheem Yacoub, Elizabeth O. Hexner, Prithviraj Bose, Stephanie G. Lee, Wolfgang R. Sperr, Elizabeth A. Griffiths, Matthew Butler, Johannes Lübke, Ilda Bidollari, Hui-Min Lin, Svetlana Rylova, Saša Dimitrijević, Javier I. Muñoz-González, Daniel J. DeAngelo
Institutions: Stanford Medicine, Stanford Cancer Institute, Stanford University, Heidelberg University, Guy's and St Thomas' NHS Foundation Trust, Hospital Virgen del Valle, University of Michigan, Michigan Medicine, University of Utah, Universitätsklinikum Aachen, RWTH Aachen University, Gdańsk Medical University, Azienda Ospedaliero-Universitaria Careggi, University of Florence, University Hospital Leipzig, Hôpital Necker-Enfants Malades, Inserm, Assistance Publique – Hôpitaux de Paris, Institut des Maladies Génétiques Imagine, Indiana Hemophilia and Thrombosis Center, Centre Hospitalier Universitaire de Toulouse, Atrium Health Wake Forest Baptist, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University Health Sciences, Rush University Medical Center, Rush University, University of Salerno, Oslo University Hospital, Herbert Irving Comprehensive Cancer Center, Columbia University, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Barnes-Jewish Hospital, Washington University in St. Louis, University of Kansas Medical Center, University of Pennsylvania, The University of Texas MD Anderson Cancer Center, St. Michael's Hospital, University of Toronto, Medical University of Vienna, Roswell Park Comprehensive Cancer Center, Mays Cancer Center at UT Health San Antonio, Blueprint Medicines (United States), Dana-Farber Cancer Institute
Language: English
Topic: Mast cells and histamine
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,800
Funders: Amgen, Aplastic Anemia and MDS International Foundation, Mastocytosis Society, Eli Lilly and Company, Pfizer, Sanofi, 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 ID: W7125973294