Dr DeAngelo on the Efficacy of Avapritinib in Advanced Systemic Mastocytosis

"Regardless of the histologic subtype [of advanced systemic mastocytosis, we saw] very high response rates [with avapritinib that were] very durable [in the PATHFINDER trial]. This led to what seemed to be improved survival based on historical controls, although that's always difficult to ascertain."

Daniel J. DeAngelo, MD, PhD, chief of the Division of Leukemia and an institute physician at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, discusses ​​the evolution of clinical data supporting the use of avapritinib (Ayvakit) in patients with ​​advanced systemic mastocytosis. 

DeAngelo begins by stating that systemic mastocytosis is a rare disorder that presents in 2 primary forms: advanced systemic mastocytosis—which is life-threatening with limited treatment options and poor prognosis— and indolent systemic mastocytosis—which follows a more benign course. Midostaurin (Rydapt) was the first multi-kinase inhibitor approved for the treatment of patients with advanced systemic mastocytosis, DeAngelo says. However, the clinical utility of this agent has been limited due to suboptimal durability of response and significant toxicity, which affects its tolerability, DeAngelo explains. 

Avapritinib, a selective KIT inhibitor, was initially investigated in patients with advanced systemic mastocytosis ​in the phase 1 EXPLORER trial (NCT02561988). The efficacy of avapritinib in this population was later validated in the phase 2 PATHFINDER trial (NCT03580655), he says. Data from PATHFINDER supported the FDA approval of this agent for the treatment of adult patients with advanced systemic mastocytosis. Notably, avapritinib was also evaluated for patients with indolent systemic mastocytosis in the randomized, placebo-controlled, phase 2 PIONEER trial (NCT03731260), though at a different dose than that used for advanced disease, according to DeAngelo. 

The PATHFINDER trial demonstrated high response rates with avapritinib across all histologic subtypes of advanced systemic mastocytosis, including aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. Responses were robust and durable, suggesting a potential improvement in survival with avapritinib compared with historical controls, though definitive conclusions regarding this agent's survival benefit remain challenging to establish, DeAngelo concludes.