Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study.
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Gotlib Jason, Reiter Andreas, Radia Deepti H, Álvarez-Twose Iván, Deininger Michael W, George Tracy I, Panse Jens, Mital Andrzej, Pettit Kristen M, Vannucchi Alessandro M, Platzbecker Uwe, Hermine Olivier, Elshoury Amro, Livideanu Cristina Bulai, Mesa Ruben, Ustun Celalettin, Triggiani Massimo, Dybedal Ingunn, Jurcic Joseph G, Zanotti Roberta, Oh Stephen T, Yacoub Abdulraheem, Hexner Elizabeth O, Bose Prithviraj, Lee Stephanie G, Sperr Wolfgang R, Griffiths Elizabeth A, Butler Matthew, Lübke Johannes, Bidollari Ilda, Lin Hui-Min, Rylova Svetlana, Dimitrijević Saša, Muñoz-González Javier I, DeAngelo Daniel J
Аннотация
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.