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Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nature medicine Gotlib, J., Reiter, A., Radia, D. H., Deininger, M. W., George, T. I., Panse, J., Vannucchi, A. M., Platzbecker, U., Alvarez-Twose, I., Mital, A., Hermine, O., Dybedal, I., Hexner, E. O., Hicks, L. K., Span, L., Mesa, R., Bose, P., Pettit, K. M., Heaney, M. L., Oh, S. T., Sen, J., Lin, H., Mar, B. G., DeAngelo, D. J. 2021

Abstract

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200mg in patients with AdvSM (n=62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P=1.6*10-9), with an ORR of 75% (95% confidence interval 57-89) in 32response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of =50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade=3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

View details for DOI 10.1038/s41591-021-01539-8

View details for PubMedID 34873345