Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

Nat Med. 2021 Dec;27(12):2183-2191. doi: 10.1038/s41591-021-01538-9. Epub 2021 Dec 6.

Abstract

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Clinical Trials, Phase I as Topic
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Mastocytosis, Systemic / drug therapy*
  • Middle Aged
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Pyrroles / administration & dosage
  • Pyrroles / adverse effects
  • Pyrroles / pharmacokinetics
  • Pyrroles / therapeutic use*
  • Triazines / administration & dosage
  • Triazines / adverse effects
  • Triazines / pharmacokinetics
  • Triazines / therapeutic use*

Substances

  • Pyrazoles
  • Pyrroles
  • Triazines
  • avapritinib

Associated data

  • ClinicalTrials.gov/NCT02561988