Additional PIONEER Study Results Back FDA Priority Review for Avapritinib in Indolent Systemic Mastocytosis

The developer of avapritinib has announced full registrationL results from the phase 2 PIONEER study of avapritinib for the treatment of indolent systemic mastocytosis.

Mariana Castells, MD, PhD

Mariana Castells, MD, PhD

Avapritinib (Ayvakit) demonstrated statistically significant and clinically meaningful improvements in total symptom score that deepened over time, with enhancements shown across all individual symptoms, meeting the primary end point of the phase 2 PIONEER study (NCT03731260).1

These full registration findings come subsequent to the FDA granted priority review to the new drug application (NDA) for avapritinib as a treatment for patients with indolent systemic mastocytosis (SM). Results were presented during the 2023 American Academy of Allergy Asthma, and Immunology in San Antonio, Texas.

"Patients with indolent systemic mastocytosis may experience debilitating symptoms, including skin lesions which can flare often, daily abdominal pain and diarrhea, as well as bone pain, brain fog and fatigue. These symptoms profoundly impact quality of life, the ability to work and opportunities to spend time with family," said Mariana Castells, MD, PhD, director, Mastocytosis Center, Brigham and Women's Hospital, and an investigator on the PIONEER trial, in a press release. "[Avapritinib] was designed to target KIT D816V, the underlying cause of most cases of indolent SM, with the potential to modify the disease biology across multiple organ systems. [Avapritinib] significantly reduced mast cell burden and improved patients' symptoms and quality of life in the PIONEER trial, representing the first positive registrational study for the treatment of indolent SM. The magnitude and consistency of benefit shown by [avapritinib] highlights its potential to become a major therapeutic breakthrough."

PIONEER is a randomized, double-blind, placebo-controlled study conducted at 49 sites across 13 countries. A total 141 patients were treated with either avapritinib 25 mg once daily plus best supportive care in the experimental arm, and the other 71 patients received placebo plus best supportive care in the control arm.

Once 24 weeks of treatment were complete, patients had the option to receive avapritinib treatment in an open-label extension study.

PIONEER investigators assessed disease symptoms using the Indolent SM Symptom Assessment Form (ISM-SAF). In addition to tumor sypmtom score (TSS), the key secondary end points evaluated in the study were ≥ 50% reduction in serum tryptase, ≥ 50% reduction in peripheral blood V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) allele fraction or undetectable for patients with a detectable baseline mutation, ≥ 50% reduction in ISM-SAF TSS, ≥ 30% reduction in ISM-SAF TSS, and ≥ 50% reduction in bone marrow mast cells or no aggregates for patients who baseline screening showed aggregates. The time frame for evaluating these end points was 6 months.2

Other secondary end points explored in the study were change in serum tryptase, change in KIT D816V allele burden in blood, change in bone marrow mast cells, change in best supportive care, change in the Mastocytosis Quality of Life Questionnaire (MC-QoL), and safety. These end points were assessed through the 5-year mark. The study also evaluated area under curve for avapritinib.

In terms of TSS at 24 weeks, there was a mean change of -15.6 points with avapritinib vs -9.2 points with placebo (P = .003). At 48 weeks, the mean change was -20.2 points with avapritinib. The proportion of patients treated with avapritinib who achieved greater than a 30% reduction in TSS was 45.4 % compared with 29.6 % in the placebo arm at 24 weeks (P = .009). The avapritinib arm showed a 60.7% proportion of 30% TSS reduction at 48 weeks. The proportion of patients with a ≥ 50% reduction in TSS at 24 weeks was 24.8 % in the avapritinib arm vs 9.9 % in the placebo arm (P = .005). At the 48-week mark, there were ≥ 50% reductions in TSS in 39.3% of patients treated with avapritinib.1

Results for the secondary end points showed that in the avapritinib arm, there was a 53.9 % mean percent reduction in serum tryptase compared with 0% in the placebo arm (P < .0001). There was also a 67.8 % mean percent reduction in KIT D816V variant allele fraction observed with avapritinib vs a 6.3 % reduction with placebo (P < .0001). Reduction in bone marrow mast cell aggregates was 52.8% with avapritinib vs 22.8% with placebo (P < .0001).

In terms of MC-QoL, there was a -34.3 % mean change in the avapritinib arms compared with -17.9% with placebo (P = .001).

Overall, avapritinib was well-tolerated among patients in the study. The majority of adverse events (AEs) were low grade. Treatment-related AEs leading to discontinuations were 1.4 in each treatment arm. Serious AEs occurred in 5.0% of the avapritinib arm vs 11.3% of the placebo arm.

The most common treatment-related AEs which occurred in ≥5 percent of patients in the avapritinib arm vs placebo arm were headache (7.8 v 9.9%), nausea (6.4% v 8.5%), peripheral edema (6.4% v 1.4%), periorbital edema (6.4% v 2.8%), and dizziness (2.8% v 7.0%). Most edema AEs were grade 1 and none led to treatment discontinuation.

"The detailed PIONEER results reported today mark the culmination of a decade of research and collaboration with the systemic mastocytosis community, with the goal of transforming treatment for all patients living with SM," said Becker Hewes, MD, chief medical officer at Blueprint Medicines, in the press release. "[Avapritinib] has shown rapid, durable and clinically meaningful benefits across trial endpoints, with improvements deepening over time, and a well-tolerated safety profile. These compelling data underscore the potential of [Avapritinib] to transform the standard of care for a broad range of patients. We are collaborating with regulatory authorities to make this treatment available to people with indolent SM as quickly as possible."


1. Blueprint Medicines presents registrational data from pioneer trial of AYVAKIT® (avapritinib) in patients with indolent systemic mastocytosis at 2023 AAAAI Annual Meeting. News release. Blueprint Medicines. February 26, 2023. Accessed February 27, 2023.

2. (PIONEER) study to evaluate efficacy and safety of avapritinib (BLU-285), a selective KIT mutation-targeted tyrosine kinase inhibitor, versus placebo in patients with indolent systemic mastocytosis. Updated September 30, 2022. Accessed February 27, 2023.

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