Avapritinib Meets Primary and Secondary End Points in PIONEER Trial in Non-Advanced Systemic Mastocytosis


Treatment with avapritinib led to clinically meaningful and statistically significant improvements in patient-reported symptoms and objective measures of mast cell burden in patients with non-advanced systemic mastocytosis.

Mariana Castells, MD, PhD

Mariana Castells, MD, PhD

Treatment with avapritinib (Ayvakit) led to clinically meaningful and statistically significant improvements in patient-reported symptoms and objective measures of mast cell burden in patients with non-advanced systemic mastocytosis, meeting the primary and key secondary end points of part 2 of the registrational phase 2 PIONEER trial (NCT03731260).

Regarding the primary end point, the results showed a statistically significant difference in the mean change in total symptom score (TSS) at 24 weeks in favor of avapritinib plus best available care vs placebo plus best available care (P = .003).

TSS was assessed by the Indolent SM Symptom Assessment Form. The avapritinib arm had a reduction of 15.6 points in mean TSS at 24 weeks, which deepened to 20.2 points at 48 weeks in patients who proceeded to the part 3 open-label extension study. At 24 weeks, the control arm had a reduction of 9.2 points in mean TSS.

Regarding secondary end points, avapritinib plus best available care also demonstrated significant improvements across all measures of mast cell burden. Specifically, more than half of avapritinib-treated patients had at least 50% reduction of serum tryptase compared with no patients in the control arm (53.9% vs 0%; P < .0001).

Based on these topline data, Blueprint Medicines plans to submit a supplemental new drug application to the FDA for avapritinib in non-advanced systemic mastocytosis in the fourth quarter of 2022, with a subsequent submission of a type II variation marketing authorization application to the European Medicines Agency expected in 2023.

The company plans to present detailed data from the PIONEER trial at an upcoming medical meeting.

“As a physician and clinical researcher who has been treating non-advanced systemic mastocytosis patients for over 25 years, I have been awaiting a therapy that decreases the abnormal mast cell burden and activation, improves a wide range of symptoms, and ultimately provides an improved quality of life to patients,” Mariana Castells, MD, PhD, director, Mastocytosis Center, Brigham and Women’s Hospital, and an investigator on the PIONEER trial, stated in a press release.

“For patients with non-advanced systemic mastocytosis, PIONEER is the first study to show significant clinical improvements over best available care across patient-reported symptoms and objective measures of disease, with a safety and tolerability profile supporting chronic treatment. The trial results suggest that if approved, avapritinib would represent a practice-changing treatment, enabling important clinical benefits for a broad range of patients with non-advanced systemic mastocytosis,” Castells added.

Avapritinib is a potent and selective inhibitor of D816V mutant KIT, the driver of systemic mastocytosis in approximately 95% of cases. The agent is approved for the treatment of patients with advanced systemic mastocytosis and has received a breakthrough therapy designation for the treatment of moderate-to-severe indolent systemic mastocytosis.

Part 2 of the PIONEER trial was designed to evaluate the efficacy and safety of 25 mg of avapritinib once daily (n = 141) vs control (n = 71) over 24 weeks of treatment.

To be eligible for enrollment, patients had to have a diagnosis of indolent systemic mastocytosis confirmed by central pathology review, and moderate-to-severe symptom burden despite an optimized regimen of best available care.

Notably, patients were allowed to continue symptom-directed therapies while receiving study therapy.

Regarding safety, avapritinib was well-tolerated and had a favorable safety profile such that 96.5% of avapritinib-treated patients completed 24 weeks of therapy compared with 93.0% of control-treated patients. Overall, 0.7% of patients in the avapritinib arm and no patients in the control arm discontinued treatment because of treatment-related adverse effects (TRAEs).

The rate of AEs was 90.8% in the avapritinib arm and 93.0% in the control arm. Serious AEs occurred in 5.0% of avapritinib-treated patients compared with 11.3% of patients in the control arm.

Additionally, the avapritinib arm had a lower rate of cognitive AEs compared with the control arm, at 2.8% vs 4.2%, respectively, and no intracranial bleeding events were reported.

TRAEs reported in at least 3 patients in the avapritinib and placebo arms, respectively, and at least 5% of avapritinib-treated patients included headache (7.8% vs 9.9%), nausea (6.4% vs 8.5%), peripheral edema (6.4% vs 1.4%), and periorbital edema (6.4% vs 2.8%). In the avapritinib arm, 93.0% of edema AEs were grade 1, and the rest were grade 2.

“The PIONEER results showcase Blueprint Medicines’ dedication to advancing the promise of precision therapy for patients with significant medical needs,” Becker Hewes, MD, chief medical officer at Blueprint Medicines, said. “Avapritinib has the potential to be the first approved medicine for non-advanced systemic mastocytosis, and the only treatment that would address the genetic root cause across advanced and non-advanced forms of the disease. Today’s milestone represents a watershed moment for the systemic mastocytosis community and Blueprint Medicines, capping a decade of collaboration with clinicians, advocates, and patients to transform standards of care, and to deepen the understanding of this disease and its impact on various aspects of patients’ lives.”


Blueprint Medicines announces positive top-line results from PIONEER trial of AYVAKIT® (avapritinib) in patients with non-advanced systemic mastocytosis achieving primary and all key secondary endpoints. Blueprint Medicines Corporation. News release. August 17, 2022. Accessed August 17, 2022. https://bit.ly/3CaGnim

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