PDGFR-alpha and KIT mutant inhibitor Treatment of gastrointestinal stromal tumor Treatment of systemic mastocytosis

摘要

More than 80% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in mast/stem cell growth factor receptor Kit (KIT) or platelet-derived growth factor receptor alpha (PDGFR-alpha; PDGFRA); on the other hand, KIT exon 17 mutation is the primary driver of systemic mastocytosis (SM), a rare myeloid neoplasm. Avapritinib (BLU-285) is a small-molecule, oral, highly potent and selective inhibitor of KIT and PDGFRA activated mutants. It demonstrated potent in vitro and in vivo activity in various KIT-driven preclinical models, and a pharmacokinetic profile in humans suitable for o.d. administration. In phase I clinical trials avapritinib was safe and showed promising activity in patients with GIST or SM. Currently, a phase III clinical study in advanced GIST patients and two phase II clinical trials to treat SM are ongoing. Avapritinib received orphan drug designations from the U.S. Food and Drug Administration (FDA) and the European Commission. In addition, the FDA granted fast track and breakthrough therapy designations for the treatment of unresectable or metastatic GIST.