TY - JOUR
T1 - Efficacy and safety of avapritinib in advanced systemic mastocytosis
T2 - 4-year follow-up of the PATHFINDER study
AU - Gotlib, Jason
AU - Reiter, Andreas
AU - Radia, Deepti H.
AU - Álvarez-Twose, Iván
AU - Deininger, Michael W.
AU - George, Tracy I.
AU - Panse, Jens
AU - Mital, Andrzej
AU - Pettit, Kristen M.
AU - Vannucchi, Alessandro M.
AU - Platzbecker, Uwe
AU - Hermine, Olivier
AU - Elshoury, Amro
AU - Livideanu, Cristina Bulai
AU - Mesa, Ruben
AU - Ustun, Celalettin
AU - Triggiani, Massimo
AU - Dybedal, Ingunn
AU - Jurcic, Joseph G.
AU - Zanotti, Roberta
AU - Oh, Stephen T.
AU - Yacoub, Abdulraheem
AU - Hexner, Elizabeth O.
AU - Bose, Prithviraj
AU - Lee, Stephanie G.
AU - Sperr, Wolfgang R.
AU - Griffiths, Elizabeth A.
AU - Butler, Matthew
AU - Lübke, Johannes
AU - Bidollari, Ilda
AU - Lin, Hui Min
AU - Rylova, Svetlana
AU - Dimitrijević, Saša
AU - Muñoz-González, Javier I.
AU - DeAngelo, Daniel J.
N1 - Publisher Copyright:
© 2026 American Society of Hematology
PY - 2026/5/26
Y1 - 2026/5/26
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105032292063
U2 - 10.1182/bloodadvances.2025017519
DO - 10.1182/bloodadvances.2025017519
M3 - Article
C2 - 41604606
AN - SCOPUS:105032292063
SN - 2473-9529
VL - 10
SP - 3676
EP - 3689
JO - Blood Advances
JF - Blood Advances
IS - 10
ER -